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  • 1.
    Andersson, Ulrika
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Experimental studies in brain tumours: with special regard to multidrug resistance and the ErbB-family2005Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Primary brain tumours, and especially the most common form malignant gliomas, usually display a pronounced resistance to other treatment modalities when surgery fails to cure. Growth factors, such as EGF and its receptor, frequently amplified and overexpressed in malignant gliomas, and factors associated with multidrug resistance have been suggested to at least partially explain the poor outcome. The aim of this thesis was to characterise factors in primary brain tumours associated with the development of resistance with focus on the epidermal growth factor receptor (ErbB) family, and multidrug resistance (MDR).

    Influences of irradiation on the expression and activity of P-glycoprotein (Pgp) in malignant gliomas was evaluated. The effects showed that irradiation increased the efflux activity of Pgp in rat brain vascular endothelial cells, but not in glioma cells. In the intracranial BT4C glioma model, Pgp was detected in the capillary endothelium in the tumour tissue but not in glioma cells.

    Expression of several factors coupled to MDR (Pgp, MRP1, LRP, and MGMT) in primary brain tumours were analysed and correlated to clinical data. In gliomas, Pgp and MRP1 were predominantly observed in capillary endothelium and in scattered tumour cells, whereas LRP occurred only in tumour cells. In meningiomas, expression of the analysed markers was demonstrated in the capillary endothelium, with a higher expression of Pgp and MRP1 in transitional compared to meningothelial meningiomas. A pronounced expression of MGMT was found independently of the histopathological grade or tumour type. Survival analysis indicated a shorter overall survival for patients suffering from low-grade gliomas with high expression of Pgp.

    To explore the importance of the epidermal growth factor receptor (EGFR), expression levels of the family members (EGFR, ErbB2-4) were analysed and their relations to various clinical parameters were evaluated in gliomas and meningiomas. In gliomas, the highest EGFR expression was observed in high-grade tumours, while ErbB4 expression was most pronounced in low-grade tumours. In meningiomas, expression of EGFR, ErbB2, and ErbB4 was observed in the majority of the tumours. An intriguing observation in low-grade gliomas was a significantly decreased overall survival for patients with high EGFR protein expression.

    The effects of different time schedules for administration of the selective EGFR inhibitor ZD1839 in relation to irradiation of glioma cells were analysed. The analyses showed a heterogeneity in the cytotoxic effects of ZD1839 between cell lines, and it was obvious that some of the cell lines showed sensitivity to ZD1839 despite no or low expression of EGFR. The study also demonstrated the importance of timing of ZD1839 administration when this agent is combined with irradiation.

    In conclusion, in order to enhance the efficacy of radiotherapy by various drugs in malignant gliomas it may be essential to inhibit drug efflux activity in endothelial cells and to deliver drugs in an optimal timing in relation to radiotherapy. The heterogeneity in expression of drug resistance markers, as well as the ErbB family reflects the complexity in classification of primary brain tumours, and indicates that subgroups of patients with low-grade gliomas expressing Pgp and EGFR might benefit from more aggressive and individualised treatment.

  • 2.
    Andersson, Ulrika
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Degerman, Sofie
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Dahlin, Anna
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Brannstrom, Thomas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Roos, Göran
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Melin, B. S.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    TELOMERE LENGTH, ALLERGIES AND RISK OF GLIOMA2017In: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 19, no Supplement: 3, p. 23-23, article id Meeting Abstract: P01.03Article in journal (Refereed)
  • 3.
    Andersson, Ulrika
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Degerman, Sofie
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Dahlin, Anna M.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Wibom, Carl
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Johansson, Gunnar
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Bondy, Melissa L.
    Melin, Beatrice S.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    The association between longer relative leukocyte telomere length and risk of glioma is independent of the potentially confounding factors allergy, BMI, and smoking2019In: Cancer Causes and Control, ISSN 0957-5243, E-ISSN 1573-7225, Vol. 30, no 2, p. 177-185Article in journal (Refereed)
    Abstract [en]

    Purpose: Previous studies have suggested an association between relative leukocyte telomere length (rLTL) and glioma risk. This association may be influenced by several factors, including allergies, BMI, and smoking. Previous studies have shown that individuals with asthma and allergy have shortened relative telomere length, and decreased risk of glioma. Though, the details and the interplay between rLTL, asthma and allergies, and glioma molecular phenotype is largely unknown. Methods: rLTL was measured by qPCR in a Swedish population-based glioma case–control cohort (421 cases and 671 controls). rLTL was related to glioma risk and health parameters associated with asthma and allergy, as well as molecular events in glioma including IDH1 mutation, 1p/19q co-deletion, and EGFR amplification. Results: Longer rLTL was associated with increased risk of glioma (OR = 1.16; 95% CI 1.02–1.31). Similar to previous reports, there was an inverse association between allergy and glioma risk. Specific, allergy symptoms including watery eyes was most strongly associated with glioma risk. High body mass index (BMI) a year prior diagnosis was significantly protective against glioma in our population. Adjusting for allergy, asthma, BMI, and smoking did not markedly change the association between longer rLTL and glioma risk. rLTL among cases was not associated with IDH1 mutation, 1p/19q co-deletion, or EGFR amplification, after adjusting for age at diagnosis and sex. Conclusions: In this Swedish glioma case–control cohort, we identified that long rLTL increases the risk of glioma, an association not confounded by allergy, BMI, or smoking. This highlights the complex interplay of the immune system, rLTL and cancer risk.

  • 4.
    Andersson, Ulrika
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Bergenheim, A. Tommy
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurosurgery.
    Behnam-Motlagh, Parviz
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Hedman, Håkan
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Rapid induction of long-lasting drug efflux activity in brain vascular endothelial cells but not malignant glioma following irradiation2002In: Medical Oncology, ISSN 1357-0560, E-ISSN 1559-131X, Vol. 19, no 1, p. 1-9Article in journal (Refereed)
    Abstract [en]

    The influence of radiotherapy on malignant glioma multidrug resistance to chemotherapy was evaluated because patients with glioma often are treated with a combination of radiotherapy and chemotherapy. Multidrug resistance gene (MDR1, mdr1a, and mdr1b) transcripts were found in human and rat glioma cell lines. P-Glycoprotein (Pgp) was immunohistochemically detected in glioma cell lines and in the rat brain vascular endothelial cell line (RBE4). A multidrug resistance pump efflux activity assay demonstrated increased calcein efflux of RBE4 endothelial cells, but not glioma cells, 2 h after irradiation and still increased 14 d after irradiation. The increased efflux was equally inhibited by verapamil with or without irradiation. In the rat intracranial glioma model (BT4C), Pgp was demonstrated in capillary endothelial cells of the tumor tissue and surrounding normal brain, but not in tumor cells. The expression of gene transcripts or Pgp was not affected by irradiation. The results indicate that long-lasting verapamil-resistant drug efflux mechanisms are activated in brain endothelial cells after irradiation. The results might explain the poor efficacy of chemotherapy following radiotherapy and contribute to consideration of new treatment strategies in the management of malignant glioma.

  • 5.
    Andersson, Ulrika
    et al.
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology.
    Guo, Dongsheng
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology.
    Malmer, Beatrice
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology.
    Bergenheim, A Tommy
    Umeå University, Faculty of Medicine, Pharmacology and Clinical Neuroscience, Neurosurgery.
    Brännström, Thomas
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Hedman, Håkan
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology.
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology.
    Epidermal growth factor receptor family (EGFR, ErbB2-4) in gliomas and meningiomas2004In: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 108, no 2, p. 135-142Article in journal (Refereed)
    Abstract [en]

    Overexpression of epidermal growth factor receptor (EGFR, ErbB1) correlates with enhanced malignant potential of many human tumor types including glioblastoma multiforme. The significance of EGFR expression in meningiomas is, however, unclear. Reports regarding the other EGFR family members, ErbB2-4, in brain tumors are sparse. In this study, the expression of the EGFR family members was analyzed in relation to various parameters for the clinical importance of these receptors in 44 gliomas and 26 meningiomas. In gliomas, quantitative real-time reverse transcription (RT)-PCR revealed the highest EGFR mRNA expression in high-grade gliomas, while ErbB2 and ErbB3 mRNA were detected only in a few high-grade gliomas. In contrast, ErbB4 expression was most pronounced in low-grade gliomas. Immunohistochemistry showed significantly higher EGFR protein expression in high-grade gliomas compared to low-grade gliomas (P= 0.004). ErbB2 protein expression was mainly seen in high-grade gliomas. ErbB3 protein expression was low in all gliomas analyzed. ErbB4 protein expression was significantly higher in low-grade gliomas than in high-grade gliomas (P= 0.007). In meningiomas, quantitative real-time RT-PCR revealed expression of EGFR, ErbB2, and ErbB4 mRNA in the majority of the tumors. ErbB3 was detected in only one of the meningiomas analyzed. Immunohistochemistry demonstrated high ErbB2 protein expression in meningiomas. An intriguing observation in astrocytomas and oligodendrogliomas grade II, was a significantly decreased overall survival for patients with high EGFR protein expression (P= 0.04). The high ErbB4 expression in low-grade compared to high-grade gliomas might suggest that ErbB4 acts as a suppressor of malignant transformation in brain tumors, which is in line with previous studies in other tumor types.

  • 6.
    Andersson, Ulrika
    et al.
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology.
    Johansson, David
    Umeå University, Faculty of Medicine, Medical Biosciences, Clinical chemistry.
    Behnam-Motlagh, Parviz
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology.
    Johansson, Mikael
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology.
    Malmer, Beatrice
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology.
    Treatment schedule is of importance when gefitinib is combined with irradiation of glioma and endothelial cells in vitro.2007In: Acta Oncologica, ISSN 0284-186X, Vol. 46, no 7, p. 951-960Article in journal (Refereed)
  • 7.
    Andersson, Ulrika
    et al.
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology.
    Malmer, Beatrice
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology.
    Bergenheim, A Tommy
    Umeå University, Faculty of Medicine, Pharmacology and Clinical Neuroscience, Neurosurgery.
    Brännström, Thomas
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology.
    Heterogeneity in the expression of markers for drug resistance in brain tumors2004In: Clinical Neuropathology, ISSN 0722-5091, Vol. 23, no 1, p. 21-27Article in journal (Refereed)
    Abstract [en]

    Brain tumors, in general, display a multidrug-resistant phenotype. This study evaluated the immunohistochemical expression and distribution of P-glycoprotein (Pgp), multidrug resistance protein (MRP1), lung resistance protein (LRP) and O6 methylguanine-DNA methyltransferase (MGMT) in low- and high-grade astrocytoma, oligodendroglioma and in different subgroups of meningioma. The results revealed a marked heterogeneity in the expression and distribution among the analyzed tumors. In astrocytoma and oligodendroglioma, Pgp and MRP1 were observed in the capillary endothelium and in scattered tumor cells, whereas LRP occurred only in tumor cells. A pronounced expression of MGMT was found independent of the histopathological grade. An enhanced expression of MRP1 and LRP in astrocytoma and oligodendroglioma were more often evident in older patients (> 50 years). Survival analysis suggested a markedly decreased overall survival for patients suffering from low-grade glioma overexpressing Pgp. In meningioma, a heterogeneous expression of Pgp, MRP1, LRP and MGMT was seen with the most prominent staining localized to the capillary endothelium. Pgp was significantly more often overexpressed (p < 0.05) in transitional compared to meningothelial meningioma. The marked heterogeneity in the expression suggests that analysis of these factors can be of importance in the selection of individualized chemotherapy, regardless of tumor type.

  • 8.
    Andersson, Ulrika
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    McKean-Cowdin, Roberta
    Hjalmars, Ulf
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Malmer, Beatrice
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Genetic variants in association studies: review of strengths and weaknesses in study design and current knowledge of impact on cancer risk2009In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 48, no 7, p. 948-954Article in journal (Refereed)
    Abstract [en]

    Sequencing of the human genome has recently been completed and mapping of the complete genomic variation is ongoing. During the last decade there has been a huge expansion of studies of genetic variants, both with respect to association studies of disease risk and for studies of genetic factors of prognosis and treatments response, i.e., pharmacogenomics. The use of genetics to predict a patient's risk of disease or treatment response is one step toward an improved personalised prevention and screening modality for the prevention of cancer and treatment selection. The technology and statistical methods for completing whole genome tagging of variants and genome wide association studies has developed rapidly over the last decade. After identifying the genetic loci with the strongest, statistical associations with disease risk, future studies will need to further characterise the genotype-phenotype relationship to provide a biological basis for prevention and treatment decisions according to genetic profile. This review discusses some of the general issues and problems of study design; we also discuss challenges in conducting valid association studies in rare cancers such as paediatric brain tumours, where there is support for genetic susceptibility but difficulties in assembling large sample sizes. The clinical interpretation and implementation of genetic association studies with respect to disease risk and treatment is not yet well defined and remains an important area of future research.

  • 9.
    Andersson, Ulrika
    et al.
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology.
    Osterman, Pia
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Sjöström, Sara
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology.
    Johansen, Christoffer
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology.
    Brännström, Thomas
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Broholm, Helle
    Christensen, Helle Collatz
    Ahlbom, Anders
    Auvinen, Anssi
    Feychting, Maria
    Lönn, Stefan
    Kiuru, Anne
    Swerdlow, Anthony
    Schoemaker, Minouk
    Roos, Göran
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Malmer, Beatrice
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology.
    MNS16A minisatellite genotypes in relation to risk of glioma and meningioma and to glioblastoma outcome.2009In: International journal of cancer. Journal international du cancer, ISSN 1097-0215, Vol. 125, no 4, p. 968-972Article in journal (Refereed)
    Abstract [en]

    The human telomerase reverse transcriptase (hTERT) gene is upregulated in a majority of malignant tumours. A variable tandem repeat, MNS16A, has been reported to be of functional significance for hTERT expression. Published data on the clinical relevance of MNS16A variants in brain tumours have been contradictory. The present population-based study in the Nordic countries and the United Kingdom evaluated brain-tumour risk and survival in relation to MNS16A minisatellite variants in 648 glioma cases, 473 meningioma cases and 1,359 age, sex and geographically matched controls. By PCR-based genotyping all study subjects with fragments of 240 or 271 bp were judged as having short (S) alleles and subjects with 299 or 331 bp fragments as having long (L) alleles. Relative risk of glioma or meningioma was estimated with logistic regression adjusting for age, sex and country. Overall survival was analysed using Kaplan-Meier estimates and equality of survival distributions using the log-rank test and Cox proportional hazard ratios. The MNS16A genotype was not associated with risk of occurrence of glioma, glioblastoma (GBM) or meningioma. For GBM there were median survivals of 15.3, 11.0 and 10.7 months for the LL, LS and SS genotypes, respectively; the hazard ratio for having the LS genotype compared with the LL was significantly increased HR 2.44 (1.56-3.82) and having the SS genotype versus the LL was nonsignificantly increased HR 1.46 (0.81-2.61). When comparing the LL versus having one of the potentially functional variants LS and SS, the HR was 2.10 (1.41-3.1). However, functionality was not supported as there was no trend towards increasing HR with number of S alleles. Collected data from our and previous studies regarding both risk and survival for the MNS16A genotypes are contradictory and warrant further investigations.

