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  • 1. Amirian, E. Susan
    et al.
    Armstrong, Georgina N.
    Zhou, Renke
    Lau, Ching C.
    Claus, Elizabeth B.
    Barnholtz-Sloan, Jill S.
    Il'yasova, Dora
    Schildkraut, Joellen
    Ali-Osman, Francis
    Sadetzki, Siegal
    Johansen, Christoffer
    Houlston, Richard S.
    Jenkins, Robert B.
    Lachance, Daniel
    Olson, Sara H.
    Bernstein, Jonine L.
    Merrell, Ryan T.
    Wrensch, Margaret R.
    Davis, Faith G.
    Lai, Rose
    Shete, Sanjay
    Amos, Christopher I.
    Scheurer, Michael E.
    Aldape, Kenneth
    Alafuzoff, Irina
    Brännström, Thomas
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap.
    Broholm, Helle
    Collins, Peter
    Giannini, Caterina
    Rosenblum, Marc
    Tihan, Tarik
    Melin, Beatrice S.
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper.
    Bondy, Melissa L.
    The Glioma International Case-Control Study: A Report From the Genetic Epidemiology of Glioma International Consortium2016Inngår i: American Journal of Epidemiology, ISSN 0002-9262, E-ISSN 1476-6256, Vol. 183, nr 2, s. 85-91Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Decades of research have established only a few etiological factors for glioma, which is a rare and highly fatal brain cancer. Common methodological challenges among glioma studies include small sample sizes, heterogeneity of tumor subtypes, and retrospective exposure assessment. Here, we briefly describe the Glioma International Case-Control (GICC) Study (recruitment, 2010-2013), a study being conducted by the Genetic Epidemiology of Glioma International Consortium that integrates data from multiple data collection sites, uses a common protocol and questionnaire, and includes biospecimen collection. To our knowledge, the GICC Study is the largest glioma study to date that includes collection of blood samples, which will allow for genetic analysis and interrogation of gene-environment interactions.

  • 2. Amirian, E. Susan
    et al.
    Armstrong, Georgina
    Zhou, Renke
    Wrensch, Margaret
    Olson, Sara
    Scheurer, Michael
    Il'yasova, Dora
    Lachance, Daniel
    Lau, Ching
    Claus, Elizabeth
    Barnholtz-Sloan, Jill
    Schildkraut, Joellen
    Ali-Osman, Francis
    Sadetzki, Siegal
    Johansen, Christoffer
    Houlston, Richard
    Jenkins, Robert
    Bernstein, Jonine
    Merrell, Ryan
    Davis, Faith
    Lai, Rose
    Shete, Sanjay
    Amos, Christopher
    Melin, Beatrice
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Bondy, Melissa
    DEMOGRAPHICS AND LIFESTYLE FACTORS IN GLIOMA RISK: A REPORT FROM THE GLIOMA INTERNATIONAL CASE-CONTROL STUDY2016Inngår i: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 18, s. 57-58Artikkel i tidsskrift (Fagfellevurdert)
  • 3. Amirian, E. Susan
    et al.
    Ostrom, Quinn T.
    Armstrong, Georgina N.
    Lai, Rose K.
    Gu, Xiangjun
    Jacobs, Daniel I.
    Jalali, Ali
    Claus, Elizabeth B.
    Barnholtz-Sloan, Jill S.
    Il'yasova, Dora
    Schildkraut, Joellen M.
    Ali-Osman, Francis
    Sadetzki, Siegal
    Jenkins, Robert B.
    Lachance, Daniel H.
    Olson, Sara H.
    Bernstein, Jonine L.
    Merrell, Ryan T.
    Wrensch, Margaret R.
    Johansen, Christoffer
    Houlston, Richard S.
    Scheurer, Michael E.
    Shete, Sanjay
    Amos, Christopher I.
    Melin, Beatrice S.
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Bondy, Melissa L.
    Aspirin, NSAIDs, and Glioma Risk: Original Data from the Glioma International Case-Control Study and a Meta-analysis2019Inngår i: Cancer Epidemiology, Biomarkers and Prevention, ISSN 1055-9965, E-ISSN 1538-7755, Vol. 28, nr 3, s. 555-562Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: There have been few studies of sufficient size to address the relationship between glioma risk and the use of aspirin or NSAIDs, and results have been conflicting. The purpose of this study was to examine the associations between glioma and aspirin/NSAID use, and to aggregate these findings with prior published studies using meta-analysis. Methods: The Glioma International Case-Control Study (GICC) consists of 4,533 glioma cases and 4,171 controls recruited from 2010 to 2013. Interviews were conducted using a standardized questionnaire to obtain information on aspirin/NSAID use. We examined history of regular use for >= 6 months and duration-response. Restricted maximum likelihood meta-regression models were used to aggregate site-specific estimates, and to combine GICC estimates with previously published studies. Results: A history of daily aspirin use for -6 months was associated with a 38% lower glioma risk, compared with not having a history of daily use [adjusted meta-OR = 0.62; 95% confidence interval (CI), 0.54-0.70]. There was a significant duration-response trend (P = 1.67 -10 -17), with lower ORs for increasing duration of aspirin use. Duration-response trends were not observed for NSAID use. In the meta-analysis aggregating GICC data with five previous studies, there was a marginally significant association between use of aspirin and glioma (mOR = 0.84; 95% CI, 0.70-1.02), but no association for NSAID use. Conclusions: Our study suggests that aspirin may be associated with a reduced risk of glioma. Impact: These results imply that aspirin use may be associated with decreased gliomarisk. Further research examining the association between aspirin use and glioma risk is warranted.

