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  • 1.
    Andersson, Ulrika
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper.
    Experimental studies in brain tumours: with special regard to multidrug resistance and the ErbB-family2005Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    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 universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Degerman, Sofie
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Dahlin, Anna
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Brannstrom, Thomas
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Roos, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Melin, B. S.
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    TELOMERE LENGTH, ALLERGIES AND RISK OF GLIOMA2017Ingår i: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 19, nr Supplement: 3, s. 23-23, artikel-id Meeting Abstract: P01.03Artikel i tidskrift (Refereegranskat)
  • 3.
    Andersson, Ulrika
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Degerman, Sofie
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Dahlin, Anna M.
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Wibom, Carl
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Johansson, Gunnar
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Bondy, Melissa L.
    Melin, Beatrice S.
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    The association between longer relative leukocyte telomere length and risk of glioma is independent of the potentially confounding factors allergy, BMI, and smoking2019Ingår i: Cancer Causes and Control, ISSN 0957-5243, E-ISSN 1573-7225, Vol. 30, nr 2, s. 177-185Artikel i tidskrift (Refereegranskat)
    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 universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Grankvist, Kjell
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Bergenheim, A. Tommy
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Neurokirurgi.
    Behnam-Motlagh, Parviz
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Hedman, Håkan
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Henriksson, Roger
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Rapid induction of long-lasting drug efflux activity in brain vascular endothelial cells but not malignant glioma following irradiation2002Ingår i: Medical Oncology, ISSN 1357-0560, E-ISSN 1559-131X, Vol. 19, nr 1, s. 1-9Artikel i tidskrift (Refereegranskat)
    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 universitet, Medicinsk fakultet, Strålningsvetenskaper, Onkologi.
    Guo, Dongsheng
    Umeå universitet, Medicinsk fakultet, Strålningsvetenskaper, Onkologi.
    Malmer, Beatrice
    Umeå universitet, Medicinsk fakultet, Strålningsvetenskaper, Onkologi.
    Bergenheim, A Tommy
    Umeå universitet, Medicinsk fakultet, Farmakologi och klinisk neurovetenskap, Neurokirurgi.
    Brännström, Thomas
    Umeå universitet, Medicinsk fakultet, Medicinsk biovetenskap, Patologi.
    Hedman, Håkan
    Umeå universitet, Medicinsk fakultet, Strålningsvetenskaper, Onkologi.
    Henriksson, Roger
    Umeå universitet, Medicinsk fakultet, Strålningsvetenskaper, Onkologi.
    Epidermal growth factor receptor family (EGFR, ErbB2-4) in gliomas and meningiomas2004Ingår i: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 108, nr 2, s. 135-142Artikel i tidskrift (Refereegranskat)
    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 universitet, Medicinsk fakultet, Strålningsvetenskaper, Onkologi.
    Johansson, David
    Umeå universitet, Medicinsk fakultet, Medicinsk biovetenskap, Klinisk kemi.
    Behnam-Motlagh, Parviz
    Umeå universitet, Medicinsk fakultet, Strålningsvetenskaper, Onkologi.
    Johansson, Mikael
    Umeå universitet, Medicinsk fakultet, Strålningsvetenskaper, Onkologi.
    Malmer, Beatrice
    Umeå universitet, Medicinsk fakultet, Strålningsvetenskaper, Onkologi.
    Treatment schedule is of importance when gefitinib is combined with irradiation of glioma and endothelial cells in vitro.2007Ingår i: Acta Oncologica, ISSN 0284-186X, Vol. 46, nr 7, s. 951-960Artikel i tidskrift (Refereegranskat)
  • 7.
    Andersson, Ulrika
    et al.
    Umeå universitet, Medicinsk fakultet, Strålningsvetenskaper, Onkologi.
    Malmer, Beatrice
    Umeå universitet, Medicinsk fakultet, Strålningsvetenskaper, Onkologi.
    Bergenheim, A Tommy
    Umeå universitet, Medicinsk fakultet, Farmakologi och klinisk neurovetenskap, Neurokirurgi.
    Brännström, Thomas
    Umeå universitet, Medicinsk fakultet, Medicinsk biovetenskap, Patologi.