  • 10.
    Andersson, Ulrika
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Schwartzbaum, Judith
    Wiklund, Fredrik
    Sjöström, Sara
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Liu, Yanhong
    Tsavachidis, Spyros
    Ahlbom, Anders
    Auvinen, Anssi
    Collatz-Laier, Helle
    Feychting, Maria
    Johansen, Christoffer
    Kiuru, Anne
    Lönn, Stefan
    Schoemaker, Minouk J
    Swerdlow, Anthony J
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Bondy, Melissa
    Melin, Beatrice
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    A comprehensive study of the association between the EGFR and ERBB2 genes and glioma risk2010In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 49, no 6, p. 767-775Article in journal (Refereed)
    Abstract [en]

    Glioma is the most common type of adult brain tumor and glioblastoma, its most aggressive form, has a dismal prognosis. Receptor tyrosine kinases such as the epidermal growth factor receptor (EGFR, ERBB2, ERBB3, ERBB4) family, and the vascular endothelial growth factor receptor (VEGFR), play a central role in tumor progression. We investigated the genetic variants of EGFR, ERBB2, VEGFR and their ligands, EGF and VEGF on glioma and glioblastoma risk. In addition, we evaluated the association of genetic variants of a newly discovered family of genes known to interact with EGFR: LRIG2 and LRIG3 with glioma and glioblastoma risk. Methods. We analyzed 191 tag single nucleotide polymorphisms (SNPs) capturing all common genetic variation of EGF, EGFR, ERBB2, LRIG2, LRIG3, VEGF and VEGFR2 genes. Material from four case-control studies with 725 glioma patients (329 of who were glioblastoma patients) and their 1 610 controls was used. Haplotype analyses were conducted using SAS/Genetics software. Results. Fourteen of the SNPs were significantly associated with glioma risk at p< 0.05, and 17 of the SNPs were significantly associated with glioblastoma risk at p< 0.05. In addition, we found that one EGFR haplotype was related to increased glioblastoma risk at p=0.009, Odds Ratio [OR] = 1.67 (95% confidence interval (CI): 1.14, 2.45). The Bonferroni correction made all p-values non-significant. One SNP, rs4947986 next to the intron/exon boundary of exon 7 in EGFR, was validated in an independent data set of 713 glioblastoma and 2 236 controls, [OR] = 1.42 (95% CI: 1.06,1.91). Discussion. Previous studies show that regulation of the EGFR pathway plays a role in glioma progression but the present study is the first to find that certain genotypes of the EGFR gene may be related to glioblastoma risk. Further studies are required to reinvestigate these findings and evaluate the functional significance.

  • 11.
    Andersson, Ulrika
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Wibom, Carl
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Cederquist, Kristina
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Aradottir, Steina
    Borg, Åke
    Armstrong, Georgina N.
    Shete, Sanjay
    Lau, Ching C.
    Bainbridge, Matthew N.
    Claus, Elizabeth B.
    Barnholtz-Sloan, Jill
    Lai, Rose
    Il'yasova, Dora
    Houlston, Richard S.
    Schildkraut, Joellen
    Bernstein, Jonine L.
    Olson, Sara H.
    Jenkins, Robert B.
    Lachance, Daniel H.
    Wrensch, Margaret
    Davis, Faith G.
    Merrell, Ryan
    Johansen, Christoffer
    Sadetzki, Siegal
    Bondy, Melissa L.
    Melin, Beatrice S
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Germline rearrangements in families with strong family history of glioma and malignant melanoma, colon, and breast cancer2014In: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 16, no 10, p. 1333-1340Article in journal (Refereed)
    Abstract [en]

    Background: Although familial susceptibility to glioma is known, the genetic basis for this susceptibility remains unidentified in the majority of glioma-specific families. An alternative approach to identifying such genes is to examine cancer pedigrees, which include glioma as one of several cancer phenotypes, to determine whether common chromosomal modifications might account for the familial aggregation of glioma and other cancers. Methods: Germline rearrangements in 146 glioma families (from the Gliogene Consortium; http://www.gliogene.org/) were examined using multiplex ligation-dependent probe amplification. These families all had at least 2 verified glioma cases and a third reported or verified glioma case in the same family or 2 glioma cases in the family with at least one family member affected with melanoma, colon, or breast cancer. The genomic areas covering TP53, CDKN2A, MLH1, and MSH2 were selected because these genes have been previously reported to be associated with cancer pedigrees known to include glioma. Results: We detected a single structural rearrangement, a deletion of exons 1-6 in MSH2, in the proband of one family with 3 cases with glioma and one relative with colon cancer. Conclusions: Large deletions and duplications are rare events in familial glioma cases, even in families with a strong family history of cancers that may be involved in known cancer syndromes.

  • 12. Berntsson, Shala Ghaderi
    et al.
    Wibom, Carl
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Sjöström, Sara
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Brännström, Thomas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Broholm, Helle
    Johansson, Christoffer
    Fleming, Sarah J
    McKinney, Patricia A
    Bethke, Lara
    Houlston, Richard
    Smits, Anja
    Andersson, Ulrika
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Melin, Beatrice S
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Analysis of DNA repair gene polymorphisms and survival in low-grade and anaplastic gliomas2011In: Journal of Neuro-Oncology, ISSN 0167-594X, E-ISSN 1573-7373, Vol. 105, no 3, p. 531-538Article in journal (Refereed)
    Abstract [en]

    The purpose of this study was to explore the variation in DNA repair genes in adults with WHO grade II and III gliomas and their relationship to patient survival. We analysed a total of 1,458 tagging single-nucleotide polymorphisms (SNPs) that were selected to cover DNA repair genes, in 81 grade II and grade III gliomas samples, collected in Sweden and Denmark. The statistically significant genetic variants from the first dataset (P < 0.05) were taken forward for confirmation in a second dataset of 72 grade II and III gliomas from northern UK. In this dataset, eight gene variants mapping to five different DNA repair genes (ATM, NEIL1, NEIL2, ERCC6 and RPA4) which were associated with survival. Finally, these eight genetic variants were adjusted for treatment, malignancy grade, patient age and gender, leaving one variant, rs4253079, mapped to ERCC6, with a significant association to survival (OR 0.184, 95% CI 0.054-0.63, P = 0.007). We suggest a possible novel association between rs4253079 and survival in this group of patients with low-grade and anaplastic gliomas that needs confirmation in larger datasets.

  • 13.
    Björkblom, Benny
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Wibom, Carl
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Jonsson, Pär
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Mörén, Lina
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Andersson, Ulrika
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Johannesen, Tom Borge
    langseth, Hilde
    Antti, Henrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Melin, Beatrice
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Metabolomic screening of pre-diagnostic serum samples identifies association between alpha- and gamma-tocopherols and glioblastoma risk2016In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 7, no 24, p. 37043-37053Article in journal (Refereed)
    Abstract [en]

    Glioblastoma is associated with poor prognosis with a median survival of one year. High doses of ionizing radiation is the only established exogenous risk factor. To explore new potential biological risk factors for glioblastoma, we investigated alterations in metabolite concentrations in pre-diagnosed serum samples from glioblastoma patients diagnosed up to 22 years after sample collection, and undiseased controls. The study points out a latent biomarker for future glioblastoma consisting of nine metabolites (gamma-tocopherol, alpha-tocopherol, erythritol, erythronic acid, myo-inositol, cystine, 2-keto-L-gluconic acid, hypoxanthine and xanthine) involved in antioxidant metabolism. We detected significantly higher serum concentrations of alpha-tocopherol (p=0.0018) and gamma-tocopherol (p=0.0009) in future glioblastoma cases. Compared to their matched controls, the cases showed a significant average fold increase of alpha- and gamma-tocopherol levels: 1.2 for alpha-T (p=0.018) and 1.6 for gamma-T (p=0.003). These tocopherol levels were associated with a glioblastoma odds ratio of 1.7 (alpha-T, 95% CI: 1.0-3.0) and 2.1 (gamma-T, 95% CI: 1.2-3.8). Our exploratory metabolomics study detected elevated serum levels of a panel of molecules with antioxidant properties as well as oxidative stress generated compounds. Additional studies are necessary to confirm the association between the observed serum metabolite pattern and future glioblastoma development.

  • 14.
    Dahlin, Anna M.
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Hollegaard, Mads V.
    Wibom, Carl
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Andersson, Ulrika
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Hougaard, David M.
    Deltour, Isabelle
    Hjalmars, Ulf
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Melin, Beatrice
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    CCND2, CTNNB1, DDX3X, GLI2, SMARCA4, MYC, MYCN, PTCH1, TP53, and MLL2 gene variants and risk of childhood medulloblastoma2015In: Journal of Neuro-Oncology, ISSN 0167-594X, E-ISSN 1573-7373, Vol. 125, no 1, p. 75-78Article in journal (Refereed)
    Abstract [en]

    Recent studies have described a number of genes that are frequently altered in medulloblastoma tumors and that have putative key roles in the development of the disease. We hypothesized that common germline genetic variations in these genes may be associated with medulloblastoma development. Based on recent publications, we selected 10 genes that were frequently altered in medulloblastoma: CCND2, CTNNB1, DDX3X, GLI2, SMARCA4, MYC, MYCN, PTCH1, TP53, and MLL2 (now renamed as KMT2D). Common genetic variants (single nucleotide polymorphisms) annotating these genes (n = 221) were genotyped in germline DNA (neonatal dried blood spot samples) from 243 childhood medulloblastoma cases and 247 control subjects from Sweden and Denmark. Eight genetic variants annotating three genes in the sonic hedgehog signaling pathway; CCND2, PTCH1, and GLI2, were found to be associated with the risk of medulloblastoma (P (combined) < 0.05). The findings were however not statistically significant following correction for multiple testing by the very stringent Bonferroni method. The results do not support our hypothesis that common germline genetic variants in the ten studied genes are associated with the risk of developing medulloblastoma.

  • 15.
    Dahlin, Anna M.
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Wibom, Carl
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Andersson, Ulrika
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Hougaard, David M.
    Bybjerg-Grauholm, Jonas
    Deltour, Isabelle
    Hultman, Christina M.
    Kähler, Anna K.
    Karlsson, Robert
    Hjalmars, Ulf
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Melin, Beatrice S.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Genetic Variants in the 9p21.3 Locus Associated with Glioma Risk in Children, Adolescents, and Young Adults: A Case-Control Study2019In: Cancer Epidemiology, Biomarkers and Prevention, ISSN 1055-9965, E-ISSN 1538-7755, Vol. 28, no 7, p. 1252-1258Article in journal (Refereed)
    Abstract [en]

    Background: Genome-wide association studies have identified germline genetic variants in 25 genetic loci that increase the risk of developing glioma in adulthood. It is not known if these variants increase the risk of developing glioma in children and adolescents and young adults (AYA). To date, no studies have performed genome-wide analyses to find novel genetic variants associated with glioma risk in children and AYA.

    Methods: We investigated the association between 8,831,628 genetic variants and risk of glioma in 854 patients diagnosed up to the age of 29 years and 3,689 controls from Sweden and Denmark. Recruitment of patients and controls was population based. Genotyping was performed using Illumina BeadChips, and untyped variants were imputed with IMPUTE2. We selected 41 established adult glioma risk variants for detailed investigation.

    Results: Three adult glioma risk variants, rs634537, rs2157719, and rs145929329, all mapping to the 9p21.3 (CDKN2B-AS1) locus, were associated with glioma risk in children and AYA. The strongest association was seen for rs634537 (odds ratioG = 1.21; 95% confidence interval = 1.09–1.35; P = 5.8 × 10−4). In genome-wide analysis, an association with risk was suggested for 129 genetic variants (P <1 × 10−5).

    Conclusions: Carriers of risk alleles in the 9p21.3 locus have an increased risk of glioma throughout life. The results from genome-wide association analyses require validation in independent cohorts.

    Impact: Our findings line up with existing evidence that some, although not all, established adult glioma risk variants are associated with risk of glioma in children and AYA. Validation of results from genome-wide analyses may reveal novel susceptibility loci for glioma in children and AYA.

  • 16.
    Dahlin, Anna M.
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Wibom, Carl
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Ghasimi, Soma
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Brännström, Thomas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Andersson, Ulrika
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Melin, Beatrice
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Relation between Established Glioma Risk Variants and DNA Methylation in the Tumor2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 10, article id e0163067Article in journal (Refereed)
    Abstract [en]

    Genome-wide association studies and candidate gene studies have identified several genetic variants that increase glioma risk. The majority of these variants are non-coding and the mechanisms behind the increased risk in carriers are not known. In this study, we hypothesize that some of the established glioma risk variants induce aberrant DNA methylation in the developing tumor, either locally (gene-specific) or globally (genome-wide). In a pilot data set including 77 glioma patients, we used Illumina beadchip technology to analyze genetic variants in blood and DNA methylation in matched tumor samples. To validate our findings, we used data from the Cancer Genome Atlas, including 401 glioblastoma patients. Consensus clustering identified the glioma CpG island methylator phenotype (gCIMP) and two additional subgroups with distinct patterns of global DNA methylation. In the pilot dataset, gCIMP was associated with two genetic variants in CDKN2B-AS1, rs1412829 and rs4977756 (9p21.3, p = 8.1 x 10(-7) and 4.8 x 10(-5), respectively). The association was in the same direction in the TCGA dataset, although statistically significant only when combining individuals with AG and GG genotypes. We also investigated the relation between glioma risk variants and DNA methylation in the promoter region of genes located within 30 kb of each variant. One association in the pilot dataset, between the TERT risk variant rs2736100 and lower methylation of cg23827991 (in TERT; p = 0.001), was confirmed in the TCGA dataset (p = 0.001). In conclusion, we found an association between rs1412829 and rs4977756 (9p21.3, CDKN2B-AS1) and global DNA methylation pattern in glioma, for which a trend was seen also in the TCGA glioblastoma dataset. We also found an association between rs2736100 (in TERT) and levels of methylation at cg23827991 (localized in the same gene, 3.3 kbp downstream of the risk variant), which was validated in the TCGA dataset. Except for this one association, we did not find strong evidence for gene-specific DNA methylation mediated by glioma risk variants.

  • 17. Dobbins, Sara E.
    et al.
    Broderick, Peter
    Melin, Beatrice
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Feychting, Maria
    Johansen, Christoffer
    Andersson, Ulrika
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Brännström, Thomas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Schramm, Johannes
    Olver, Bianca
    Lloyd, Amy
    Ma, Yussanne P.
    Hosking, Fay J.
    Lönn, Stefan
    Ahlbom, Anders
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Schoemaker, Minouk J.
    Hepworth, Sarah J.
    Hoffmann, Per
    Muehleisen, Thomas W.
    Noethen, Markus M.
    Moebus, Susanne
    Eisele, Lewin
    Kosteljanetz, Michael
    Muir, Kenneth
    Swerdlow, Anthony
    Simon, Matthias
    Houlston, Richard S.
    Common variation at 10p12.31 near MLLT10 influences meningioma risk2011In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 43, no 9, p. 825-827Article in journal (Refereed)
    Abstract [en]

    To identify susceptibility loci for meningioma, we conducted a genome-wide association study of 859 affected individuals (cases) and 704 controls with validation in two independent sample sets totaling 774 cases and 1,764 controls. We identified a new susceptibility locus for meningioma at 10p12.31 (MLLT10, rs11012732, odds ratio = 1.46, P(combined) = 1.88 x 10(-14)). This finding advances our understanding of the genetic basis of meningioma development.