  • 4. Amirian, E. Susan
    et al.
    Scheurer, Michael E.
    Wrensch, Margaret
    Olson, Sara H.
    Lai, Rose
    Lachance, Daniel
    Armstrong, Georgina
    Zhou, Renke
    Wiemels, Joseph
    Lau, Ching
    Claus, Elizabeth
    Barnholtz-Sloan, Jill
    Il'yasova, Dora
    Schildkraut, Joellen
    Houlston, Richard
    Shete, Sanjay
    Bernstein, Jonine
    Jenkins, Robert
    Davis, Faith
    Merrell, Ryan
    Johansen, Christoffer
    Sadetzki, Siegal
    Melin, Beatrice
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Bondy, Melissa
    ATOPIC CONDITIONS, ANTIHISTAMINE USE, AND GLIOMA RISK: PRELIMINARY RESULTS FROM THE GLIOMA INTERNATIONAL CASE-CONTROL STUDY2013Inngår i: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 15, nr Supplement: 3, s. 32-32Artikkel i tidsskrift (Annet vitenskapelig)
  • 5. Amirian, E. Susan
    et al.
    Scheurer, Michael E.
    Zhou, Renke
    Wrensch, Margaret R.
    Armstrong, Georgina N.
    Lachance, Daniel
    Olson, Sara H.
    Lau, Ching C.
    Claus, Elizabeth B.
    Barnholtz-Sloan, Jill S.
    Il'yasova, Dora
    Schildkraut, Joellen
    Ali-Osman, Francis
    Sadetzki, Siegal
    Jenkins, Robert B.
    Bernstein, Jonine L.
    Merrell, Ryan T.
    Davis, Faith G.
    Lai, Rose
    Shete, Sanjay
    Amos, Christopher I.
    Melin, Beatrice S.
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Bondy, Melissa L.
    History of chickenpox in glioma risk: a report from the glioma international case-control study (GICC)2016Inngår i: Cancer Medicine, ISSN 2045-7634, E-ISSN 2045-7634, Vol. 5, nr 6, s. 1352-1358Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Varicella zoster virus (VZV) is a neurotropic alpha-herpesvirus that causes chickenpox and establishes life-long latency in the cranial nerve and dorsal root ganglia of the host. To date, VZV is the only virus consistently reported to have an inverse association with glioma. The Glioma International Case-Control Study (GICC) is a large, multisite consortium with data on 4533 cases and 4171 controls collected across five countries. Here, we utilized the GICC data to confirm the previously reported associations between history of chickenpox and glioma risk in one of the largest studies to date on this topic. Using two-stage random-effects restricted maximum likelihood modeling, we found that a positive history of chickenpox was associated with a 21% lower glioma risk, adjusting for age and sex (95% confidence intervals (CI): 0.65-0.96). Furthermore, the protective effect of chickenpox was stronger for high-grade gliomas. Our study provides additional evidence that the observed protective effect of chickenpox against glioma is unlikely to be coincidental. Future studies, including meta-analyses of the literature and investigations of the potential biological mechanism, are warranted.

  • 6. Amirian, E. Susan
    et al.
    Zhou, Renke
    Wrensch, Margaret R.
    Olson, Sara H.
    Scheurer, Michael E.
    Il'yasova, Dora
    Lachance, Daniel
    Armstrong, Georgina N.
    McCoy, Lucie S.
    Lau, Ching C.
    Claus, Elizabeth B.
    Barnholtz-Sloan, Jill S.
    Schildkraut, Joellen
    Ali-Osman, Francis
    Sadetzki, Siegal
    Johansen, Christoffer
    Houlston, Richard S.
    Jenkins, Robert B.
    Bernstein, Jonine L.
    Merrell, Ryan T.
    Davis, Faith G.
    Lai, Rose
    Shete, Sanjay
    Amos, Christopher I.
    Melin, Beatrice S.
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Bondy, Melissa L.
    Approaching a Scientific Consensus on the Association between Allergies and Glioma Risk: a report from the Glioma International Case-Control Study2016Inngår i: Cancer Epidemiology, Biomarkers and Prevention, ISSN 1055-9965, E-ISSN 1538-7755, Vol. 25, nr 2, s. 282-290Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Several previous studies have found inverse associations between glioma susceptibility and a history of allergies or other atopic conditions. Some evidence indicates that respiratory allergies are likely to be particularly relevant with regard to glioma risk. Using data from the Glioma International Case-Control Study (GICC), we examined the effects of respiratory allergies and other atopic conditions on glioma risk. Methods: The GICC contains detailed information on history of atopic conditions for 4,533 cases and 4,171 controls, recruited from 14 study sites across five countries. Using two-stage random-effects restricted maximum likelihood modeling to calculate meta-analysis ORs, we examined the associations between glioma and allergy status, respiratory allergy status, asthma, and eczema. Results: Having a history of respiratory allergies was associated with an approximately 30% lower glioma risk, compared with not having respiratory allergies (mOR, 0.72; 95% confidence interval, 0.58-0.90). This association was similar when restricting to high-grade glioma cases. Asthma and eczema were also significantly protective against glioma. Conclusion: A substantial amount of data on the inverse association between atopic conditions and glioma has accumulated, and findings from the GICC study further strengthen the existing evidence that the relationship between atopy and glioma is unlikely to be coincidental. Impact: As the literature approaches a consensus on the impact of allergies in glioma risk, future research can begin to shift focus to what the underlying biologic mechanism behind this association may be, which could, in turn, yield new opportunities for immunotherapy or cancer prevention. (C) 2016 AACR.