    Henriksson, Roger
    Umeå universitet, Medicinsk fakultet, Strålningsvetenskaper, Onkologi.
    Heterogeneity in the expression of markers for drug resistance in brain tumors2004Ingår i: Clinical Neuropathology, ISSN 0722-5091, Vol. 23, nr 1, s. 21-27Artikel i tidskrift (Refereegranskat)
    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 universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    McKean-Cowdin, Roberta
    Hjalmars, Ulf
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Malmer, Beatrice
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Genetic variants in association studies: review of strengths and weaknesses in study design and current knowledge of impact on cancer risk2009Ingår i: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 48, nr 7, s. 948-954Artikel i tidskrift (Refereegranskat)
    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 universitet, Medicinsk fakultet, Strålningsvetenskaper, Onkologi.
    Osterman, Pia
    Umeå universitet, Medicinsk fakultet, Medicinsk biovetenskap, Patologi.
    Sjöström, Sara
    Umeå universitet, Medicinsk fakultet, Strålningsvetenskaper, Onkologi.
    Johansen, Christoffer
    Henriksson, Roger
    Umeå universitet, Medicinsk fakultet, Strålningsvetenskaper, Onkologi.
    Brännström, Thomas
    Umeå universitet, Medicinsk fakultet, Medicinsk biovetenskap, Patologi.
    Broholm, Helle
    Christensen, Helle Collatz
    Ahlbom, Anders
    Auvinen, Anssi
    Feychting, Maria
    Lönn, Stefan
    Kiuru, Anne
    Swerdlow, Anthony
    Schoemaker, Minouk
    Roos, Göran
    Umeå universitet, Medicinsk fakultet, Medicinsk biovetenskap, Patologi.
    Malmer, Beatrice
    Umeå universitet, Medicinsk fakultet, Strålningsvetenskaper, Onkologi.
    MNS16A minisatellite genotypes in relation to risk of glioma and meningioma and to glioblastoma outcome.2009Ingår i: International journal of cancer. Journal international du cancer, ISSN 1097-0215, Vol. 125, nr 4, s. 968-972Artikel i tidskrift (Refereegranskat)
    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 universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Schwartzbaum, Judith
    Wiklund, Fredrik
    Sjöström, Sara
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    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 universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Bondy, Melissa
    Melin, Beatrice
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    A comprehensive study of the association between the EGFR and ERBB2 genes and glioma risk2010Ingår i: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 49, nr 6, s. 767-775Artikel i tidskrift (Refereegranskat)
    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 universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Wibom, Carl
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Cederquist, Kristina
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    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 universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Germline rearrangements in families with strong family history of glioma and malignant melanoma, colon, and breast cancer2014Ingår i: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 16, nr 10, s. 1333-1340Artikel i tidskrift (Refereegranskat)
    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 universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Sjöström, Sara
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Henriksson, Roger
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Brännström, Thomas
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Broholm, Helle
    Johansson, Christoffer
    Fleming, Sarah J
    McKinney, Patricia A
    Bethke, Lara
    Houlston, Richard
    Smits, Anja
    Andersson, Ulrika
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Melin, Beatrice S
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Analysis of DNA repair gene polymorphisms and survival in low-grade and anaplastic gliomas2011Ingår i: Journal of Neuro-Oncology, ISSN 0167-594X, E-ISSN 1573-7373, Vol. 105, nr 3, s. 531-538Artikel i tidskrift (Refereegranskat)
    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 universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Wibom, Carl
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Jonsson, Pär
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Mörén, Lina
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Andersson, Ulrika
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Johannesen, Tom Borge
    langseth, Hilde
    Antti, Henrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Melin, Beatrice
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Metabolomic screening of pre-diagnostic serum samples identifies association between alpha- and gamma-tocopherols and glioblastoma risk2016Ingår i: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 7, nr 24, s. 37043-37053Artikel i tidskrift (Refereegranskat)
    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 universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Hollegaard, Mads V.
    Wibom, Carl
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Andersson, Ulrika
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Hougaard, David M.