  • 18.
    Ghasimi, Soma
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Haapasalo, H.
    Eray, M.
    Korhonen, K.
    Brannstrom, Thomas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Hedman, Håkan
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Andersson, Ulrika
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Immunohistochemical analysis of LRIG proteins in meningiomas: correlation between estrogen receptor status and LRIG expression2012In: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 14, no Suppl 3, p. 69-69Article in journal (Other academic)
  • 19.
    Ghasimi, Soma
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Haapasalo, Hannu
    Department of Pathology, Center of Laboratory Medicine, Tampere University .
    Eray, Mine
    Department of Pathology, Center of Laboratory Medicine, Tampere University .
    Korhonen, Katariina
    Department of Neurosurgery, Turku University Hospital, Turku, Finland.
    Brännström, Thomas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Hedman, Håkan
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Andersson, Ulrika
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Immunohistochemical analysis of LRIG proteins in meningiomas: correlation between estrogen receptor status and LRIG expression2012In: Journal of Neuro-Oncology, ISSN 0167-594X, E-ISSN 1573-7373, Vol. 108, no 3, p. 435-441Article in journal (Refereed)
    Abstract [en]

    The leucine-rich repeats and immunoglobulin-like domains (LRIG) protein family is comprised of three integral membrane proteins: LRIG1, LRIG2, and LRIG3. LRIG1 is a negative regulator of growth factor signaling. The expression and subcellular localization of LRIG proteins have prognostic implications in primary brain tumors, such as oligodendrogliomas and astrocytomas. The expression of LRIG proteins has not previously been studied in meningiomas. In this study, the expression of LRIG1, LRIG2, and LRIG3 was analyzed in 409 meningiomas by immunohistochemistry, and potential associations between LRIG protein expression and tumor grade, gender, progesterone receptor status, and estrogen receptor (ER) status were investigated. The LRIG proteins were most often expressed in the cytoplasm, though LRIG1 also showed prominent nuclear expression. Cytoplasmic expression of LRIG1 and LRIG2 correlated with histological subtypes of meningiomas (p = 0.038 and 0.013, respectively). Nuclear and cytoplasmic expression of LRIG1 was correlated with ER status (p = 0.003 and 0.004, respectively), as was cytoplasmic expression of LRIG2 (p = 0.006). This study is the first to examine the expression of LRIG proteins in meningiomas, and it shows a correlation between ER status and the expression of LRIG1 and LRIG2, which suggests a possible role for LRIG proteins in meningioma pathogenesis.

  • 20.
    Ghasimi, Soma
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Wibom, Carl
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Brännström, Thomas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Haapasalo, H
    Eray, M
    Dobbins, S
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Ahlbom, A
    Auvinen, A
    Collatz-Laier, H
    Feychting, M
    Johansen, C
    Kiuru, A
    Houlston, R
    Melin, Beatrice
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Andersson, Ulrika
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Genetic variants in EGF, EGFR, ERBB2, LRIG2, LRIG3 and meningioma riskManuscript (preprint) (Other academic)
  • 21.
    Ghasimi, Soma
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Wibom, Carl
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Dahlin, Anna
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Brännström, Thomas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Golovleva, Irina
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Andersson, Ulrika
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Melin, Beatrice
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Genetic risk variants in the EGFR regions are associated with copy number variation in the EGFR gene as well as IDH1, and p53 protein expressionManuscript (preprint) (Other academic)
  • 22.
    Ghasimi, Soma
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Wibom, Carl
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Dahlin, Anna M.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Brännström, Thomas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Golovleva, Irina
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Andersson, Ulrika
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Melin, Beatrice
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Genetic risk variants in the CDKN2A/B, RTEL1 and EGFR genes are associated with somatic biomarkers in glioma2016In: Journal of Neuro-Oncology, ISSN 0167-594X, E-ISSN 1573-7373, Vol. 127, no 3, p. 483-492Article in journal (Refereed)
    Abstract [en]

    During the last years, genome wide association studies have discovered common germline genetic variants associated with specific glioma subtypes. We aimed to study the association between these germline risk variants and tumor phenotypes, including copy number aberrations and protein expression. A total of 91 glioma patients were included. Thirteen well known genetic risk variants in TERT, EGFR, CCDC26, CDKN2A, CDKN2B, PHLDB1, TP53, and RTEL1 were selected for investigation of possible correlations with the glioma somatic markers: EGFR amplification, 1p/19q codeletion and protein expression of p53, Ki-67, and mutated IDH1. The CDKN2A/B risk variant, rs4977756, and the CDKN2B risk variant, rs1412829 were inversely associated (p = 0.049 and p = 0.002, respectively) with absence of a mutated IDH1, i.e., the majority of patients homozygous for the risk allele showed no or low expression of mutated IDH1. The RTEL1 risk variant, rs6010620 was associated (p = 0.013) with not having 1p/19q codeletion, i.e., the majority of patients homozygous for the risk allele did not show 1p/19q codeletion. In addition, the EGFR risk variant rs17172430 and the CDKN2B risk variant rs1412829, both showed a trend for association (p = 0.055 and p = 0.051, respectively) with increased EGFR copy number, i.e., the majority of patients homozygote for the risk alleles showed chromosomal gain or amplification of EGFR. Our findings indicate that CDKN2A/B risk genotypes are associated with primary glioblastoma without IDH mutation, and that there is an inverse association between RTEL1 risk genotypes and 1p/19q codeletion, suggesting that these genetic variants have a molecular impact on the genesis of high graded brain tumors. Further experimental studies are needed to delineate the functional mechanism of the association between genotype and somatic genetic aberrations.

  • 23. Jacobs, Kevin B
    et al.
    Yeager, Meredith
    Zhou, Weiyin
    Wacholder, Sholom
    Wang, Zhaoming
    Rodriguez-Santiago, Benjamin
    Hutchinson, Amy
    Deng, Xiang
    Liu, Chenwei
    Horner, Marie-Josephe
    Cullen, Michael
    Epstein, Caroline G
    Burdett, Laurie
    Dean, Michael C
    Chatterjee, Nilanjan
    Sampson, Joshua
    Chung, Charles C
    Kovaks, Joseph
    Gapstur, Susan M
    Stevens, Victoria L
    Teras, Lauren T
    Gaudet, Mia M
    Albanes, Demetrius
    Weinstein, Stephanie J
    Virtamo, Jarmo
    Taylor, Philip R
    Freedman, Neal D
    Abnet, Christian C
    Goldstein, Alisa M
    Hu, Nan
    Yu, Kai
    Yuan, Jian-Min
    Liao, Linda
    Ding, Ti
    Qiao, You-Lin
    Gao, Yu-Tang
    Koh, Woon-Puay
    Xiang, Yong-Bing
    Tang, Ze-Zhong
    Fan, Jin-Hu
    Aldrich, Melinda C
    Amos, Christopher
    Blot, William J
    Bock, Cathryn H
    Gillanders, Elizabeth M
    Harris, Curtis C
    Haiman, Christopher A
    Henderson, Brian E
    Kolonel, Laurence N
    Le Marchand, Loic
    McNeill, Lorna H
    Rybicki, Benjamin A
    Schwartz, Ann G
    Signorello, Lisa B
    Spitz, Margaret R
    Wiencke, John K
    Wrensch, Margaret
    Wu, Xifeng
    Zanetti, Krista A
    Ziegler, Regina G
    Figueroa, Jonine D
    Garcia-Closas, Montserrat
    Malats, Nuria
    Marenne, Gaelle
    Prokunina-Olsson, Ludmila
    Baris, Dalsu
    Schwenn, Molly
    Johnson, Alison
    Landi, Maria Teresa
    Goldin, Lynn
    Consonni, Dario
    Bertazzi, Pier Alberto
    Rotunno, Melissa
    Rajaraman, Preetha
    Andersson, Ulrika
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Freeman, Laura E Beane
    Berg, Christine D
    Buring, Julie E
    Butler, Mary A
    Carreon, Tania
    Feychting, Maria
    Ahlbom, Anders
    Gaziano, J Michael
    Giles, Graham G
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Hankinson, Susan E
    Hartge, Patricia
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Inskip, Peter D
    Johansen, Christoffer
    Landgren, Annelie
    McKean-Cowdin, Roberta
    Michaud, Dominique S
    Melin, Beatrice S
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Peters, Ulrike
    Ruder, Avima M
    Sesso, Howard D
    Severi, Gianluca
    Shu, Xiao-Ou
    Visvanathan, Kala
    White, Emily
    Wolk, Alicja
    Zeleniuch-Jacquotte, Anne
    Zheng, Wei
    Silverman, Debra T
    Kogevinas, Manolis
    Gonzalez, Juan R
    Villa, Olaya
    Li, Donghui
    Duell, Eric J
    Risch, Harvey A
    Olson, Sara H
    Kooperberg, Charles
    Wolpin, Brian M
    Jiao, Li
    Hassan, Manal
    Wheeler, William
    Arslan, Alan A
    Bueno-de-Mesquita, H Bas
    Fuchs, Charles S
    Gallinger, Steven
    Gross, Myron D
    Holly, Elizabeth A
    Klein, Alison P
    Lacroix, Andrea
    Mandelson, Margaret T
    Petersen, Gloria
    Boutron-Ruault, Marie-Christine
    Bracci, Paige M
    Canzian, Federico
    Chang, Kenneth
    Cotterchio, Michelle
    Giovannucci, Edward L
    Goggins, Michael
    Bolton, Judith A Hoffman
    Jenab, Mazda
    Khaw, Kay-Tee
    Krogh, Vittorio
    Kurtz, Robert C
    McWilliams, Robert R
    Mendelsohn, Julie B
    Rabe, Kari G
    Riboli, Elio
    Tjønneland, Anne
    Tobias, Geoffrey S
    Trichopoulos, Dimitrios
    Elena, Joanne W
    Yu, Herbert
    Amundadottir, Laufey
    Stolzenberg-Solomon, Rachael Z
    Kraft, Peter
    Schumacher, Fredrick
    Stram, Daniel
    Savage, Sharon A
    Mirabello, Lisa
    Andrulis, Irene L
    Wunder, Jay S
    García, Ana Patiño
    Sierrasesúmaga, Luis
    Barkauskas, Donald A
    Gorlick, Richard G
    Purdue, Mark
    Chow, Wong-Ho
    Moore, Lee E
    Schwartz, Kendra L
    Davis, Faith G
    Hsing, Ann W
    Berndt, Sonja I
    Black, Amanda
    Wentzensen, Nicolas
    Brinton, Louise A
    Lissowska, Jolanta
    Peplonska, Beata
    McGlynn, Katherine A
    Cook, Michael B
    Graubard, Barry I
    Kratz, Christian P
    Greene, Mark H
    Erickson, Ralph L
    Hunter, David J
    Thomas, Gilles
    Hoover, Robert N
    Real, Francisco X
    Fraumeni, Joseph F
    Caporaso, Neil E
    Tucker, Margaret
    Rothman, Nathaniel
    Pérez-Jurado, Luis A
    Chanock, Stephen J
    Detectable clonal mosaicism and its relationship to aging and cancer.2012In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 44, no 6, p. 651-658Article in journal (Refereed)
    Abstract [en]

    In an analysis of 31,717 cancer cases and 26,136 cancer-free controls from 13 genome-wide association studies, we observed large chromosomal abnormalities in a subset of clones in DNA obtained from blood or buccal samples. We observed mosaic abnormalities, either aneuploidy or copy-neutral loss of heterozygosity, of >2 Mb in size in autosomes of 517 individuals (0.89%), with abnormal cell proportions of between 7% and 95%. In cancer-free individuals, frequency increased with age, from 0.23% under 50 years to 1.91% between 75 and 79 years (P = 4.8 × 10(-8)). Mosaic abnormalities were more frequent in individuals with solid tumors (0.97% versus 0.74% in cancer-free individuals; odds ratio (OR) = 1.25; P = 0.016), with stronger association with cases who had DNA collected before diagnosis or treatment (OR = 1.45; P = 0.0005). Detectable mosaicism was also more common in individuals for whom DNA was collected at least 1 year before diagnosis with leukemia compared to cancer-free individuals (OR = 35.4; P = 3.8 × 10(-11)). These findings underscore the time-dependent nature of somatic events in the etiology of cancer and potentially other late-onset diseases.

  • 24.
    Johansson, David
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Johansson, Anders
    Umeå University, Faculty of Medicine, Department of Odontology, Periodontology.
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Andersson, Ulrika
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Bergström, Per
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Brännström, Thomas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Behnam Motlagh, Parviz
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Verotoxin-1 Induction of Apoptosis in Gb3-Expressing Human Glioma Cell Lines2006In: Cancer Biology & Therapy, ISSN 1538-4047, E-ISSN 1555-8576, Vol. 5, no 9, p. 1211-1217Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to examine the cytotoxicity and mechanism of apoptosis induction of verotoxin-1 (VT-1) in human glioma cell lines. VT-1 is a member of the shiga-toxin family expressed by some serotypes of Escherichia coli and Shigella dysenteriae. Shiga-toxins have been shown to induce apoptosis by binding to its membrane receptor Gb3. The human glioma cell lines SF-767, U-343 MG, and U-251 MG were studied together with BT4C, a rat glioma cell line. Cells were first screened for Gb3 expression by flow cytometry. Fluorescein diacetate was used to determine cell viability after VT-1 and irradiation exposure and apoptosis was studied by TUNEL staining, a mitochondrial membrane potential assay, and caspase activity assays. SF-767 and U-343 MG cells were found to express Gb3 and were also sensitive to VT-1-induced cytotoxicity, whereas nonGb3-expressing U-251 MG and BT4C glioma cells were not. VT-1 depolarized the mitochondrial membrane and activated caspase-9 and -3 of SF-767 and U-343 MG cells. VT-1 exposure for 72 h resulted in approx. 60 and 90% TUNEL-stained cells, respectively. D, L-Threo-1-phenyl-2-palmitoylamino-3-morpholino-1-propanol (PPMP) an inhibitor of glucosylceramide synthesis was used to block Gb3 synthesis. Two mumol/L PPMP for 72 h abolished SF-767 and U-343 MG expression of Gb3 and made the cells completely resistant to VT-1 induced apoptosis. Key components of MAP kinase signalling pathways that control BAX and mitochondrial function were investigated. VT-1 induced JNK phosphorylation in both cell lines, suggesting that survival signal pathways were overruled by VT-1-induced JNK activation leading to mitochondrial depolarization, caspase-9 activation and apoptosis. Immunohistochemistry of cryostat section from glioma biopsies demonstrated expression of Gb3 was in the vascular endothelial cells as well as tumor cells, but not in astrocytes. The high specificity and apoptosis inducing properties of verotoxin-1 indicates that the toxin may be a potential anti-neoplastic agent for Gb3-expressing gliomas.