  • 7. Andersen, Niels S
    et al.
    Pedersen, Lone B
    Laurell, Anna
    Elonen, Erkki
    Kolstad, Arne
    Boesen, Anne Marie
    Pedersen, Lars M
    Lauritzsen, Grete F
    Ekanger, Roald
    Nilsson-Ehle, Herman
    Nordström, Marie
    Fredén, Susanne
    Jerkeman, Mats
    Eriksson, Mikael
    Väärt, Jaan
    Malmer, Beatrice
    Umeå universitet, Medicinsk fakultet, Strålningsvetenskaper, Onkologi.
    Geisler, Christian H
    Pre-emptive treatment with rituximab of molecular relapse after autologous stem cell transplantation in mantle cell lymphoma.2009Inngår i: Journal of clinical oncology : official journal of the American Society of Clinical Oncology, ISSN 1527-7755, Vol. 27, nr 26, s. 4365-70Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    PURPOSE: Minimal residual disease (MRD) is predictive of clinical progression in mantle-cell lymphoma (MCL). According to the Nordic MCL-2 protocol we prospectively analyzed the efficacy of pre-emptive treatment using rituximab to MCL patients in molecular relapse after autologous stem cell transplantation (ASCT). PATIENTS AND MATERIALS: MCL patients enrolled onto the study, who had polymerase chain reaction (PCR) detectable molecular markers and underwent ASCT, were followed with serial PCR assessments of MRD in consecutive bone marrow and peripheral blood samples after ASCT. In case of molecular relapse with increasing MRD levels, patients were offered pre-emptive treatment with rituximab 375 mg/m(2) weekly for 4 weeks. RESULTS: Of 160 MCL patients enrolled, 145 underwent ASCT, of whom 78 had a molecular marker. Of these, 74 were in complete remission (CR) and four had progressive disease after ASCT. Of the CR patients, 36 underwent a molecular relapse up to 6 years (mean, 18.5 months) after ASCT. Ten patients did not receive pre-emptive treatment mainly due to a simultaneous molecular and clinical relapse, while 26 patients underwent pre-emptive treatment leading to reinduction of molecular remission in 92%. Median molecular and clinical relapse-free survival after pre-emptive treatment were 1.5 and 3.7 years, respectively. Of the 38 patients who remain in molecular remission for now for a median of 3.3 years (range, 0.4 to 6.6 years), 33 are still in clinical CR. CONCLUSION: Molecular relapse may occur many years after ASCT in MCL, and PCR based pre-emptive treatment using rituximab is feasible, reinduce molecular remission, and may prevent clinical relapse.

  • 8.
    Andersson, Anne
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Enblad, Gunilla
    Department of Oncology, Radiology and Clinical immunology, Section of Oncology, Uppsala University, Uppsala.
    Gustavsson, Anita
    Department of Oncology, Skåne University Hospital, Lund University, Lund .
    Erlanson, Martin
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Hagberg, Hans
    Department of Oncology, Radiology and Clinical immunology, Section of Oncology, Uppsala University, Uppsala .
    Molin, Daniel
    Department of Oncology, Radiology and Clinical immunology, Section of Oncology, Uppsala University, Uppsala .
    Tavelin, Björn
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Melin, Beatrice
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Long term risk of infections in Hodgkin lymphoma long-term survivors2011Inngår i: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 154, nr 5, s. 661-663Artikkel i tidsskrift (Fagfellevurdert)
  • 9.
    Andersson, Anne
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Enblad, Gunilla
    Uppsala universitet.
    Gustavsson, Anita
    Lunds universitet.
    Erlanson, Martin
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Hagberg, Hans
    Uppsala universitet.
    Molin, Daniel
    Uppsala universitet.
    Tavelin, Björn
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Näslund, Ulf
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Melin, Beatrice
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Cardiovascular side effects following treatment of Hodgkin’s lymphoma: comorbidity factors and a strategy for interventionManuskript (preprint) (Annet vitenskapelig)
  • 10.
    Andersson, Anne
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Enblad, Gunilla
    Tavelin, Björn
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Björkholm, Magnus
    Linderoth, Johan
    Lagerlöf, I
    Merup, Mats
    Sender, Mark
    Malmer, Beatrice
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Family history of cancer as a risk factor for second malignancies after Hodgkin's lymphoma2008Inngår i: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 98, nr 5, s. 1001-1005Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    This study estimated the risk of second primary malignancies after Hodgkin's lymphoma (HL) in relation to family history of cancer, age at diagnosis and latency, among 6946 patients treated for HL in Sweden in 1965–1995 identified through the Swedish Cancer Register (SCR). First-degree relatives (FDRs) to the HL patients and their malignancies were then ascertained together with their malignancies through the Multi-Generation Registry and SCR. The HL patient cohort was stratified on the number of FDRs with cancer, and standardised incidence ratios (SIRs) of developing SM were analysed. In the HL cohort, 781 SM were observed 1 year or longer after HL diagnosis. The risk for developing SM increased with the number of FDRs with cancer, SIRs being 2.26, 3.01, and 3.45 with 0, 1, or ≥2 FDRs with cancer, respectively. Hodgkin's lymphoma long-term survivors treated at a young age with a family history of cancer carry an increased risk for developing SM and may represent a subgroup where standardised screening for the most common cancer sites could be offered in a stringent surveillance programme.

  • 11.
    Andersson, Anne
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Näslund, Ulf
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Tavelin, Björn
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Enblad, Gunilla
    Gustavsson, Anita
    Malmer, Beatrice
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Long-term risk of cardiovascular disease in Hodgkin lymphoma survivors: retrospective cohort analyses and a concept for prospective intervention2009Inngår i: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 124, nr 8, s. 1914-1917Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Previous studies have shown increased cardiovascular mortality as late side effects in Hodgkin lymphoma (HL) patients. This study identifies stratifying risk factors for surveillance and defines concepts for a clinical feasible and noninvasive prospective protocol for intervention of cardiovascular side effects. HL patients diagnosed between 1965 and 1995 (n = 6.946) and their first-degree relatives (FDR) were identified through the Swedish Cancer Registry and the Swedish Multigeneration Registry. For the HL and FDR cohort, in-patient care for cardiovascular disease (CVD) was registered through the Hospital Discharge Registry, Sweden. Standard incidence ratios of developing CVD for the HL cohort were calculated. A markedly increased risk for in-patient care of CVD was observed in HL patients with HL diagnosed at age 40 years or younger and with more than 10 years follow-up. In the HL survivors, a family history of congestive heart failure (CHF) and coronary artery disease (CAD) increased the risk for these diseases. The Swedish Hodgkin Intervention and Prevention study started in 2007. In the pilot feasibility study for prospective intervention (47 patients), about 25% of the cases had side effects and laboratory abnormalities. These patients were referred to a cardiologist or general practitioner. In the prospective cohort, a positive family history for CHF or CAD could be a stratifying risk factor when setting up a surveillance model. The prospective on-going study presents an intervention model that screens and treats for comorbidity factors. This article also presents an overview of the study concept.