    Deltour, Isabelle
    Hjalmars, Ulf
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Melin, Beatrice
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    CCND2, CTNNB1, DDX3X, GLI2, SMARCA4, MYC, MYCN, PTCH1, TP53, and MLL2 gene variants and risk of childhood medulloblastoma2015Ingår i: Journal of Neuro-Oncology, ISSN 0167-594X, E-ISSN 1573-7373, Vol. 125, nr 1, s. 75-78Artikel i tidskrift (Refereegranskat)
    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 universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Wibom, Carl
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Andersson, Ulrika
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Hougaard, David M.
    Bybjerg-Grauholm, Jonas
    Deltour, Isabelle
    Hultman, Christina M.
    Kähler, Anna K.
    Karlsson, Robert
    Hjalmars, Ulf
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Melin, Beatrice S.
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Genetic Variants in the 9p21.3 Locus Associated with Glioma Risk in Children, Adolescents, and Young Adults: A Case-Control Study2019Ingår i: Cancer Epidemiology, Biomarkers and Prevention, ISSN 1055-9965, E-ISSN 1538-7755, Vol. 28, nr 7, s. 1252-1258Artikel i tidskrift (Refereegranskat)
    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 universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Wibom, Carl
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Ghasimi, Soma
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Brännström, Thomas
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Andersson, Ulrika
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Melin, Beatrice
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Relation between Established Glioma Risk Variants and DNA Methylation in the Tumor2016Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, nr 10, artikel-id e0163067Artikel i tidskrift (Refereegranskat)
    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 universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Feychting, Maria
    Johansen, Christoffer
    Andersson, Ulrika
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Brännström, Thomas
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap.
    Schramm, Johannes
    Olver, Bianca
    Lloyd, Amy
    Ma, Yussanne P.
    Hosking, Fay J.
    Lönn, Stefan
    Ahlbom, Anders
    Henriksson, Roger
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    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 risk2011Ingår i: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 43, nr 9, s. 825-827Artikel i tidskrift (Refereegranskat)
    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 universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Haapasalo, H.
    Eray, M.
    Korhonen, K.
    Brannstrom, Thomas
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Hedman, Håkan
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Andersson, Ulrika
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Immunohistochemical analysis of LRIG proteins in meningiomas: correlation between estrogen receptor status and LRIG expression2012Ingår i: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 14, nr Suppl 3, s. 69-69Artikel i tidskrift (Övrigt vetenskapligt)
  • 19.
    Ghasimi, Soma
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper.
    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 universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap.
    Hedman, Håkan
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper.
    Andersson, Ulrika
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper.
    Immunohistochemical analysis of LRIG proteins in meningiomas: correlation between estrogen receptor status and LRIG expression2012Ingår i: Journal of Neuro-Oncology, ISSN 0167-594X, E-ISSN 1573-7373, Vol. 108, nr 3, s. 435-441Artikel i tidskrift (Refereegranskat)
    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 universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Wibom, Carl
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Brännström, Thomas
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Haapasalo, H
    Eray, M
    Dobbins, S
    Henriksson, Roger
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Ahlbom, A
    Auvinen, A
    Collatz-Laier, H
    Feychting, M
    Johansen, C
    Kiuru, A
    Houlston, R
    Melin, Beatrice
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Andersson, Ulrika
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Genetic variants in EGF, EGFR, ERBB2, LRIG2, LRIG3 and meningioma riskManuskript (preprint) (Övrigt vetenskapligt)
  • 21.
    Ghasimi, Soma
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Wibom, Carl
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Dahlin, Anna
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Brännström, Thomas
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Golovleva, Irina
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Andersson, Ulrika
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Melin, Beatrice
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Genetic risk variants in the EGFR regions are associated with copy number variation in the EGFR gene as well as IDH1, and p53 protein expressionManuskript (preprint) (Övrigt vetenskapligt)
  • 22.
    Ghasimi, Soma
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Wibom, Carl
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Dahlin, Anna M.
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Brännström, Thomas
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Golovleva, Irina
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Andersson, Ulrika
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Melin, Beatrice
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Genetic risk variants in the CDKN2A/B, RTEL1 and EGFR genes are associated with somatic biomarkers in glioma2016Ingår i: Journal of Neuro-Oncology, ISSN 0167-594X, E-ISSN 1573-7373, Vol. 127, nr 3, s. 483-492Artikel i tidskrift (Refereegranskat)
    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 universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    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 universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Näringsforskning.