  • 25.
    Johansson, Gunnar
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Andersson, Ulrika
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Melin, Beatrice
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Recent developments in brain tumor predisposing syndromes2016In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 55, no 4, p. 401-411Article, review/survey (Refereed)
    Abstract [en]

    The etiologies of brain tumors are in the most cases unknown, but improvements in genetics and DNA screening have helped to identify a wide range of brain tumor predisposition disorders. In this review we are discussing some of the most common predisposition disorders, namely: neurofibromatosis type 1 and 2, schwannomatosis, rhabdoid tumor predisposition disorder, nevoid basal cell carcinoma syndrome (Gorlin), tuberous sclerosis complex, von Hippel-Lindau, Li-Fraumeni and Turcot syndromes. Recent findings from the GLIOGENE collaboration and the newly identified glioma causing gene POT1, will also be discussed. Genetics. We will describe these disorders from a genetic and clinical standpoint, focusing on the difference in clinical symptoms depending on the underlying gene or germline mutation. Central nervous system (CNS) tumors. Most of these disorders predispose the carriers to a wide range of symptoms. Herein, we will focus particularly on tumors affecting the CNS and discuss improvements of targeted therapy for the particular disorders.

  • 26. Kitahara, Cari M
    et al.
    Wang, Sophia S
    Melin, Beatrice S
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Wang, Zhaoming
    Braganza, Melissa
    Inskip, Peter D
    Albanes, Demetrius
    Andersson, Ulrika
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Beane Freeman, Laura E
    Buring, Julie E
    Carreón, Tania
    Feychting, Maria
    Gapstur, Susan M
    Gaziano, J Michael
    Giles, Graham G
    Hallmans, Goran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Hankinson, Susan E
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Hsing, Ann W
    Johansen, Christoffer
    Linet, Martha S
    McKean-Cowdin, Roberta
    Michaud, Dominique S
    Peters, Ulrike
    Purdue, Mark P
    Rothman, Nathaniel
    Ruder, Avima M
    Sesso, Howard D
    Severi, Gianluca
    Shu, Xiao-Ou
    Stevens, Victoria L
    Visvanathan, Kala
    Waters, Martha A
    White, Emily
    Wolk, Alicja
    Zeleniuch-Jacquotte, Anne
    Zheng, Wei
    Hoover, Robert
    Fraumeni, Joseph F
    Chatterjee, Nilanjan
    Yeager, Meredith
    Chanock, Stephen J
    Hartge, Patricia
    Rajaraman, Preetha
    Association between adult height, genetic susceptibility and risk of glioma.2012In: International Journal of Epidemiology, ISSN 0300-5771, E-ISSN 1464-3685, Vol. 41, no 4, p. 1075-1085Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Some, but not all, observational studies have suggested that taller stature is associated with a significant increased risk of glioma. In a pooled analysis of observational studies, we investigated the strength and consistency of this association, overall and for major sub-types, and investigated effect modification by genetic susceptibility to the disease. METHODS: We standardized and combined individual-level data on 1354 cases and 4734 control subjects from 13 prospective and 2 case-control studies. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) for glioma and glioma sub-types were estimated using logistic regression models stratified by sex and adjusted for birth cohort and study. Pooled ORs were additionally estimated after stratifying the models according to seven recently identified glioma-related genetic variants. RESULTS: Among men, we found a positive association between height and glioma risk (≥190 vs 170-174 cm, pooled OR = 1.70, 95% CI: 1.11-2.61; P-trend = 0.01), which was slightly stronger after restricting to cases with glioblastoma (pooled OR = 1.99, 95% CI: 1.17-3.38; P-trend = 0.02). Among women, these associations were less clear (≥175 vs 160-164 cm, pooled OR for glioma = 1.06, 95% CI: 0.70-1.62; P-trend = 0.22; pooled OR for glioblastoma = 1.36, 95% CI: 0.77-2.39; P-trend = 0.04). In general, we did not observe evidence of effect modification by glioma-related genotypes on the association between height and glioma risk. CONCLUSION: An association of taller adult stature with glioma, particularly for men and stronger for glioblastoma, should be investigated further to clarify the role of environmental and genetic determinants of height in the etiology of this disease.

  • 27. Liu, Yanhong
    et al.
    Melin, Beatrice S
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Rajaraman, Preetha
    Wang, Zhaoming
    Linet, Martha
    Shete, Sanjay
    Amos, Christopher I
    Lau, Ching C
    Scheurer, Michael E
    Tsavachidis, Spiridon
    Armstrong, Georgina N
    Houlston, Richard S
    Hosking, Fay J
    Claus, Elizabeth B
    Barnholtz-Sloan, Jill
    Lai, Rose
    Il'yasova, Dora
    Schildkraut, Joellen
    Sadetzki, Siegal
    Johansen, Christoffer
    Bernstein, Jonine L
    Olson, Sara H
    Jenkins, Robert B
    Lachance, Daniel
    Vick, Nicholas A
    Wrensch, Margaret
    Davis, Faith
    McCarthy, Bridget J
    Andersson, Ulrika
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Thompson, Patricia A
    Chanock, Stephen
    Bondy, Melissa L
    Insight in glioma susceptibility through an analysis of 6p22.3, 12p13.33-12.1, 17q22-23.2 and 18q23 SNP genotypes in familial and non-familial glioma2012In: Human Genetics, ISSN 0340-6717, E-ISSN 1432-1203, Vol. 131, no 9, p. 1507-1517Article in journal (Refereed)
    Abstract [en]

    The risk of glioma has consistently been shown to be increased twofold in relatives of patients with primary brain tumors (PBT). A recent genome-wide linkage study of glioma families provided evidence for a disease locus on 17q12-21.32, with the possibility of four additional risk loci at 6p22.3, 12p13.33-12.1, 17q22-23.2, and 18q23. To identify the underlying genetic variants responsible for the linkage signals, we compared the genotype frequencies of 5,122 SNPs mapping to these five regions in 88 glioma cases with and 1,100 cases without a family history of PBT (discovery study). An additional series of 84 familial and 903 non-familial cases were used to replicate associations. In the discovery study, 12 SNPs showed significant associations with family history of PBT (P < 0.001). In the replication study, two of the 12 SNPs were confirmed: 12p13.33-12.1 PRMT8 rs17780102 (P = 0.031) and 17q12-21.32 SPOP rs650461 (P = 0.025). In the combined analysis of discovery and replication studies, the strongest associations were attained at four SNPs: 12p13.33-12.1 PRMT8 rs17780102 (P = 0.0001), SOX5 rs7305773 (P = 0.0001) and STKY1 rs2418087 (P = 0.0003), and 17q12-21.32 SPOP rs6504618 (P = 0.0006). Further, a significant gene-dosage effect was found for increased risk of family history of PBT with these four SNPs in the combined data set (P (trend) <1.0 × 10(-8)). The results support the linkage finding that some loci in the 12p13.33-12.1 and 17q12-q21.32 may contribute to gliomagenesis and suggest potential target genes underscoring linkage signals.

  • 28. Liu, Yanhong
    et al.
    Shete, Sanjay
    Etzel, Carol J
    Scheurer, Michael
    Alexiou, George
    Armstrong, Georgina
    Tsavachidis, Spyros
    Liang, Fu-Wen
    Gilbert, Mark
    Aldape, Ken
    Armstrong, Terri
    Houlston, Richard
    Hosking, Fay
    Robertson, Lindsay
    Xiao, Yuanyuan
    Wiencke, John
    Wrensch, Margaret
    Andersson, Ulrika
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Melin, Beatrice S
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Bondy, Melissa
    Polymorphisms of LIG4, BTBD2, HMGA2, and RTEL1 genes involved in the double-strand break repair pathway predict glioblastoma survival2010In: Journal of Clinical Oncology, ISSN 0732-183X, E-ISSN 1527-7755, Vol. 28, no 14, p. 2467-2474Article in journal (Refereed)
    Abstract [en]

    PURPOSE: Glioblastoma (GBM) is the most common and aggressive type of glioma and has the poorest survival. However, a small percentage of patients with GBM survive well beyond the established median. Therefore, identifying the genetic variants that influence this small number of unusually long-term survivors may provide important insight into tumor biology and treatment. PATIENTS AND METHODS: Among 590 patients with primary GBM, we evaluated associations of survival with the 100 top-ranking glioma susceptibility single nucleotide polymorphisms from our previous genome-wide association study using Cox regression models. We also compared differences in genetic variation between short-term survivors (STS; or= 36 months), and explored classification and regression tree analysis for survival data. We tested results using two independent series totaling 543 GBMs. RESULTS: We identified LIG4 rs7325927 and BTBD2 rs11670188 as predictors of STS in GBM and CCDC26 rs10464870 and rs891835, HMGA2 rs1563834, and RTEL1 rs2297440 as predictors of LTS. Further survival tree analysis revealed that patients >or= 50 years old with LIG4 rs7325927 (V) had the worst survival (median survival time, 1.2 years) and exhibited the highest risk of death (hazard ratio, 17.53; 95% CI, 4.27 to 71.97) compared with younger patients with combined RTEL1 rs2297440 (V) and HMGA2 rs1563834 (V) genotypes (median survival time, 7.8 years). CONCLUSION: Polymorphisms in the LIG4, BTBD2, HMGA2, and RTEL1 genes, which are involved in the double-strand break repair pathway, are associated with GBM survival.

  • 29.
    Melin, Beatrice
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Dahlin, Anna M
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Andersson, Ulrika
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Wang, Zhaoming
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Umeå University, Faculty of Medicine, Department of Biobank Research.
    Bondy, Melissa L
    Johansen, Christoffer
    Feychting, Maria
    Ahlbom, Anders
    Kitahara, Cari M
    Wang, Sophia S
    Ruder, Avima M
    Carreon, Tania
    Butler, Mary Ann
    Inskip, Peter D
    Purdue, Mark
    Hsing, Ann W
    Mechanic, Leah
    Gillanders, Elizabeth
    Yeager, Meredith
    Linet, Martha
    Chanock, Stephen J
    Hartge, Patricia
    Rajaraman, Preetha
    Known glioma risk loci are associated with glioma with a family history of brain tumours: a case-control gene association study2013In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 132, no 10, p. 2464-2468Article in journal (Refereed)
    Abstract [en]

    Familial cancer can be used to leverage genetic association studies. Recent genome-wide association studies have reported independent associations between seven single nucleotide polymorphisms (SNPs) and risk of glioma. The aim of this study was to investigate whether glioma cases with a positive family history of brain tumours, defined as having at least one first- or second-degree relative with a history of brain tumour, are associated with known glioma risk loci. One thousand four hundred and thirty-one glioma cases and 2,868 cancer-free controls were identified from four casecontrol studies and two prospective cohorts from USA, Sweden and Denmark and genotyped for seven SNPs previously reported to be associated with glioma risk in casecontrol designed studies. Odds ratios were calculated by unconditional logistic regression. In analyses including glioma cases with a family history of brain tumours (n = 104) and control subjects free of glioma at baseline, three of seven SNPs were associated with glioma risk: rs2736100 (5p15.33, TERT), rs4977756 (9p21.3, CDKN2A-CDKN2B) and rs6010620 (20q13.33, RTEL1). After Bonferroni correction for multiple comparisons, only one marker was statistically significantly associated with glioma risk, rs6010620 (ORtrend for the minor (A) allele, 0.39; 95% CI: 0.250.61; Bonferroni adjusted ptrend, 1.7 x 104). In conclusion, as previously shown for glioma regardless of family history of brain tumours, rs6010620 (RTEL1) was associated with an increased risk of glioma when restricting to cases with family history of brain tumours. These findings require confirmation in further studies with a larger number of glioma cases with a family history of brain tumours.

  • 30.
    Melin, Beatrice S.
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Barnholtz-Sloan, Jill S.
    Wrensch, Margaret R.
    Johansen, Christoffer
    Il'yasova, Dora
    Kinnersley, Ben
    Ostrom, Quinn T.
    Labreche, Karim
    Chen, Yanwen
    Armstrong, Georgina
    Liu, Yanhong
    Eckel-Passow, Jeanette E.
    Decker, Paul A.
    Labussiere, Marianne
    Idbaih, Ahmed
    Hoang-Xuan, Khe
    Di Stefano, Anna-Luisa
    Mokhtari, Karima
    Delattre, Jean-Yves
    Broderick, Peter
    Galan, Pilar
    Gousias, Konstantinos
    Schramm, Johannes
    Schoemaker, Minouk J.
    Fleming, Sarah J.
    Herms, Stefan
    Heilmann, Stefanie
    Noethen, Markus M.
    Wichmann, Heinz-Erich
    Schreiber, Stefan
    Swerdlow, Anthony
    Lathrop, Mark
    Simon, Matthias
    Sanson, Marc
    Andersson, Ulrika
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Rajaraman, Preetha
    Chanock, Stephen
    Linet, Martha
    Wang, Zhaoming
    Yeager, Meredith
    Wiencke, John K.
    Hansen, Helen
    Mccoy, Lucie
    Rice, Terri
    Kosel, Matthew L.
    Sicotte, Hugues
    Amos, Christopher I.
    Bernstein, Jonine L.
    Davis, Faith
    Lachance, Dan
    Lau, Ching
    Merrell, Ryan T.
    Shildkraut, Joellen
    Ali-Osman, Francis
    Sadetzki, Siegal
    Scheurer, Michael
    Shete, Sanjay
    Lai, Rose K.
    Claus, Elizabeth B.
    Olson, Sara H.
    Jenkins, Robert B.
    Houlston, Richard S.
    Bondy, Melissa L.
    Genome-wide association study of glioma subtypes identifies specific differences in genetic susceptibility to glioblastoma and non-glioblastoma tumors2017In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 49, no 5, p. 789-794Article in journal (Refereed)
    Abstract [en]

    Genome-wide association studies (GWAS) have transformed our understanding of glioma susceptibility, but individual studies have had limited power to identify risk loci. We performed a meta-analysis of existing GWAS and two new GWAS, which totaled 12,496 cases and 18,190 controls. We identified five new loci for glioblastoma (GBM) at 1p31.3 (rs12752552; P = 2.04 x 10(-9), odds ratio (OR) = 1.22), 11q14.1 (rs11233250; P = 9.95 x 10(-10), OR = 1.24), 16p13.3 (rs2562152; P = 1.93 x 10-8, OR = 1.21), 16q12.1 (rs10852606; P = 1.29 x 10(-11), OR = 1.18) and 22q13.1 (rs2235573; P = 1.76 x 10(-10), OR = 1.15), as well as eight loci for non-GBM tumors at 1q32.1 (rs4252707; P = 3.34 x 10(-9), OR = 1.19), 1q44 (rs12076373; P = 2.63 x 10(-10), OR = 1.23), 2q33.3 (rs7572263; P = 2.18 x 10(-10), OR = 1.20), 3p14.1 (rs11706832; P = 7.66 x 10(-9), OR = 1.15), 10q24.33 (rs11598018; P = 3.39 x 10-8, OR = 1.14), 11q21 (rs7107785; P = 3.87 x 10(-10), OR = 1.16), 14q12 (rs10131032; P = 5.07 x 10(-11), OR = 1.33) and 16p13.3 (rs3751667; P = 2.61 x 10(-9), OR = 1.18). These data substantiate that genetic susceptibility to GBM and non-GBM tumors are highly distinct, which likely reflects different etiology.