  • 12.
    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 smoking2019Inngår i: Cancer Causes and Control, ISSN 0957-5243, E-ISSN 1573-7225, Vol. 30, nr 2, s. 177-185Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 13.
    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 meningiomas2004Inngår i: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 108, nr 2, s. 135-142Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 14.
    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.2007Inngår i: Acta Oncologica, ISSN 0284-186X, Vol. 46, nr 7, s. 951-960Artikkel i tidsskrift (Fagfellevurdert)
  • 15.
    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 tumors2004Inngår i: Clinical Neuropathology, ISSN 0722-5091, Vol. 23, nr 1, s. 21-27Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 16.
    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 risk2009Inngår i: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 48, nr 7, s. 948-954Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 17.
    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.2009Inngår i: International journal of cancer. Journal international du cancer, ISSN 1097-0215, Vol. 125, nr 4, s. 968-972Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 18.
    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 risk2010Inngår i: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 49, nr 6, s. 767-775Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 19.
    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 cancer2014Inngår i: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 16, nr 10, s. 1333-1340Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 20. Antoniou, Antonis C
    et al.
    Beesley, Jonathan
    McGuffog, Lesley
    Sinilnikova, Olga M
    Healey, Sue
    Neuhausen, Susan L
    Ding, Yuan Chun
    Rebbeck, Timothy R
    Weitzel, Jeffrey N
    Lynch, Henry T
    Isaacs, Claudine
    Ganz, Patricia A
    Tomlinson, Gail
    Olopade, Olufunmilayo I
    Couch, Fergus J
    Wang, Xianshu
    Lindor, Noralane M
    Pankratz, Vernon S
    Radice, Paolo
    Manoukian, Siranoush
    Peissel, Bernard
    Zaffaroni, Daniela
    Barile, Monica
    Viel, Alessandra
    Allavena, Anna
    Dall'Olio, Valentina
    Peterlongo, Paolo
    Szabo, Csilla I
    Zikan, Michal
    Claes, Kathleen
    Poppe, Bruce
    Foretova, Lenka
    Mai, Phuong L
    Greene, Mark H
    Rennert, Gad
    Lejbkowicz, Flavio
    Glendon, Gord
    Ozcelik, Hilmi
    Andrulis, Irene L
    Thomassen, Mads
    Gerdes, Anne-Marie
    Sunde, Lone
    Cruger, Dorthe
    Birk Jensen, Uffe
    Caligo, Maria
    Friedman, Eitan
    Kaufman, Bella
    Laitman, Yael
    Milgrom, Roni
    Dubrovsky, Maya
    Cohen, Shimrit
    Borg, Åke
    Jernström, Helena
    Lindblom, Annika
    Rantala, Johanna
    Stenmark-Askmalm, Marie
    Melin, Beatrice
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Nathanson, Kate
    Domchek, Susan
    Jakubowska, Ania
    Lubinski, Jan
    Huzarski, Tomasz
    Osorio, Ana
    Lasa, Adriana
    Durán, Mercedes
    Tejada, Maria-Isabel
    Godino, Javier
    Benitez, Javier
    Hamann, Ute
    Kriege, Mieke
    Hoogerbrugge, Nicoline
    van der Luijt, Rob B
    van Asperen, Christi J
    Devilee, Peter
    Meijers-Heijboer, EJ
    Blok, Marinus J
    Aalfs, Cora M
    Hogervorst, Frans
    Rookus, Matti
    Cook, Margaret
    Oliver, Clare
    Frost, Debra
    Conroy, Don
    Evans, D Gareth
    Lalloo, Fiona
    Pichert, Gabriella
    Davidson, Rosemarie
    Cole, Trevor
    Cook, Jackie
    Paterson, Joan
    Hodgson, Shirley
    Morrison, Patrick J
    Porteous, Mary E
    Walker, Lisa
    Kennedy, M John
    Dorkins, Huw
    Peock, Susan
    Godwin, Andrew K
    Stoppa-Lyonnet, Dominique
    de Pauw, Antoine