    Hankinson, Susan E
    Hartge, Patricia
    Henriksson, Roger
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Inskip, Peter D
    Johansen, Christoffer
    Landgren, Annelie
    McKean-Cowdin, Roberta
    Michaud, Dominique S
    Melin, Beatrice S
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    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.2012Ingår i: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 44, nr 6, s. 651-658Artikel i tidskrift (Refereegranskat)
    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 universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Johansson, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi, Parodontologi.
    Grankvist, Kjell
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Andersson, Ulrika
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Henriksson, Roger
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Bergström, Per
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Brännström, Thomas
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Behnam Motlagh, Parviz
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Verotoxin-1 Induction of Apoptosis in Gb3-Expressing Human Glioma Cell Lines2006Ingår i: Cancer Biology & Therapy, ISSN 1538-4047, E-ISSN 1555-8576, Vol. 5, nr 9, s. 1211-1217Artikel i tidskrift (Refereegranskat)
    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 universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Andersson, Ulrika
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Melin, Beatrice
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Recent developments in brain tumor predisposing syndromes2016Ingår i: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 55, nr 4, s. 401-411Artikel, forskningsöversikt (Refereegranskat)
    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 universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Wang, Zhaoming
    Braganza, Melissa
    Inskip, Peter D
    Albanes, Demetrius
    Andersson, Ulrika
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Beane Freeman, Laura E
    Buring, Julie E
    Carreón, Tania
    Feychting, Maria
    Gapstur, Susan M
    Gaziano, J Michael
    Giles, Graham G
    Hallmans, Goran
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Näringsforskning.
    Hankinson, Susan E
    Henriksson, Roger
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    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.2012Ingår i: International Journal of Epidemiology, ISSN 0300-5771, E-ISSN 1464-3685, Vol. 41, nr 4, s. 1075-1085Artikel i tidskrift (Refereegranskat)
    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 universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    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 universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    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 glioma2012Ingår i: Human Genetics, ISSN 0340-6717, E-ISSN 1432-1203, Vol. 131, nr 9, s. 1507-1517Artikel i tidskrift (Refereegranskat)
    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 universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Melin, Beatrice S
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Bondy, Melissa
    Polymorphisms of LIG4, BTBD2, HMGA2, and RTEL1 genes involved in the double-strand break repair pathway predict glioblastoma survival2010Ingår i: Journal of Clinical Oncology, ISSN 0732-183X, E-ISSN 1527-7755, Vol. 28, nr 14, s. 2467-2474Artikel i tidskrift (Refereegranskat)
    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 universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Dahlin, Anna M
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Andersson, Ulrika
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Wang, Zhaoming
    Henriksson, Roger
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Hallmans, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Näringsforskning. Umeå universitet, Medicinska fakulteten, Enheten för biobanksforskning.
    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 study2013Ingår i: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 132, nr 10, s. 2464-2468Artikel i tidskrift (Refereegranskat)
    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 universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper.
    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 universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper.
    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 tumors2017Ingår i: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 49, nr 5, s. 789-794Artikel i tidskrift (Refereegranskat)
    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 universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Nordfjall, Katarina
    Andersson, Ulrika
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Roos, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    hTERT Cancer Risk Genotypes Are Associated With Telomere Length2012Ingår i: Genetic Epidemiology, ISSN 0741-0395, E-ISSN 1098-2272, Vol. 36, nr 4, s. 368-372Artikel i tidskrift (Refereegranskat)
    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 universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper.
    Rajaraman, Preetha
    Chanock, Stephen J.
    Linet, Martha S.
    Wang, Zhaoming
    Yeager, Meredith
    Melin, Beatrice S.
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper.
    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 risk2019Ingår i: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 21, nr 1, s. 71-82Artikel i tidskrift (Refereegranskat)
    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 universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper.
    Rajaraman, Preetha
    Chanock, Stephen J.
    Linet, Martha S.
    Wang, Zhaoming
    Yeager, Meredith
    Houlston, Richard S.
    Jenkins, Robert B.
    Wrensch, Margaret R.
    Melin, Beatrice
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper.
    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 age2018Ingår i: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 143, nr 10, s. 2359-2366Artikel i tidskrift (Refereegranskat)
    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.