  • 31.
    Melin, Beatrice S.
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Nordfjall, Katarina
    Andersson, Ulrika
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Roos, Göran
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    hTERT Cancer Risk Genotypes Are Associated With Telomere Length2012In: Genetic Epidemiology, ISSN 0741-0395, E-ISSN 1098-2272, Vol. 36, no 4, p. 368-372Article in journal (Refereed)
    Abstract [en]

    Telomere biology is associated with cancer initiation and prognosis. Collected data suggest that blood cell telomere length (TL) can change over time, which may be related to development of common disorders, such as cardiovascular diseases and cancer. Recently, single nucleotide polymorphisms in the region of the human telomerase reverse transcriptase (hTERT) gene were associated with various malignancies, including glioma, lung and urinary bladder cancer, and telomerase RNA gene hTERC genotypes were recently linked to TL. In the present study a hypothetical association between identified genotypes in hTERT and hTERC genes and TL were investigated. We analyzed 21 polymorphisms, covering 90% of the genetic variance, in the hTERT gene, two genetic variants in hTERC, and relative TL(RTL) at average age 50 and 60 in 959 individuals with repeated blood samples. Mean RTL at age 60 was associated with four genetic variants of the hTERT gene (rs2736100, rs2853672, rs2853677, and rs2853676), two of which reported to be associated with cancer risk. Two alleles (rs12696304, rs16847897) near the hTERC gene were confirmed as also being associated with RTL at age 60. Our data suggest that hTERT and hTERC genotypes have an impact on TL of potential relevance and detectable first at higher ages, which gives us further insight to the complex regulation of TL. Genet. Epidemiol. 36:368-372, 2012. (c) 2012 Wiley Periodicals, Inc.

  • 32. Ostrom, Quinn T.
    et al.
    Coleman, Warren
    Huang, William
    Rubin, Joshua B.
    Lathia, Justin D.
    Berens, Michael E.
    Speyer, Gil
    Liao, Peter
    Wrensch, Margaret R.
    Eckel-Passow, Jeanette E.
    Armstrong, Georgina
    Rice, Terri
    Wiencke, John K.
    McCoy, Lucie S.
    Hansen, Helen M.
    Amos, Christopher I.
    Bernstein, Jonine L.
    Claus, Elizabeth B.
    Houlston, Richard S.
    Il'yasova, Dora
    Jenkins, Robert B.
    Johansen, Christoffer
    Lachance, Daniel H.
    Lai, Rose K.
    Merrell, Ryan T.
    Olson, Sara H.
    Sadetzki, Siegal
    Schildkraut, Joellen M.
    Shete, Sanjay
    Andersson, Ulrika
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Rajaraman, Preetha
    Chanock, Stephen J.
    Linet, Martha S.
    Wang, Zhaoming
    Yeager, Meredith
    Melin, Beatrice S.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Bondy, Melissa L.
    Barnholtz-Sloan, Jill S.
    Freeman, Laura E. Beane
    Koutros, Stella
    Albanes, Demetrius
    Visvanathan, Kala
    Stevens, Victoria L.
    Henriksson, Roger
    Michaud, Dominique S.
    Feychting, Maria
    Ahlbom, Anders
    Giles, Graham G.
    Milne, Roger
    McKean-Cowdin, Roberta
    Le Marchand, Loic
    Stampfer, Meir
    Ruder, Avima M.
    Carreon, Tania
    Hallmans, Goran
    Zeleniuch-Jacquotte, Anne
    Gaziano, J. Michael
    Sesso, Howard D.
    Purdue, Mark P.
    White, Emily
    Peters, Ulrike
    Buring, Julie
    Sex-specific gene and pathway modeling of inherited glioma risk2019In: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 21, no 1, p. 71-82Article in journal (Refereed)
    Abstract [en]

    Background To date, genome-wide association studies (GWAS) have identified 25 risk variants for glioma, explaining 30% of heritable risk. Most histologies occur with significantly higher incidence in males, and this difference is not explained by currently known risk factors. A previous GWAS identified sex-specific glioma risk variants, and this analysis aims to further elucidate risk variation by sex using gene- and pathway-based approaches. Methods Results from the Glioma International Case-Control Study were used as a testing set, and results from 3 GWAS were combined via meta-analysis and used as a validation set. Using summary statistics for nominally significant autosomal SNPs (P < 0.01 in a previous meta-analysis) and nominally significant X-chromosome SNPs (P < 0.01), 3 algorithms (Pascal, BimBam, and GATES) were used to generate gene scores, and Pascal was used to generate pathway scores. Results were considered statistically significant in the discovery set when P < 3.3 x 10(-6) and in the validation set when P < 0.001 in 2 of 3 algorithms. Results Twenty-five genes within 5 regions and 19 genes within 6 regions reached statistical significance in at least 2 of 3 algorithms in males and females, respectively. EGFR was significantly associated with all glioma and glioblastoma in males only and a female-specific association in TERT, all of which remained nominally significant after conditioning on known risk loci. There were nominal associations with the BioCarta telomeres pathway in both males and females. Conclusions These results provide additional evidence that there may be differences by sex in genetic risk for glioma. Additional analyses may further elucidate the biological processes through which this risk is conferred.

  • 33. Ostrom, Quinn T.
    et al.
    Kinnersley, Ben
    Armstrong, Georgina
    Rice, Terri
    Chen, Yanwen
    Wiencke, John K.
    McCoy, Lucie S.
    Hansen, Helen M.
    Amos, Christopher I.
    Bernstein, Jonine L.
    Claus, Elizabeth B.
    Eckel-Passow, Jeanette E.
    Il'yasova, Dora
    Johansen, Christoffer
    Lachance, Daniel H.
    Lai, Rose K.
    Merrell, Ryan T.
    Olson, Sara H.
    Sadetzki, Siegal
    Schildkraut, Joellen M.
    Shete, Sanjay
    Rubin, Joshua B.
    Andersson, Ulrika
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Rajaraman, Preetha
    Chanock, Stephen J.
    Linet, Martha S.
    Wang, Zhaoming
    Yeager, Meredith
    Houlston, Richard S.
    Jenkins, Robert B.
    Wrensch, Margaret R.
    Melin, Beatrice
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Bondy, Melissa L.
    Barnholtz-Sloan, Jill. S.
    Age‐specific genome‐wide association study in glioblastoma identifies increased proportion of 'lower grade glioma'‐like features associated with younger age2018In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 143, no 10, p. 2359-2366Article in journal (Refereed)
    Abstract [en]

    Glioblastoma (GBM) is the most common malignant brain tumor in the United States. Incidence of GBM increases with age, and younger age‐at‐diagnosis is significantly associated with improved prognosis. While the relationship between candidate GBM risk SNPs and age‐at‐diagnosis has been explored, genome‐wide association studies (GWAS) have not previously been stratified by age. Potential age‐specific genetic effects were assessed in autosomal SNPs for GBM patients using data from four previous GWAS. Using age distribution tertiles (18–53, 54–64, 65+) datasets were analyzed using age‐stratified logistic regression to generate p values, odds ratios (OR), and 95% confidence intervals (95%CI), and then combined using meta‐analysis. There were 4,512 total GBM cases, and 10,582 controls used for analysis. Significant associations were detected at two previously identified SNPs in 7p11.2 (rs723527 [p54–63 = 1.50x10−9, OR54–63 = 1.28, 95%CI54–63 = 1.18–1.39; p64+ = 2.14x10−11, OR64+ = 1.32, 95%CI64+ = 1.21–1.43] and rs11979158 [p54–63 = 6.13x10−8, OR54–63 = 1.35, 95%CI54–63 = 1.21–1.50; p64+ = 2.18x10−10, OR64+ = 1.42, 95%CI64+ = 1.27–1.58]) but only in persons >54. There was also a significant association at the previously identified lower grade glioma (LGG) risk locus at 8q24.21 (rs55705857) in persons ages 18–53 (p18–53 = 9.30 × 10−11, OR18–53 = 1.76, 95%CI18–53 = 1.49–2.10). Within The Cancer Genome Atlas (TCGA) there was higher prevalence of ‘LGG’‐like tumor characteristics in GBM samples in those 18–53, with IDH1/2 mutation frequency of 15%, as compared to 2.1% [54–63] and 0.8% [64+] (p = 0.0005). Age‐specific differences in cancer susceptibility can provide important clues to etiology. The association of a SNP known to confer risk for IDH1/2 mutant glioma and higher prevalence of IDH1/2 mutation within younger individuals 18–53 suggests that more younger individuals may present initially with ‘secondary glioblastoma.’

  • 34. Ostrom, Quinn T.
    et al.
    Kinnersley, Ben
    Wrensch, Margaret R.
    Eckel-Passow, Jeanette E.
    Armstrong, Georgina
    Rice, Terri
    Chen, Yanwen
    Wiencke, John K.
    McCoy, Lucie S.
    Hansen, Helen M.
    Amos, Christopher I.
    Bernstein, Jonine L.
    Claus, Elizabeth B.
    Il'yasova, Dora
    Johansen, Christoffer
    Lachance, Daniel H.
    Lai, Rose K.
    Merrell, Ryan T.
    Olson, Sara H.
    Sadetzki, Siegal
    Schildkraut, Joellen M.
    Shete, Sanjay
    Rubin, Joshua B.
    Lathia, Justin D.
    Berens, Michael E.
    Andersson, Ulrika
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Rajaraman, Preetha
    Chanock, Stephen J.
    Linet, Martha S.
    Wang, Zhaoming
    Yeager, Meredith
    Houlston, Richard S.
    Jenkins, Robert B.
    Melin, Beatrice S.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Bondy, Melissa L.
    Barnholtz-Sloan, Jill. S.
    Sex-specific glioma genome-wide association study identifies new risk locus at 3p21.31 in females, and finds sex-differences in risk at 8q24.212018In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 7352Article in journal (Refereed)
    Abstract [en]

    Incidence of glioma is approximately 50% higher in males. Previous analyses have examined exposures related to sex hormones in women as potential protective factors for these tumors, with inconsistent results. Previous glioma genome-wide association studies (GWAS) have not stratified by sex. Potential sex-specific genetic effects were assessed in autosomal SNPs and sex chromosome variants for all glioma, GBM and non-GBM patients using data from four previous glioma GWAS. Datasets were analyzed using sex-stratified logistic regression models and combined using meta-analysis. There were 4,831 male cases, 5,216 male controls, 3,206 female cases and 5,470 female controls. A significant association was detected at rs11979158 (7p11.2) in males only. Association at rs55705857 (8q24.21) was stronger in females than in males. A large region on 3p21.31 was identified with significant association in females only. The identified differences in effect of risk variants do not fully explain the observed incidence difference in glioma by sex.

  • 35. Rajaraman, Preetha
    et al.
    Melin, Beatrice S
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Wang, Zhaoming
    McKean-Cowdin, Roberta
    Michaud, Dominique S
    Wang, Sophia S
    Bondy, Melissa
    Houlston, Richard
    Jenkins, Robert B
    Wrensch, Margaret
    Yeager, Meredith
    Ahlbom, Anders
    Albanes, Demetrius
    Andersson, Ulrika
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Freeman, Laura E Beane
    Buring, Julie E
    Butler, Mary Ann
    Braganza, Melissa
    Carreon, Tania
    Feychting, Maria
    Fleming, Sarah J
    Gapstur, Susan M
    Gaziano, J Michael
    Giles, Graham G
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Hoffman-Bolton, Judith
    Inskip, Peter D
    Johansen, Christoffer
    Kitahara, Cari M
    Lathrop, Mark
    Liu, Chenwei
    Le Marchand, Loic
    Linet, Martha S
    Lonn, Stefan
    Peters, Ulrike
    Purdue, Mark P
    Rothman, Nathaniel
    Ruder, Avima M
    Sanson, Marc
    Sesso, Howard D
    Severi, Gianluca
    Shu, Xiao-Ou
    Simon, Matthias
    Stampfer, Meir
    Stevens, Victoria L
    Visvanathan, Kala
    White, Emily
    Wolk, Alicja
    Zeleniuch-Jacquotte, Anne
    Zheng, Wei
    Decker, Paul
    Enciso-Mora, Victor
    Fridley, Brooke
    Gao, Yu-Tang
    Kosel, Matthew
    Lachance, Daniel H
    Lau, Ching
    Rice, Terri
    Swerdlow, Anthony
    Wiemels, Joseph L
    Wiencke, John K
    Shete, Sanjay
    Xiang, Yong-Bing
    Xiao, Yuanyuan
    Hoover, Robert N
    Fraumeni, Joseph F
    Chatterjee, Nilanjan
    Hartge, Patricia
    Chanock, Stephen J
    Genome-wide association study of glioma and meta-analysis2012In: Human Genetics, ISSN 0340-6717, E-ISSN 1432-1203, Vol. 131, no 12, p. 1877-1888Article in journal (Refereed)
    Abstract [en]

    Gliomas account for approximately 80 % of all primary malignant brain tumors and, despite improvements in clinical care over the last 20 years, remain among the most lethal tumors, underscoring the need for gaining new insights that could translate into clinical advances. Recent genome-wide association studies (GWAS) have identified seven new susceptibility regions. We conducted a new independent GWAS of glioma using 1,856 cases and 4,955 controls (from 14 cohort studies, 3 case-control studies, and 1 population-based case-only study) and found evidence of strong replication for three of the seven previously reported associations at 20q13.33 (RTEL), 5p15.33 (TERT), and 9p21.3 (CDKN2BAS), and consistent association signals for the remaining four at 7p11.2 (EGFR both loci), 8q24.21 (CCDC26) and 11q23.3 (PHLDB1). The direction and magnitude of the signal were consistent for samples from cohort and case-control studies, but the strength of the association was more pronounced for loci rs6010620 (20q,13.33; RTEL) and rs2736100 (5p15.33, TERT) in cohort studies despite the smaller number of cases in this group, likely due to relatively more higher grade tumors being captured in the cohort studies. We further examined the 85 most promising single nucleotide polymorphism (SNP) markers identified in our study in three replication sets (5,015 cases and 11,601 controls), but no new markers reached genome-wide significance. Our findings suggest that larger studies focusing on novel approaches as well as specific tumor subtypes or subgroups will be required to identify additional common susceptibility loci for glioma risk.

  • 36. Robertson, Lindsay B
    et al.
    Armstrong, Georgina N
    Olver, Bianca D
    Lloyd, Amy L
    Shete, Sanjay
    Lau, Ching
    Claus, Elizabeth B
    Barnholtz-Sloan, Jill
    Lai, Rose
    Il'yasova, Dora
    Schildkraut, Joellen
    Bernstein, Jonine L
    Olson, Sara H
    Jenkins, Robert B
    Yang, Ping
    Rynearson, Amanda Lynn
    Wrensch, Margaret
    McCoy, Lucie
    Wienkce, John K
    McCarthy, Bridget
    Davis, Faith
    Vick, Nicholas A
    Johansen, Christoffer
    Bødtcher, Hanne
    Sadetzki, Siegal
    Bruchim, Revital Bar-Sade
    Yechezkel, Galit Hirsh
    Andersson, Ulrika
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Melin, Beatrice
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Bondy, Melissa L
    Houlston, Richard S
    Survey of familial glioma and role of germline p16INK4A/p14ARF and p53 mutation2010In: Familial Cancer, ISSN 1389-9600, E-ISSN 1573-7292, Vol. 9, no 3, p. 413-421Article in journal (Refereed)
    Abstract [en]

    There is increasing recognition of familial propensity to glioma as a distinct clinical entity beyond a few rare syndromes; however its genetic basis is poorly understood. The role of p16(INK4A)/p14(ARF) and p53 mutations in sporadic glioma provides a strong rationale for investigating germline mutations in these genes as a cause of familial glioma. To survey the familial glioma phenotype and examine the contribution of germline mutation in p16(INK4A)/p14(ARF) and p53 to the disease we have analyzed a series of 101 index familial cases collected through the GLIOGENE Consortium (http://braintumor.epigenetic.org/). There was little evidence for within family correlations for tumour histology, suggesting generic susceptibility to glial tumors. We did not detect any functional mutations in p16(INK4A) or p14(ARF). One index case with glioblastoma multiforme (GBM) diagnosed at age 54 and had a family history comprised of a paternal aunt with GBM at age 55, carried the p53 R158H mutation, which is predicted to be functional and has previously been implicated as a cause of Li-Fraumeni syndrome. Our findings provide no evidence that p16(INK4A)/p14(ARF) and p53 mutations contribute significantly to familial glioma.