    Mazoyer, Sylvie
    Bonadona, Valérie
    Lasset, Christine
    Dreyfus, Hélène
    Leroux, Dominique
    Hardouin, Agnès
    Berthet, Pascaline
    Faivre, Laurence
    Loustalot, Catherine
    Noguchi, Tetsuro
    Sobol, Hagay
    Rouleau, Etienne
    Nogues, Catherine
    Frénay, Marc
    Vénat-Bouvet, Laurence
    Hopper, John L
    Daly, Mary B
    Terry, Mary B
    John, Esther M
    Buys, Saundra S
    Yassin, Yosuf
    Miron, Alexander
    Goldgar, David
    Singer, Christian F
    Dressler, Anne Catharina
    Gschwantler-Kaulich, Daphne
    Pfeiler, Georg
    Hansen, Thomas VO
    Jønson, Lars
    Agnarsson, Bjarni A
    Kirchhoff, Tomas
    Offit, Kenneth
    Devlin, Vincent
    Dutra-Clarke, Ana
    Piedmonte, Marion
    Rodriguez, Gustavo C
    Wakeley, Katie
    Boggess, John F
    Basil, Jack
    Schwartz, Peter E
    Blank, Stephanie V
    Toland, Amanda Ewart
    Montagna, Marco
    Casella, Cinzia
    Imyanitov, Evgeny
    Tihomirova, Laima
    Blanco, Ignacio
    Lazaro, Conxi
    Ramus, Susan J
    Sucheston, Lara
    Karlan, Beth Y
    Gross, Jenny
    Schmutzler, Rita
    Wappenschmidt, Barbara
    Engel, Christoph
    Meindl, Alfons
    Lochmann, Magdalena
    Arnold, Norbert
    Heidemann, Simone
    Varon-Mateeva, Raymonda
    Niederacher, Dieter
    Sutter, Christian
    Deissler, Helmut
    Gadzicki, Dorothea
    Preisler-Adams, Sabine
    Kast, Karin
    Schönbuchner, Ines
    Caldes, Trinidad
    de la Hoya, Miguel
    Aittomäki, Kristiina
    Nevanlinna, Heli
    Simard, Jacques
    Spurdle, Amanda B
    Holland, Helene
    Chen, Xiaoqing
    Platte, Radka
    Chenevix-Trench, Georgia
    Easton, Douglas F
    Common breast cancer susceptibility alleles and the risk of breast cancer for BRCA1 and BRCA2 mutation carriers: implications for risk prediction2010Inngår i: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 70, nr 23, s. 9742-9754Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The known breast cancer susceptibility polymorphisms in FGFR2, TNRC9/TOX3, MAP3K1, LSP1, and 2q35 confer increased risks of breast cancer for BRCA1 or BRCA2 mutation carriers. We evaluated the associations of 3 additional single nucleotide polymorphisms (SNPs), rs4973768 in SLC4A7/NEK10, rs6504950 in STXBP4/COX11, and rs10941679 at 5p12, and reanalyzed the previous associations using additional carriers in a sample of 12,525 BRCA1 and 7,409 BRCA2 carriers. Additionally, we investigated potential interactions between SNPs and assessed the implications for risk prediction. The minor alleles of rs4973768 and rs10941679 were associated with increased breast cancer risk for BRCA2 carriers (per-allele HR = 1.10, 95% CI: 1.03-1.18, P = 0.006 and HR = 1.09, 95% CI: 1.01-1.19, P = 0.03, respectively). Neither SNP was associated with breast cancer risk for BRCA1 carriers, and rs6504950 was not associated with breast cancer for either BRCA1 or BRCA2 carriers. Of the 9 polymorphisms investigated, 7 were associated with breast cancer for BRCA2 carriers (FGFR2, TOX3, MAP3K1, LSP1, 2q35, SLC4A7, 5p12, P = 7 × 10(-11) - 0.03), but only TOX3 and 2q35 were associated with the risk for BRCA1 carriers (P = 0.0049, 0.03, respectively). All risk-associated polymorphisms appear to interact multiplicatively on breast cancer risk for mutation carriers. Based on the joint genotype distribution of the 7 risk-associated SNPs in BRCA2 mutation carriers, the 5% of BRCA2 carriers at highest risk (i.e., between 95th and 100th percentiles) were predicted to have a probability between 80% and 96% of developing breast cancer by age 80, compared with 42% to 50% for the 5% of carriers at lowest risk. Our findings indicated that these risk differences might be sufficient to influence the clinical management of mutation carriers.