  • 37. Sampson, Joshua N.
    et al.
    Wheeler, William A.
    Yeager, Meredith
    Panagiotou, Orestis
    Wang, Zhaoming
    Berndt, Sonja I.
    Lan, Qing
    Abnet, Christian C.
    Amundadottir, Laufey T.
    Figueroa, Jonine D.
    Landi, Maria Teresa
    Mirabello, Lisa
    Savage, Sharon A.
    Taylor, Philip R.
    De Vivo, Immaculata
    McGlynn, Katherine A.
    Purdue, Mark P.
    Rajaraman, Preetha
    Adami, Hans-Olov
    Ahlbom, Anders
    Albanes, Demetrius
    Amary, Maria Fernanda
    An, She-Juan
    Andersson, Ulrika
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Andriole, Gerald, Jr.
    Andrulis, Irene L.
    Angelucci, Emanuele
    Ansell, Stephen M.
    Arici, Cecilia
    Armstrong, Bruce K.
    Arslan, Alan A.
    Austin, Melissa A.
    Baris, Dalsu
    Barkauskas, Donald A.
    Bassig, Bryan A.
    Becker, Nikolaus
    Benavente, Yolanda
    Benhamou, Simone
    Berg, Christine
    Van Den Berg, David
    Bernstein, Leslie
    Bertrand, Kimberly A.
    Birmann, Brenda M.
    Black, Amanda
    Boeing, Heiner
    Boffetta, Paolo
    Boutron-Ruault, Marie-Christine
    Bracci, Paige M.
    Brinton, Louise
    Brooks-Wilson, Angela R.
    Bueno-de-Mesquita, H. Bas
    Burdett, Laurie
    Buring, Julie
    Butler, Mary Ann
    Cai, Qiuyin
    Cancel-Tassin, Geraldine
    Canzian, Federico
    Carrato, Alfredo
    Carreon, Tania
    Carta, Angela
    Chan, John K. C.
    Chang, Ellen T.
    Chang, Gee-Chen
    Chang, I-Shou
    Chang, Jiang
    Chang-Claude, Jenny
    Chen, Chien-Jen
    Chen, Chih-Yi
    Chen, Chu
    Chen, Chung-Hsing
    Chen, Constance
    Chen, Hongyan
    Chen, Kexin
    Chen, Kuan-Yu
    Chen, Kun-Chieh
    Chen, Ying
    Chen, Ying-Hsiang
    Chen, Yi-Song
    Chen, Yuh-Min
    Chien, Li-Hsin
    Chirlaque, Maria-Dolores
    Choi, Jin Eun
    Choi, Yi Young
    Chow, Wong-Ho
    Chung, Charles C.
    Clavel, Jacqueline
    Clavel-Chapelon, Franoise
    Cocco, Pierluigi
    Colt, Joanne S.
    Comperat, Eva
    Conde, Lucia
    Connors, Joseph M.
    Conti, David
    Cortessis, Victoria K.
    Cotterchio, Michelle
    Cozen, Wendy
    Crouch, Simon
    Crous-Bou, Marta
    Cussenot, Olivier
    Davis, Faith G.
    Ding, Ti
    Diver, W. Ryan
    Dorronsoro, Miren
    Dossus, Laure
    Duell, Eric J.
    Ennas, Maria Grazia
    Erickson, Ralph L.
    Feychting, Maria
    Flanagan, Adrienne M.
    Foretova, Lenka
    Fraumeni, Joseph F., Jr.
    Freedman, Neal D.
    Freeman, Laura E. Beane
    Fuchs, Charles
    Gago-Dominguez, Manuela
    Gallinger, Steven
    Gao, Yu-Tang
    Gapstur, Susan M.
    Garcia-Closas, Montserrat
    Garcia-Closas, Reina
    Gascoyne, Randy D.
    Gastier-Foster, Julie
    Gaudet, Mia M.
    Gaziano, J. Michael
    Giffen, Carol
    Giles, Graham G.
    Giovannucci, Edward
    Glimelius, Bengt
    Goggins, Michael
    Gokgoz, Nalan
    Goldstein, Alisa M.
    Gorlick, Richard
    Gross, Myron
    Grubb, Robert, III
    Gu, Jian
    Guan, Peng
    Gunter, Marc
    Guo, Huan
    Habermann, Thomas M.
    Haiman, Christopher A.
    Halai, Dina
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Hassan, Manal
    Hattinger, Claudia
    He, Qincheng
    He, Xingzhou
    Helzlsouer, Kathy
    Henderson, Brian
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Hjalgrim, Henrik
    Hoffman-Bolton, Judith
    Hohensee, Chancellor
    Holford, Theodore R.
    Holly, Elizabeth A.
    Hong, Yun-Chul
    Hoover, Robert N.
    Horn-Ross, Pamela L.
    Hosain, G. M. Monawar
    Hosgood, H. Dean, III
    Hsiao, Chin-Fu
    Hu, Nan
    Hu, Wei
    Hu, Zhibin
    Huang, Ming-Shyan
    Huerta, Jose-Maria
    Hung, Jen-Yu
    Hutchinson, Amy
    Inskip, Peter D.
    Jackson, Rebecca D.
    Jacobs, Eric J.
    Jenab, Mazda
    Jeon, Hyo-Sung
    Ji, Bu-Tian
    Jin, Guangfu
    Jin, Li
    Johansen, Christoffer
    Johnson, Alison
    Jung, Yoo Jin
    Kaaks, Rudolph
    Kamineni, Aruna
    Kane, Eleanor
    Kang, Chang Hyun
    Karagas, Margaret R.
    Kelly, Rachel S.
    Khaw, Kay-Tee
    Kim, Christopher
    Kim, Hee Nam
    Kim, Jin Hee
    Kim, Jun Suk
    Kim, Yeul Hong
    Kim, Young Tae
    Kim, Young-Chul
    Kitahara, Cari M.
    Klein, Alison P.
    Klein, Robert J.
    Kogevinas, Manolis
    Kohno, Takashi
    Kolonel, Laurence N.
    Kooperberg, Charles
    Kricker, Anne
    Krogh, Vittorio
    Kunitoh, Hideo
    Kurtz, Robert C.
    Kweon, Sun-Seog
    LaCroix, Andrea
    Lawrence, Charles
    Lecanda, Fernando
    Lee, Victor Ho Fun
    Li, Donghui
    Li, Haixin
    Li, Jihua
    Li, Yao-Jen
    Li, Yuqing
    Liao, Linda M.
    Liebow, Mark
    Lightfoot, Tracy
    Lim, Wei-Yen
    Lin, Chien-Chung
    Lin, Dongxin
    Lindstrom, Sara
    Linet, Martha S.
    Link, Brian K.
    Liu, Chenwei
    Liu, Jianjun
    Liu, Li
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Lloreta, Josep
    Di Lollo, Simonetta
    Lu, Daru
    Lund, Eiluv
    Malats, Nuria
    Mannisto, Satu
    Le Marchand, Loic
    Marina, Neyssa
    Masala, Giovanna
    Mastrangelo, Giuseppe
    Matsuo, Keitaro
    Maynadie, Marc
    Mckay, James
    McKean-Cowdin, Roberta
    Melbye, Mads
    Melin, Beatrice S.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Michaud, Dominique S.
    Mitsudomi, Tetsuya
    Monnereau, Alain
    Montalvan, Rebecca
    Moore, Lee E.
    Mortensen, Lotte Maxild
    Nieters, Alexandra
    North, Kari E.
    Novak, Anne J.
    Oberg, Ann L.
    Offit, Kenneth
    Oh, In-Jae
    Olson, Sara H.
    Palli, Domenico
    Pao, William
    Park, In Kyu
    Park, Jae Yong
    Park, Kyong Hwa
    Patino-Garcia, Ana
    Pavanello, Sofia
    Peeters, Petra H. M.
    Perng, Reury-Perng
    Peters, Ulrike
    Petersen, Gloria M.
    Picci, Piero
    Pike, Malcolm C.
    Porru, Stefano
    Prescott, Jennifer
    Prokunina-Olsson, Ludmila
    Qian, Biyun
    Qiao, You-Lin
    Rais, Marco
    Riboli, Elio
    Riby, Jacques
    Risch, Harvey A.
    Rizzato, Cosmeri
    Rodabough, Rebecca
    Roman, Eve
    Roupret, Morgan
    Ruder, Avima M.
    de Sanjose, Silvia
    Scelo, Ghislaine
    Schned, Alan
    Schumacher, Fredrick
    Schwartz, Kendra
    Schwenn, Molly
    Scotlandi, Katia
    Seow, Adeline
    Serra, Consol
    Serra, Massimo
    Sesso, Howard D.
    Setiawan, Veronica Wendy
    Severi, Gianluca
    Severson, Richard K.
    Shanafelt, Tait D.
    Shen, Hongbing
    Shen, Wei
    Shin, Min-Ho
    Shiraishi, Kouya
    Shu, Xiao-Ou
    Siddiq, Afshan
    Sierrasesumaga, Luis
    Sihoe, Alan Dart Loon
    Skibola, Christine F.
    Smith, Alex
    Smith, Martyn T.
    Southey, Melissa C.
    Spinelli, John J.
    Staines, Anthony
    Stampfer, Meir
    Stern, Marianna C.
    Stevens, Victoria L.
    Stolzenberg-Solomon, Rachael S.
    Su, Jian
    Su, Wu-Chou
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Sung, Jae Sook
    Sung, Sook Whan
    Tan, Wen
    Tang, Wei
    Tardon, Adonina
    Thomas, David
    Thompson, Carrie A.
    Tinker, Lesley F.
    Tirabosco, Roberto
    Tjonneland, Anne
    Travis, Ruth C.
    Trichopoulos, Dimitrios
    Tsai, Fang-Yu
    Tsai, Ying-Huang
    Tucker, Margaret
    Turner, Jenny
    Vajdic, Claire M.
    Vermeulen, Roel C. H.
    Villano, Danylo J.
    Vineis, Paolo
    Virtamo, Jarmo
    Visvanathan, Kala
    Wactawski-Wende, Jean
    Wang, Chaoyu
    Wang, Chih-Liang
    Wang, Jiu-Cun
    Wang, Junwen
    Wei, Fusheng
    Weiderpass, Elisabete
    Weiner, George J.
    Weinstein, Stephanie
    Wentzensen, Nicolas
    White, Emily
    Witzig, Thomas E.
    Wolpin, Brian M.
    Wong, Maria Pik
    Wu, Chen
    Wu, Guoping
    Wu, Junjie
    Wu, Tangchun
    Wu, Wei
    Wu, Xifeng
    Wu, Yi-Long
    Wunder, Jay S.
    Xiang, Yong-Bing
    Xu, Jun
    Xu, Ping
    Yang, Pan-Chyr
    Yang, Tsung-Ying
    Ye, Yuanqing
    Yin, Zhihua
    Yokota, Jun
    Yoon, Ho-Il
    Yu, Chong-Jen
    Yu, Herbert
    Yu, Kai
    Yuan, Jian-Min
    Zelenetz, Andrew
    Zeleniuch-Jacquotte, Anne
    Zhang, Xu-Chao
    Zhang, Yawei
    Zhao, Xueying
    Zhao, Zhenhong
    Zheng, Hong
    Zheng, Tongzhang
    Zheng, Wei
    Zhou, Baosen
    Zhu, Meng
    Zucca, Mariagrazia
    Boca, Simina M.
    Cerhan, James R.
    Ferri, Giovanni M.
    Hartge, Patricia
    Hsiung, Chao Agnes
    Magnani, Corrado
    Miligi, Lucia
    Morton, Lindsay M.
    Smedby, Karin E.
    Teras, Lauren R.
    Vijai, Joseph
    Wang, Sophia S.
    Brennan, Paul
    Caporaso, Neil E.
    Hunter, David J.
    Kraft, Peter
    Rothman, Nathaniel
    Silverman, Debra T.
    Slager, Susan L.
    Chanock, Stephen J.
    Chatterjee, Nilanjan
    Analysis of Heritability and Shared Heritability Based on Genome-Wide Association Studies for 13 Cancer Types2015In: Journal of the National Cancer Institute, ISSN 0027-8874, E-ISSN 1460-2105, Vol. 107, no 12, article id djv279Article in journal (Refereed)
    Abstract [en]

    Background: Studies of related individuals have consistently demonstrated notable familial aggregation of cancer. We aim to estimate the heritability and genetic correlation attributable to the additive effects of common single-nucleotide polymorphisms (SNPs) for cancer at 13 anatomical sites.

    Methods: Between 2007 and 2014, the US National Cancer Institute has generated data from genome-wide association studies (GWAS) for 49 492 cancer case patients and 34 131 control patients. We apply novel mixed model methodology (GCTA) to this GWAS data to estimate the heritability of individual cancers, as well as the proportion of heritability attributable to cigarette smoking in smoking-related cancers, and the genetic correlation between pairs of cancers.

    Results: GWAS heritability was statistically significant at nearly all sites, with the estimates of array-based heritability, h(l)(2), on the liability threshold (LT) scale ranging from 0.05 to 0.38. Estimating the combined heritability of multiple smoking characteristics, we calculate that at least 24% (95% confidence interval [CI] = 14% to 37%) and 7% (95% CI = 4% to 11%) of the heritability for lung and bladder cancer, respectively, can be attributed to genetic determinants of smoking. Most pairs of cancers studied did not show evidence of strong genetic correlation. We found only four pairs of cancers with marginally statistically significant correlations, specifically kidney and testes (rho = 0.73, SE = 0.28), diffuse large B-cell lymphoma (DLBCL) and pediatric osteosarcoma (rho = 0.53, SE = 0.21), DLBCL and chronic lymphocytic leukemia (CLL) (rho = 0.51, SE = 0.18), and bladder and lung (rho = 0.35, SE = 0.14). Correlation analysis also indicates that the genetic architecture of lung cancer differs between a smoking population of European ancestry and a nonsmoking Asian population, allowing for the possibility that the genetic etiology for the same disease can vary by population and environmental exposures.

    Conclusion: Our results provide important insights into the genetic architecture of cancers and suggest new avenues for investigation.

  • 38.
    Sandström, Maria
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Johansson, Mikael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Andersson, Ulrika
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. Patologi.
    Bergenheim, A Tommy
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience.
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    The tyrosine kinase inhibitor ZD6474 inhibits tumour growth in an intracerebral rat glioma model2004In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 91, no 6, p. 1174-1180Article in journal (Refereed)
  • 39. Shete, Sanjay
    et al.
    Hosking, Fay J
    Robertson, Lindsay B
    Dobbins, Sara E
    Sanson, Marc
    Malmer, Beatrice
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Simon, Matthias
    Marie, Yannick
    Boisselier, Blandine
    Delattre, Jean-Yves
    Hoang-Xuan, Khe
    El Hallani, Soufiane
    Idbaih, Ahmed
    Zelenika, Diana
    Andersson, Ulrika
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Bergenheim, A Tommy
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurosurgery.
    Feychting, Maria
    Lönn, Stefan
    Ahlbom, Anders
    Schramm, Johannes
    Linnebank, Michael
    Hemminki, Kari
    Kumar, Rajiv
    Hepworth, Sarah J
    Price, Amy
    Armstrong, Georgina
    Liu, Yanhong
    Gu, Xiangjun
    Yu, Robert
    Lau, Ching
    Schoemaker, Minouk
    Muir, Kenneth
    Swerdlow, Anthony
    Lathrop, Mark
    Bondy, Melissa
    Houlston, Richard S
    Genome-wide association study identifies five susceptibility loci for glioma.2009In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Nature genetics, ISSN 1546-1718, Vol. 41, no 8, p. 899-904Article in journal (Refereed)
    Abstract [en]

    To identify risk variants for glioma, we conducted a meta-analysis of two genome-wide association studies by genotyping 550K tagging SNPs in a total of 1,878 cases and 3,670 controls, with validation in three additional independent series totaling 2,545 cases and 2,953 controls. We identified five risk loci for glioma at 5p15.33 (rs2736100, TERT; P = 1.50 x 10(-17)), 8q24.21 (rs4295627, CCDC26; P = 2.34 x 10(-18)), 9p21.3 (rs4977756, CDKN2A-CDKN2B; P = 7.24 x 10(-15)), 20q13.33 (rs6010620, RTEL1; P = 2.52 x 10(-12)) and 11q23.3 (rs498872, PHLDB1; P = 1.07 x 10(-8)). These data show that common low-penetrance susceptibility alleles contribute to the risk of developing glioma and provide insight into disease causation of this primary brain tumor.

  • 40.
    Sjöström, Sara
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Andersson, Ulrika
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Liu, Yanhong
    Brännström, Thomas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Broholm, Helle
    Johansen, Christoffer
    Collatz-Laier, Helle
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Bondy, Melissa
    Melin, Beatrice
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Genetic variations in EGF and EGFR and glioblastoma outcome2010In: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 12, no 8, p. 815-821Article in journal (Refereed)
    Abstract [en]

    Few prognostic factors have been associated with glioblastoma survival. We analyzed a complete tagging of the epidermal growth factor (EGF) and EGF receptor (EGFR) gene polymorphisms as potential prognostic factors. Thirty tagging single-nucleotide polymorphisms (SNPs) in EGF and 89 tagging SNPs in EGFR were analyzed for association with survival in 176 glioblastoma cases. Validation analyses were performed for 4 SNPs in a set of 638 glioblastoma patients recruited at The University of Texas M. D. Anderson Cancer Center (MDACC). Three hundred and seventy-four glioblastoma patients aged 50 years or older at diagnosis were subanalyzed to enrich for de novo arising glioblastoma. We found 7 SNPs in haplotype 4 in EGF that were associated with prognosis in glioblastoma patients. In EGFR, 4 of 89 SNPs were significantly associated with prognosis but judged as false positives. Four of the significantly associated EGF polymorphisms in haplotype block 4 were validated in a set from MDACC; however, none of the associations were clearly replicated. rs379644 had a hazard ratio (HR) of 1.19 (0.94-1.51) in the whole population with 18.6 months survival in the risk genotype compared with 24.5 in the reference category. As the median age differed slightly between the 2 study sets, the MDACC cases aged 50 or older at diagnosis were analyzed separately (rs379644, HR 1.32 [0.99-1.78]), which is marginally significant and partially validates our findings. This study is, to our knowledge, the first to perform a comprehensive tagging of the EGF and EGFR genes, and the data give some support that EGF polymorphisms might be associated with poor prognosis. Further confirmation in independent data sets of prospective studies is necessary to establish EGF as prognostic risk factor.

  • 41.
    Sjöström, Sara
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Ghasimi, Soma
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Broholm, H.
    Brannstrom, Thomas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Johansen, C.
    Collatz-Laier, H.
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Andersson, Ulrika
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Melin, Beatrice
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    EGFR expression and glioblastoma outcome2012In: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 14, no Suppl. 3, p. 19-19Article in journal (Other academic)
  • 42.
    Sjöström, Sara
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Wibom, Carl
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Andersson, Ulrika
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Brännstrom, Thomas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Broholm, H
    Department of Pathology, The Center of Diagnostic Investigations, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
    Johansen, C
    Institute of Cancer Epidemiology, Danish Cancer Society, Copenhagen, Denmark.
    Collatz-Laier, H
    Department of ENT Head and Neck Surgery, Slagelse Hospital, Slagelse, Denmark.
    Liu, Y
    Department of Epidemiology, MD Anderson Cancer Center, Houston, TX, USA.
    Bondy, M
    Department of Epidemiology, MD Anderson Cancer Center, Houston, TX, USA.
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Melin, Beatrice
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Genetic variations in VEGF and VEGFR2 and glioblastoma outcome2011In: Journal of Neuro-Oncology, ISSN 0167-594X, E-ISSN 1573-7373, Vol. 104, no 2, p. 523-527Article in journal (Refereed)
    Abstract [en]

    Vascular endothelial growth factor (VEGF) and its receptors (VEGFR) are central components in the development and progression of glioblastoma. To investigate if genetic variation in VEGF and VEGFR2 is associated with glioblastoma prognosis, we examined blood samples from 154 glioblastoma cases collected in Sweden and Denmark between 2000 and 2004. Seventeen tagging single nucleotide polymorphisms (SNPs) in VEGF and 27 in VEGFR2 were genotyped and analysed, covering 90% of the genetic variability within the genes. In VEGF, we found no SNPs associated with survival. In VEGFR2, we found two SNPs significantly associated to survival, namely rs2071559 and rs12502008. However, these results are likely to be false positives due to multiple testing and could not be confirmed in a separate dataset. Overall, this study provides little evidence that VEGF and VEGFR2 polymorphisms are important for glioblastoma survival.

  • 43.
    Späth, Florentin
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Andersson, Ulrika
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Dahlin, Anna M.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology. Computational Life Science Cluster (CLiC), Umeå University, 901 87 Umeå, Sweden.
    Langseth, Hilde
    Hovig, Eivind
    Johannesen, Tom Borge
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Björkblom, Benny
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Wibom, Carl
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology. Computational Life Science Cluster (CLiC), Umeå University, 901 87 Umeå, Sweden.
    Melin, Beatrice
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Pre-diagnostic serum levels of EGFR and ErbB2 and genetic glioma risk variants: a nested case-control study2016In: Tumor Biology, ISSN 1010-4283, E-ISSN 1423-0380, Vol. 37, no 8, p. 11065-11072Article in journal (Refereed)
    Abstract [en]

    Genetic variants have been associated with the risk of developing glioma, but functional mechanisms on disease phenotypic traits remain to be investigated. One phenotypic trait of glioblastoma is the mutation and amplification of the epidermal growth factor receptor (EGFR) gene. We investigated associations between pre-diagnostic serum protein concentrations of EGFR and ErbB2, both members of the EGFR family, and future risk of glioma. Further, we studied if EGFR glioma risk variants were associated with EGFR and ErbB2 serum levels. We assessed the associations between genetic glioma risk variants and serum concentrations of EGFR and ErbB2, as measured in pre-diagnostic cohort serum samples of 593 glioma patients and 590 matched cancer-free controls. High serum EGFR and ErbB2 levels were associated with risk of developing glioblastoma (P = 0.008; OR = 1.58, 95 % CI = 1.13-2.22 and P = 0.017, OR = 1.63, 95 % CI = 1.09-2.44, respectively). High serum ErbB2 concentration was also associated with glioma risk overall (P = 0.049; OR = 1.39, 95 % CI = 1.00-1.93). Glioma risk variants were not associated with high serum protein abundance. In contrast, the EGFR risk variant rs4947986 (T) was correlated with decreased EGFR serum levels (study cohort P = 0.024 and controls P = 0.009). To our knowledge, this is the first study showing an association of EGFR and ErbB2 serum levels with glioma more than a decade before diagnosis, indicating that EGFR and ErbB2 serum proteins are important in early gliomagenesis. However, we did not find evidence that glioma risk variants were associated with high pre-diagnostic serum concentrations of EGFR and ErbB2.

  • 44. Wang, Zhaoming
    et al.
    Rajaraman, Preetha
    Melin, Beatrice S.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Chung, Charles C.
    Zhang, Weijia
    McKean-Cowdin, Roberta
    Michaud, Dominique
    Yeager, Meredith
    Ahlbom, Anders
    Albanes, Demetrius
    Andersson, Ulrika
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Freeman, Laura E. Beane
    Buring, Julie E.
    Butler, Mary Ann
    Carreon, Tania
    Feychting, Maria
    Gapstur, Susan M.
    Gaziano, J. Michael
    Giles, Graham G.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Biobank Research. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Hoffman-Bolton, Judith
    Inskip, Peter D.
    Kitahara, Cari M.
    Marchand, Loic Le
    Linet, Martha S.
    Li, Shengchao
    Peters, Ulrike
    Purdue, Mark P.
    Rothman, Nathaniel
    Ruder, Avima M.
    Sesso, Howard D.
    Severi, Gianluca
    Stampfer, Meir
    Stevens, Victoria L.
    Visvanathan, Kala
    Wang, Sophia S.
    White, Emily
    Zeleniuch-Jacquotte, Anne
    Hoover, Robert
    Fraumeni, Joseph F.
    Chatterjee, Nilanjan
    Hartge, Patricia
    Chanock, Stephen J.
    Further Confirmation of Germline Glioma Risk Variant rs78378222 in TP53 and Its Implication in Tumor Tissues via Integrative Analysis of TCGA Data2015In: Human Mutation, ISSN 1059-7794, E-ISSN 1098-1004, Vol. 36, no 7, p. 684-688Article in journal (Refereed)
    Abstract [en]

    We confirmed strong association of rs78378222:A>C (per allele odds ratio [OR] = 3.14; P = 6.48 x 10(-11)), a germline rare single-nucleotide polymorphism (SNP) in TP53, via imputation of a genome-wide association study of glioma (1,856 cases and 4,955 controls). We subsequently performed integrative analyses on the Cancer Genome Atlas (TCGA) data for GBM (glioblastoma multiforme) and LUAD (lung adenocarcinoma). Based on SNP data, we imputed genotypes for rs78378222 and selected individuals carrying rare risk allele (C). Using RNA sequencing data, we observed aberrant transcripts with approximate to 3 kb longer than normal for those individuals. Using exome sequencing data, we further showed that loss of haplotype carrying common protective allele (A) occurred somatically in GBM but not in LUAD. Our bioinformatic analysis suggests rare risk allele (C) disrupts mRNA termination, and an allelic loss of a genomic region harboring common protective allele (A) occurs during tumor initiation or progression for glioma.