  • 21. Antoniou, Antonis C
    et al.
    Kartsonaki, Christiana
    Sinilnikova, Olga M
    Soucy, Penny
    McGuffog, Lesley
    Healey, Sue
    Lee, Andrew
    Peterlongo, Paolo
    Manoukian, Siranoush
    Peissel, Bernard
    Zaffaroni, Daniela
    Cattaneo, Elisa
    Barile, Monica
    Pensotti, Valeria
    Pasini, Barbara
    Dolcetti, Riccardo
    Giannini, Giuseppe
    Putignano, Anna Laura
    Varesco, Liliana
    Radice, Paolo
    Mai, Phuong L
    Greene, Mark H
    Andrulis, Irene L
    Glendon, Gord
    Ozcelik, Hilmi
    Thomassen, Mads
    Gerdes, Anne-Marie
    Kruse, Torben A
    Birk Jensen, Uffe
    Crüger, Dorthe G
    Caligo, Maria A
    Laitman, Yael
    Milgrom, Roni
    Kaufman, Bella
    Paluch-Shimon, Shani
    Friedman, Eitan
    Loman, Niklas
    Harbst, Katja
    Lindblom, Annika
    Arver, Brita
    Ehrencrona, Hans
    Melin, Beatrice
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Nathanson, Katherine L
    Domchek, Susan M
    Rebbeck, Timothy
    Jakubowska, Ania
    Lubinski, Jan
    Gronwald, Jacek
    Huzarski, Tomasz
    Byrski, Tomasz
    Cybulski, Cezary
    Gorski, Bohdan
    Osorio, Ana
    Ramón y Cajal, Teresa
    Fostira, Florentia
    Andrés, Raquel
    Benitez, Javier
    Hamann, Ute
    Hogervorst, Frans B
    Rookus, Matti A
    Hooning, Maartje J
    Nelen, Marcel R
    van der Luijt, Rob B
    van Os, Theo A M
    van Asperen, Christi J
    Devilee, Peter
    Meijers-Heijboer, Hanne E J
    Garcia, Encarna B Gómez
    Peock, Susan
    Cook, Margaret
    Frost, Debra
    Platte, Radka
    Leyland, Jean
    Evans, D Gareth
    Lalloo, Fiona
    Eeles, Ros
    Izatt, Louise
    Adlard, Julian
    Davidson, Rosemarie
    Eccles, Diana
    Ong, Kai-ren
    Cook, Jackie
    Douglas, Fiona
    Paterson, Joan
    Kennedy, M John
    Miedzybrodzka, Zosia
    Godwin, Andrew
    Stoppa-Lyonnet, Dominique
    Buecher, Bruno
    Belotti, Muriel
    Tirapo, Carole
    Mazoyer, Sylvie
    Barjhoux, Laure
    Lasset, Christine
    Leroux, Dominique
    Faivre, Laurence
    Bronner, Myriam
    Prieur, Fabienne
    Nogues, Catherine
    Rouleau, Etienne
    Pujol, Pascal
    Coupier, Isabelle
    Frénay, Marc
    Hopper, John L
    Daly, Mary B
    Terry, Mary B
    John, Esther M
    Buys, Saundra S
    Yassin, Yosuf
    Miron, Alexander
    Goldgar, David
    Singer, Christian F
    Tea, Muy-Kheng
    Pfeiler, Georg
    Dressler, Anne Catharina
    Hansen, Thomas v O
    Jønson, Lars
    Ejlertsen, Bent
    Barkardottir, Rosa Bjork
    Kirchhoff, Tomas
    Offit, Kenneth
    Piedmonte, Marion
    Rodriguez, Gustavo
    Small, Laurie
    Boggess, John
    Blank, Stephanie
    Basil, Jack
    Azodi, Masoud
    Toland, Amanda Ewart
    Montagna, Marco
    Tognazzo, Silvia
    Agata, Simona
    Imyanitov, Evgeny
    Janavicius, Ramunas
    Lazaro, Conxi
    Blanco, Ignacio
    Pharoah, Paul D P
    Sucheston, Lara
    Karlan, Beth Y
    Walsh, Christine S
    Olah, Edith
    Bozsik, Aniko
    Teo, Soo-Hwang
    Seldon, Joyce L
    Beattie, Mary S
    van Rensburg, Elizabeth J
    Sluiter, Michelle D
    Diez, Orland
    Schmutzler, Rita K
    Wappenschmidt, Barbara
    Engel, Christoph
    Meindl, Alfons
    Ruehl, Ina
    Varon-Mateeva, Raymonda
    Kast, Karin
    Deissler, Helmut
    Niederacher, Dieter
    Arnold, Norbert
    Gadzicki, Dorothea
    Schönbuchner, Ines
    Caldes, Trinidad
    de la Hoya, Miguel
    Nevanlinna, Heli
    Aittomäki, Kristiina
    Dumont, Martine
    Chiquette, Jocelyne
    Tischkowitz, Marc
    Chen, Xiaoqing
    Beesley, Jonathan
    Spurdle, Amanda B
    Neuhausen, Susan L
    Chun Ding, Yuan
    Fredericksen, Zachary
    Wang, Xianshu
    Pankratz, Vernon S
    Couch, Fergus
    Simard, Jacques
    Easton, Douglas F
    Chenevix-Trench, Georgia
    Common alleles at 6q25.1 and 1p11.2 are associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers2011Inngår i: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 20, nr 16, s. 3304-3321Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Two single nucleotide polymorphisms (SNPs) at 6q25.1, near the ESR1 gene, have been implicated in the susceptibility to breast cancer for Asian (rs2046210) and European women (rs9397435). A genome-wide association study in Europeans identified two further breast cancer susceptibility variants: rs11249433 at 1p11.2 and rs999737 in RAD51L1 at 14q24.1. Although previously identified breast cancer susceptibility variants have been shown to be associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers, the involvement of these SNPs to breast cancer susceptibility in mutation carriers is currently unknown. To address this, we genotyped these SNPs in BRCA1 and BRCA2 mutation carriers from 42 studies from the Consortium of Investigators of Modifiers of BRCA1/2. In the analysis of 14 123 BRCA1 and 8053 BRCA2 mutation carriers of European ancestry, the 6q25.1 SNPs (r(2) = 0.14) were independently associated with the risk of breast cancer for BRCA1 mutation carriers [hazard ratio (HR) = 1.17, 95% confidence interval (CI): 1.11-1.23, P-trend = 4.5 × 10(-9) for rs2046210; HR = 1.28, 95% CI: 1.18-1.40, P-trend = 1.3 × 10(-8) for rs9397435], but only rs9397435 was associated with the risk for BRCA2 carriers (HR = 1.14, 95% CI: 1.01-1.28, P-trend = 0.031). SNP rs11249433 (1p11.2) was associated with the risk of breast cancer for BRCA2 mutation carriers (HR = 1.09, 95% CI: 1.02-1.17, P-trend = 0.015), but was not associated with breast cancer risk for BRCA1 mutation carriers (HR = 0.97, 95% CI: 0.92-1.02, P-trend = 0.20). SNP rs999737 (RAD51L1) was not associated with breast cancer risk for either BRCA1 or BRCA2 mutation carriers (P-trend = 0.27 and 0.30, respectively). The identification of SNPs at 6q25.1 associated with breast cancer risk for BRCA1 mutation carriers will lead to a better understanding of the biology of tumour development in these women.

  • 22. Arason, Adalgeir
    et al.
    Gunnarsson, Haukur
    Johannesdottir, Gudrun
    Jonasson, Kristjan
    Bendahl, Pär-Ola
    Gillanders, Elizabeth M
    Agnarsson, Bjarni A
    Jönsson, Göran
    Pylkäs, Katri
    Mustonen, Aki
    Heikkinen, Tuomas
    Aittomäki, Kristiina
    Blomqvist, Carl
    Melin, Beatrice
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Johannsson, Oskar TH
    Møller, Pål
    Winqvist, Robert
    Nevanlinna, Heli
    Borg, Åke
    Barkardottir, Rosa B
    Genome-wide search for breast cancer linkage in large Icelandic non-BRCA1/2 families2010Inngår i: Breast Cancer Research, ISSN 1465-5411, E-ISSN 1465-542X, Vol. 12, nr 4, s. R50-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Chromosomes 2p, 6q and 14q are candidate sites for genes contributing together to high breast cancer risk. A polygenic model is supported, suggesting the joint effect of genes in contributing to breast cancer risk to be rather common in non-BRCA1/2 families. For genetic counselling it would seem important to resolve the mode of genetic interaction.

  • 23. Arroyo, Vidal M.
    et al.
    Lupo, Philip J.
    Melin, Beatrice S.
    Umeå universitet.
    Styring, Emelie
    Zaikova, Olga
    Papworth, Karin
    Umeå universitet.
    Soft tissue sarcoma clinical presentation, treatment, and survival in adolescents and young adults compared to older adults: A report from the Scandinavian Sarcoma Group2018Inngår i: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 78, nr 13Artikkel i tidsskrift (Annet vitenskapelig)
    Abstract [en]

    Background: Five-year survival rates for those diagnosed with soft tissue sarcoma (STS) have improved significantly among children and older adults (OAs), but these same trends have not been observed for adolescents and young adults (AYAs). While these disparities could be due to differences in biology or treatment, few studies have evaluated STS occurrence and outcome in AYAs. Therefore, the purpose of this study was to evaluate differences between adolescents and young adults (AYAs) and older adults (OAs) diagnosed with STS by stratifying analysis by: (1) clinical presentation; (2) treatment; and (3) survival.

    Methods: Data were obtained from the Scandinavian Sarcoma Group (SSG) Central Register, which includes information on 5,747 patients from Sweden and Norway, diagnosed with a STS during 1986-2011. Variables included: age at diagnosis, metastasis at diagnosis, tumor size, histology, adjuvant treatment, date of death or last follow-up. AYAs were defined as those diagnosed ages 15-39 years. Categorical variables were analyzed using chi-square tests, and continuous variables were analyzed using t-tests. Overall survival (OS) and recurrence-free survival (RFS) were compared between AYAs and OAs using Kaplan-Meier estimates and log-rank tests. All analyses were conducted overall and by common STS subtypes.

    Results: Overall and by STS subtype, there were significant differences between AYAs and OAs on presentation, treatment, and survival. The distribution of STS subtypes was different between OAs and AYAs. For example, OAs were more likely to be diagnosed with leiomyosarcoma compared to AYAs (18% vs. 10%, p<0.001), whereas AYAs were more likely to be diagnosed with malignant peripheral nerve sheath tumor (MPNST, 9% vs. 4%, p<0.001). OAs were also more likely to have larger tumors (>5 cm, 67% vs. 52%, p<0.001) and higher malignancy grade (grade IV, 45% vs. 31%, p<0.001). Interestingly, AYAs were more likely to be treated with radiotherapy and chemotherapy compared to OAs (12% vs. 5%, p<0.001). There were also differences within STS subtypes. For example, OAs were more likely to have metastasis compared to AYAs if diagnosed with leiomyosarcoma (18% vs. 10%, p=0.04). In most scenarios AYAs had significantly better OS and RFS compared to OAs, other than for MPNST (OS: p=0.19, RFS: p=0.28).

    Conclusions: There were several differences between AYAs and OAs on STS presentation, treatment, and outcome. AYAs not only had differences in terms of STS subtypes but also tumor size and malignancy grade within subtypes. Additional work is needed to characterize the biology underlying these differences, which will inform future treatment strategies for both AYAs and OAs with STS.

  • 24. Atkins, Isabelle
    et al.
    Kinnersley, Ben
    Ostrom, Quinn T.
    Labreche, Karim
    Il'yasova, Dora
    Armstrong, Georgina N.
    Eckel-Passow, Jeanette E.
    Schoemaker, Minouk J.
    Nothen, Markus M.
    Barnholtz-Sloan, Jill S.
    Swerdlow, Anthony J.
    Simon, Matthias
    Rajaraman, Preetha
    Chanock, Stephen J.
    Shildkraut, Joellen
    Bernstein, Jonine L.
    Hoffman, Per
    Jockel, Karl-Heinz
    Lai, Rose K.
    Claus, Elizabeth B.
    Olson, Sara H.
    Johansen, Christoffer
    Wrensch, Margaret R.
    Melin, Beatrice S.
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper.
    Jenkins, Robert B.
    Sanson, Marc
    Bondy, Melissa L.
    Houlston, Richard S.
    Transcriptome-Wide Association Study Identifies New Candidate Susceptibility Genes for Glioma2019Inngår i: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 79, nr 8, s. 2065-2071Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Genome-wide association studies (GWAS) have so far identified 25 loci associated with glioma risk, with most showing specificity for either glioblastoma (GBM) or non-GBM tumors. The majority of these GWAS susceptibility variants reside in noncoding regions and the causal genes underlying the associations are largely unknown. Here we performed a transcriptome-wide association study to search for novel risk loci and candidate causal genes at known GWAS loci using Genotype-Tissue Expression Project (GTEx) data to predict cis-predicted gene expression in relation to GBM and non-GBM risk in conjunction with GWAS summary statistics on 12,488 glioma cases (6,183 GBM and 5,820 non-GBM) and 18,169 controls. Imposing a Bonferroni-corrected significance level of P < 5.69 x 10(-6), candidate novel risk locus for GBM (mean Z = 4.43; P = 5.68 x 10(-6)). GALNT6 resides at least 55 Mb away from any previously identified glioma risk variant, while all other 30 significantly associated genes were located within 1 Mb of known GWAS-identified loci and were not significant after conditioning on the known GWAS-identified variants. These data identify a novel locus (GALNT6 at 12q13.33) and 30 genes at 12 known glioma risk loci associated with glioma risk, providing further insights into glioma tumorigenesis.

    Significance: This study identifies new genes associated with glioma risk, increasing understanding of how these tumors develop.