  • 45. Wang, Zhaoming
    et al.
    Zhu, Bin
    Zhang, Mingfeng
    Parikh, Hemang
    Jia, Jinping
    Chung, Charles C
    Sampson, Joshua N
    Hoskins, Jason W
    Hutchinson, Amy
    Burdette, Laurie
    Ibrahim, Abdisamad
    Hautman, Christopher
    Raj, Preethi S
    Abnet, Christian C
    Adjei, Andrew A
    Ahlbom, Anders
    Albanes, Demetrius
    Allen, Naomi E
    Ambrosone, Christine B
    Aldrich, Melinda
    Amiano, Pilar
    Amos, Christopher
    Andersson, Ulrika
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Andriole, Gerald
    Andrulis, Irene L
    Arici, Cecilia
    Arslan, Alan A
    Austin, Melissa A
    Baris, Dalsu
    Barkauskas, Donald A
    Bassig, Bryan A
    Beane Freeman, Laura E
    Berg, Christine D
    Berndt, Sonja I
    Bertazzi, Pier Alberto
    Biritwum, Richard B
    Black, Amanda
    Blot, William
    Boeing, Heiner
    Boffetta, Paolo
    Bolton, Kelly
    Boutron-Ruault, Marie-Christine
    Bracci, Paige M
    Brennan, Paul
    Brinton, Louise A
    Brotzman, Michelle
    Bueno-de-Mesquita, H Bas
    Buring, Julie E
    Butler, Mary Ann
    Cai, Qiuyin
    Cancel-Tassin, Geraldine
    Canzian, Federico
    Cao, Guangwen
    Caporaso, Neil E
    Carrato, Alfredo
    Carreon, Tania
    Carta, Angela
    Chang, Gee-Chen
    Chang, I-Shou
    Chang-Claude, Jenny
    Che, Xu
    Chen, Chien-Jen
    Chen, Chih-Yi
    Chen, Chung-Hsing
    Chen, Constance
    Chen, Kuan-Yu
    Chen, Yuh-Min
    Chokkalingam, Anand P
    Chu, Lisa W
    Clavel-Chapelon, Francoise
    Colditz, Graham A
    Colt, Joanne S
    Conti, David
    Cook, Michael B
    Cortessis, Victoria K
    Crawford, E David
    Cussenot, Olivier
    Davis, Faith G
    De Vivo, Immaculata
    Deng, Xiang
    Ding, Ti
    Dinney, Colin P
    Di Stefano, Anna Luisa
    Diver, W Ryan
    Duell, Eric J
    Elena, Joanne W
    Fan, Jin-Hu
    Feigelson, Heather Spencer
    Feychting, Maria
    Figueroa, Jonine D
    Flanagan, Adrienne M
    Fraumeni, Joseph F
    Freedman, Neal D
    Fridley, Brooke L
    Fuchs, Charles S
    Gago-Dominguez, Manuela
    Gallinger, Steven
    Gao, Yu-Tang
    Gapstur, Susan M
    Garcia-Closas, Montserrat
    Garcia-Closas, Reina
    Gastier-Foster, Julie M
    Gaziano, J Michael
    Gerhard, Daniela S
    Giffen, Carol A
    Giles, Graham G
    Gillanders, Elizabeth M
    Giovannucci, Edward L
    Goggins, Michael
    Gokgoz, Nalan
    Goldstein, Alisa M
    Gonzalez, Carlos
    Gorlick, Richard
    Greene, Mark H
    Gross, Myron
    Grossman, H Barton
    Grubb, Robert
    Gu, Jian
    Guan, Peng
    Haiman, Christopher A
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Biobank Research. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Hankinson, Susan E
    Harris, Curtis C
    Hartge, Patricia
    Hattinger, Claudia
    Hayes, Richard B
    He, Qincheng
    Helman, Lee
    Henderson, Brian E
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Hoffman-Bolton, Judith
    Hohensee, Chancellor
    Holly, Elizabeth A
    Hong, Yun-Chul
    Hoover, Robert N
    Hosgood, H Dean
    Hsiao, Chin-Fu
    Hsing, Ann W
    Hsiung, Chao Agnes
    Hu, Nan
    Hu, Wei
    Hu, Zhibin
    Huang, Ming-Shyan
    Hunter, David J
    Inskip, Peter D
    Ito, Hidemi
    Jacobs, Eric J
    Jacobs, Kevin B
    Jenab, Mazda
    Ji, Bu-Tian
    Johansen, Christoffer
    Johansson, Mattias
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine. International Agency for Research on Cancer (IARC-WHO), Lyon, France.
    Johnson, Alison
    Kaaks, Rudolf
    Kamat, Ashish M
    Kamineni, Aruna
    Karagas, Margaret
    Khanna, Chand
    Khaw, Kay-Tee
    Kim, Christopher
    Kim, In-Sam
    Kim, Jin Hee
    Kim, Yeul Hong
    Kim, Young-Chul
    Kim, Young Tae
    Kang, Chang Hyun
    Jung, Yoo Jin
    Kitahara, Cari M
    Klein, Alison P
    Klein, Robert
    Kogevinas, Manolis
    Koh, Woon-Puay
    Kohno, Takashi
    Kolonel, Laurence N
    Kooperberg, Charles
    Kratz, Christian P
    Krogh, Vittorio
    Kunitoh, Hideo
    Kurtz, Robert C
    Kurucu, Nilgun
    Lan, Qing
    Lathrop, Mark
    Lau, Ching C
    Lecanda, Fernando
    Lee, Kyoung-Mu
    Lee, Maxwell P
    Le Marchand, Loic
    Lerner, Seth P
    Li, Donghui
    Liao, Linda M
    Lim, Wei-Yen
    Lin, Dongxin
    Lin, Jie
    Lindstrom, Sara
    Linet, Martha S
    Lissowska, Jolanta
    Liu, Jianjun
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Lloreta, Josep
    Lu, Daru
    Ma, Jing
    Malats, Nuria
    Mannisto, Satu
    Marina, Neyssa
    Mastrangelo, Giuseppe
    Matsuo, Keitaro
    McGlynn, Katherine A
    McKean-Cowdin, Roberta
    McNeill, Lorna H
    McWilliams, Robert R
    Melin, Beatrice S
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Meltzer, Paul S
    Mensah, James E
    Miao, Xiaoping
    Michaud, Dominique S
    Mondul, Alison M
    Moore, Lee E
    Muir, Kenneth
    Niwa, Shelley
    Olson, Sara H
    Orr, Nick
    Panico, Salvatore
    Park, Jae Yong
    Patel, Alpa V
    Patino-Garcia, Ana
    Pavanello, Sofia
    Peeters, Petra H M
    Peplonska, Beata
    Peters, Ulrike
    Petersen, Gloria M
    Picci, Piero
    Pike, Malcolm C
    Porru, Stefano
    Prescott, Jennifer
    Pu, Xia
    Purdue, Mark P
    Qiao, You-Lin
    Rajaraman, Preetha
    Riboli, Elio
    Risch, Harvey A
    Rodabough, Rebecca J
    Rothman, Nathaniel
    Ruder, Avima M
    Ryu, Jeong-Seon
    Sanson, Marc
    Schned, Alan
    Schumacher, Fredrick R
    Schwartz, Ann G
    Schwartz, Kendra L
    Schwenn, Molly
    Scotlandi, Katia
    Seow, Adeline
    Serra, Consol
    Serra, Massimo
    Sesso, Howard D
    Severi, Gianluca
    Shen, Hongbing
    Shen, Min
    Shete, Sanjay
    Shiraishi, Kouya
    Shu, Xiao-Ou
    Siddiq, Afshan
    Sierrasesumaga, Luis
    Sierri, Sabina
    Loon Sihoe, Alan Dart
    Silverman, Debra T
    Simon, Matthias
    Southey, Melissa C
    Spector, Logan
    Spitz, Margaret
    Stampfer, Meir
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Stern, Mariana C
    Stevens, Victoria L
    Stolzenberg-Solomon, Rachael Z
    Stram, Daniel O
    Strom, Sara S
    Su, Wu-Chou
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Sung, Sook Whan
    Swerdlow, Anthony
    Tan, Wen
    Tanaka, Hideo
    Tang, Wei
    Tang, Ze-Zhang
    Tardon, Adonina
    Tay, Evelyn
    Taylor, Philip R
    Tettey, Yao
    Thomas, David M
    Tirabosco, Roberto
    Tjonneland, Anne
    Tobias, Geoffrey S
    Toro, Jorge R
    Travis, Ruth C
    Trichopoulos, Dimitrios
    Troisi, Rebecca
    Truelove, Ann
    Tsai, Ying-Huang
    Tucker, Margaret A
    Tumino, Rosario
    Van Den Berg, David
    Van Den Eeden, Stephen K
    Vermeulen, Roel
    Vineis, Paolo
    Visvanathan, Kala
    Vogel, Ulla
    Wang, Chaoyu
    Wang, Chengfeng
    Wang, Junwen
    Wang, Sophia S
    Weiderpass, Elisabete
    Weinstein, Stephanie J
    Wentzensen, Nicolas
    Wheeler, William
    White, Emily
    Wiencke, John K
    Wolk, Alicja
    Wolpin, Brian M
    Wong, Maria Pik
    Wrensch, Margaret
    Wu, Chen
    Wu, Tangchun
    Wu, Xifeng
    Wu, Yi-Long
    Wunder, Jay S
    Xiang, Yong-Bing
    Xu, Jun
    Yang, Hannah P
    Yang, Pan-Chyr
    Yatabe, Yasushi
    Ye, Yuanqing
    Yeboah, Edward D
    Yin, Zhihua
    Ying, Chen
    Yu, Chong-Jen
    Yu, Kai
    Yuan, Jian-Min
    Zanetti, Krista A
    Zeleniuch-Jacquotte, Anne
    Zheng, Wei
    Zhou, Baosen
    Mirabello, Lisa
    Savage, Sharon A
    Kraft, Peter
    Chanock, Stephen J
    Yeager, Meredith
    Landi, Maria Terese
    Shi, Jianxin
    Chatterjee, Nilanjan
    Amundadottir, Laufey T
    Imputation and subset-based association analysis across different cancer types identifies multiple independent risk loci in the TERT-CLPTM1L region on chromosome 5p15.332014In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 23, no 24, p. 6616-6633Article in journal (Refereed)
    Abstract [en]

    Genome-wide association studies (GWAS) have mapped risk alleles for at least 10 distinct cancers to a small region of 63 000 bp on chromosome 5p15.33. This region harbors the TERT and CLPTM1L genes; the former encodes the catalytic subunit of telomerase reverse transcriptase and the latter may play a role in apoptosis. To investigate further the genetic architecture of common susceptibility alleles in this region, we conducted an agnostic subset-based meta-analysis (association analysis based on subsets) across six distinct cancers in 34 248 cases and 45 036 controls. Based on sequential conditional analysis, we identified as many as six independent risk loci marked by common single-nucleotide polymorphisms: five in the TERT gene (Region 1: rs7726159, P = 2.10 × 10(-39); Region 3: rs2853677, P = 3.30 × 10(-36) and PConditional = 2.36 × 10(-8); Region 4: rs2736098, P = 3.87 × 10(-12) and PConditional = 5.19 × 10(-6), Region 5: rs13172201, P = 0.041 and PConditional = 2.04 × 10(-6); and Region 6: rs10069690, P = 7.49 × 10(-15) and PConditional = 5.35 × 10(-7)) and one in the neighboring CLPTM1L gene (Region 2: rs451360; P = 1.90 × 10(-18) and PConditional = 7.06 × 10(-16)). Between three and five cancers mapped to each independent locus with both risk-enhancing and protective effects. Allele-specific effects on DNA methylation were seen for a subset of risk loci, indicating that methylation and subsequent effects on gene expression may contribute to the biology of risk variants on 5p15.33. Our results provide strong support for extensive pleiotropy across this region of 5p15.33, to an extent not previously observed in other cancer susceptibility loci.

  • 46.
    Wibom, Carl
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Ghasimi, Soma
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Van Loo, P.
    Brännström, Thomas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Trygg, Johan
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Bergenheim, Tommy
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Andersson, Ulrika
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Ryden, Patrik
    Umeå University, Faculty of Science and Technology, Department of Mathematics and Mathematical Statistics.
    Melin, Beatrice
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    EGFR gene variants are associated with specific somatic aberrations in glioma2012In: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 14, no Suppl. 3, p. 46-46Article in journal (Other academic)
  • 47.
    Wibom, Carl
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Ghasimi, Soma
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Van Loo, Peter
    Brännström, Thomas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Trygg, Johan
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Lau, Ching
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Bergenheim, Tommy
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Andersson, Ulrika
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Rydén, Patrik
    Umeå University, Faculty of Science and Technology, Department of Mathematics and Mathematical Statistics.
    Melin, Beatrice
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    EGFR gene variants are associated with specific somatic aberrations in glioma2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 12, p. e47929-Article in journal (Refereed)
    Abstract [en]

    A number of gene variants have been associated with an increased risk of developing glioma. We hypothesized that the reported risk variants may be associated with tumor genomic instability. To explore potential correlations between germline risk variants and somatic genetic events, we analyzed matched tumor and blood samples from 95 glioma patients by means of SNP genotyping. The generated genotype data was used to calculate genome-wide allele-specific copy number profiles of the tumor samples. We compared the copy number profiles across samples and found two EGFR gene variants (rs17172430 and rs11979158) that were associated with homozygous deletion at the CDKN2A/B locus. One of the EGFR variants (rs17172430) was also associated with loss of heterozygosity at the EGFR locus. Our findings were confirmed in a separate dataset consisting of matched blood and tumor samples from 300 glioblastoma patients, compiled from publically available TCGA data. These results imply there is a functional effect of germline EGFR variants on tumor progression.

  • 48.
    Wibom, Carl
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Sjöström, Sara
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Brännström, Thomas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Broholm, Helle
    Rydén, Patrik
    Umeå University, Faculty of Science and Technology, Department of Mathematics and Mathematical Statistics.
    Johansen, Christoffer
    Collatz-Laier, Helle
    Hepworth, Sara
    McKinney, Patricia A
    Bethke, Lara
    Houlston, Richard S
    Andersson, Ulrika
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Melin, Beatrice S
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    DNA-repair gene variants are associated with glioblastoma survival2012In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 51, no 3, p. 325-332Article in journal (Refereed)
    Abstract [en]

    Patient outcome from glioma may be influenced by germline variation. Considering the importance of DNA repair in cancer biology as well as in response to treatment, we studied the relationship between 1458 SNPs, which captured the majority of the common genetic variation in 136 DNA repair genes, in 138 glioblastoma samples from Sweden and Denmark. We confirmed our findings in an independent cohort of 121 glioblastoma patients from the UK. Our analysis revealed nine SNPs annotating MSH2, RAD51L1 and RECQL4 that were significantly (p < 0.05) associated with glioblastoma survival.

  • 49.
    Wibom, Carl
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Spaeth, Florentin
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Dahlin, Anna
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Langseth, H.
    Cancer Registry of Norway, Oslo, Norway.
    Hovig, E.
    University of Oslo, Oslo, Norway.
    Rajaraman, P.
    National Cancer Institute, Rockville, MD, United States.
    Andersson, Ulrika
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Melin, Beatrice
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Glioma Gwas Hits - Markers for Risk or for Prognosis?2014In: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 16, no Suppl. 2, p. ii109-ii110Article in journal (Refereed)
    Abstract [en]

    One obstacle to developing new treatments for glioma is the generally poor understanding of glioma aetiology. The only generally accepted environmental risk factor or glioma is ionizing radiation. Glioma aetiology has also been shown to contain a genetic component, in part through observations that individuals in families with a history of glioma have an elevated risk of developing glioma themselves. The genetic component in glioma aetiology has been further substantiated through genome wide association studies (GWAS). These studies have identified associations between a number of common genetic variants and an increased glioma risk. However, the studies have all been of case-control design (i.e. including cases at diagnosis), and as such they presumably suffer from a degree of survival bias. Survival bias risks being introduced in a study when rapidly fatal cases are not included. This is an inherent risk of case-control designs, which is particularly pronounced when studying a disease with very poor prognosis, such as glioma. Ultimately, survival bias may result in erroneous conclusions, as it is impossible to separate associations with prognosis from associations with risk of disease. To accurately confirm previously identified glioma risk variants, and ascertain whether they are associated with risk or with prolonged survival, we investigated these variants in a set of pre-diagnostic serum samples (594 cases and 591 matched controls). Analyses of population based, pre-diagnostic samples eliminates the risk of survival bias, and enables distinction between genetic variants associated with glioma risk (i.e. aetiology) and genetic variants associated with prognosis. The serum samples were acquired through The Janus Serum Bank, a Norwegian population based biobank reserved for cancer research. Variant detection was achieved by means of cycling temperature capillary electrophoresis. Our investigation confirmed the association with glioma risk for the investigated variants within five genomic regions; 8q24.21 (CCDC26), 9p21.3 (CDKN2B-AS1), 11q23.3 (PHLDB1), 17p13.1 (TP53), and 20q13.33 (RTEL1). This is indicative of these variants being truly associated with glioma risk, and thus may impact gliomagenesis. However, previously identified risk variants within the 5p15.33 (TERT) and 7p11.2 (EGFR) could not be positively confirmed by this study. The lack of positive confirmation raises the question whether EGFR and TERT genetic variants are linked with prolonged survival, rather than with glioma aetiology.

  • 50.
    Wibom, Carl
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Späth, Florentin
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Dahlin, Anna M.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Langseth, Hilde
    Hovig, Eivind
    Rajaraman, Preetha
    Johannesen, Tom Borge
    Andersson, Ulrika
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Melin, Beatrice
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Investigation of Established Genetic Risk Variants for Glioma in Prediagnostic Samples from a Population-Based Nested Case-Control Study2015In: Cancer Epidemiology, Biomarkers and Prevention, ISSN 1055-9965, E-ISSN 1538-7755, Vol. 24, no 5, p. 810-816Article in journal (Refereed)
    Abstract [en]

    Background: Although glioma etiology is poorly understood in general, growing evidence indicates a genetic component. Four large genome-wide association studies (GWAS) have linked common genetic variants with an increased glioma risk. However, to date, these studies are based largely on a case-control design, where cases have been recruited at the time of or after diagnosis. They may therefore suffer from a degree of survival bias, introduced when rapidly fatal cases are not included.

    Methods: To confirm glioma risk variants in a prospective setting, we have analyzed 11 previously identified risk variants in a set of prediagnostic serum samples with 598 cases and 595 matched controls. Serum samples were acquired from The Janus Serum Bank, a Norwegian population-based biobank reserved for cancer research.

    Results: We confirmed the association with glioma risk for variants within five genomic regions: 8q24.21 (CCDC26), 9p21.3 (CDKN2B-AS1), 11q23.3 (PHLDB1), 17p13.1 (TP53), and 20q13.33 (RTEL1). However, previously identified risk variants within the 7p11.2 (EGFR) region were not confirmed by this study.

    Conclusions: Our results indicate that the risk variants that were confirmed by this study are truly associated with glioma risk and may, consequently, affect gliomagenesis. Though the lack of positive confirmation of EGFR risk variants may be attributable to relatively limited statistical power, it nevertheless raises the question whether they truly are risk variants or markers for glioma prognosis.

    Impact: Our findings indicate the need for further studies to clarify the role of glioma risk loci with respect to prolonged survival versus etiology.

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