  • 25. Bainbridge, Matthew N
    et al.
    Armstrong, Georgina N
    Gramatges, M Monica
    Bertuch, Alison A
    Jhangiani, Shalini N
    Doddapaneni, Harsha
    Lewis, Lora
    Tombrello, Joseph
    Tsavachidis, Spyros
    Liu, Yanhong
    Jalali, Ali
    Plon, Sharon E
    Lau, Ching C
    Parsons, Donald W
    Claus, Elizabeth B
    Barnholtz-Sloan, Jill
    Il'yasova, Dora
    Schildkraut, Joellen
    Ali-Osman, Francis
    Sadetzki, Siegal
    Johansen, Christoffer
    Houlston, Richard S
    Jenkins, Robert B
    Lachance, Daniel
    Olson, Sara H
    Bernstein, Jonine L.
    Merrell, Ryan T
    Wrensch, Margaret R
    Walsh, Kyle M
    Davis, Faith G
    Lai, Rose
    Shete, Sanjay
    Aldape, Kenneth
    Amos, Christopher I
    Thompson, Patricia A
    Muzny, Donna M
    Gibbs, Richard A
    Melin, Beatrice S
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Bondy, Melissa L
    Germline mutations in shelterin complex genes are associated with familial glioma2015Inngår i: Journal of the National Cancer Institute, ISSN 0027-8874, E-ISSN 1460-2105, Vol. 107, nr 1, artikkel-id dju384Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Gliomas are the most common brain tumor, with several histological subtypes of various malignancy grade. The genetic contribution to familial glioma is not well understood. Using whole exome sequencing of 90 individuals from 55 families, we identified two families with mutations in POT1 (p.G95C, p.E450X), a member of the telomere shelterin complex, shared by both affected individuals in each family and predicted to impact DNA binding and TPP1 binding, respectively. Validation in a separate cohort of 264 individuals from 246 families identified an additional mutation in POT1 (p.D617Efs), also predicted to disrupt TPP1 binding. All families with POT1 mutations had affected members with oligodendroglioma, a specific subtype of glioma more sensitive to irradiation. These findings are important for understanding the origin of glioma and could have importance for the future diagnostics and treatment of glioma.

  • 26. Bengtsson, Daniel
    et al.
    Joost, Patrick
    Aravidis, Christos
    Stenmark, Marie Askmalm
    Backman, Ann-Sofie
    Melin, Beatrice
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    von Salome, Jenny
    Zagoras, Theofanis
    Gebre-Medhin, Samuel
    Burman, Pia
    Corticotroph Pituitary Carcinoma in a Patient With Lynch Syndrome (LS) and Pituitary Tumors in a Nationwide LS Cohort2017Inngår i: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 102, nr 11, s. 3928-3932Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Context: Lynch syndrome (LS) is a cancer-predisposing syndrome caused by germline mutations in genes involved in DNA mismatch repair (MMR). Patients are at high risk for several types of cancer, but pituitary tumors have not previously been reported.

    Case: A 51-year-old man with LS (MSH2 mutation) and a history of colon carcinoma presented with severe Cushing disease and a locally aggressive pituitary tumor. The tumor harbored a mutation consistent with the patient’s germline mutation and displayed defect MMR function. Sixteen months later, the tumor had developed into a carcinoma with widespread liver metastases. The patient prompted us to perform a nationwide study in LS.

    Nationwide Study: A diagnosis consistent with a pituitary tumor was sought for in the Swedish National Patient Registry. In 910 patients with LS, representing all known cases in Sweden, another two clinically relevant pituitary tumors were found: an invasive nonsecreting macroadenoma and a microprolactinoma (i.e., in total three tumors vs. one expected).

    Conclusion: Germline mutations in MMR genes may contribute to the development and/or the clinical course of pituitary tumors. Because tumors with MMR mutations are susceptible to treatment with immune checkpoint inhibitors, we suggest to actively ask for a family history of LS in the workup of patients with aggressive pituitary tumors.

  • 27. Berntsson, Shala G.
    et al.
    Merrell, Ryan T.
    Amirian, E. Susan
    Armstrong, Georgina N.
    Lachance, Daniel
    Smits, Anja
    Zhou, Renke
    Jacobs, Daniel I.
    Wrensch, Margaret R.
    Olson, Sara H.
    Il'yasova, Dora
    Claus, Elizabeth B.
    Barnholtz-Sloan, Jill S.
    Schildkraut, Joellen
    Sadetzki, Siegal
    Johansen, Christoffer
    Houlston, Richard S.
    Jenkins, Robert B.
    Bernstein, Jonine L.
    Lai, Rose
    Shete, Sanjay
    Amos, Christopher I.
    Bondy, Melissa L.
    Melin, Beatrice S.
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Glioma-related seizures in relation to histopathological subtypes: a report from the glioma international case-control study2018Inngår i: Journal of Neurology, ISSN 0340-5354, E-ISSN 1432-1459, Vol. 265, nr 6, s. 1432-1442Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: The purpose of this study was to evaluate the distribution of glioma-related seizures and seizure control at the time of tumor diagnosis with respect to tumor histologic subtypes, tumor treatment and patient characteristics, and to compare seizure history preceding tumor diagnosis (or study enrollment) between glioma patients and healthy controls.

    Methods: The Glioma International Case Control study (GICC) risk factor questionnaire collected information on demographics, past medical/medication history, and occupational history. Cases from eight centers were also asked detailed questions on seizures in relation to glioma diagnosis; cases (n = 4533) and controls (n = 4171) were also asked about seizures less than 2 years from diagnosis and previous seizure history more than 2 years prior to tumor diagnosis, including childhood seizures.

    Results: Low-grade gliomas (LGGs), particularly oligodendrogliomas/oligoastrocytomas, had the highest proportion of glioma-related seizures. Patients with low-grade astrocytoma demonstrated the most medically refractory seizures. A total of 83% of patients were using only one antiepileptic drug (AED), which was levetiracetam in 71% of cases. Gross total resection was strongly associated with reduced seizure frequency (p < 0.009). No significant difference was found between glioma cases and controls in terms of seizure occurring more than 2 years before diagnosis or during childhood.

    Conclusions: Our study showed that glioma-related seizures were most common in low-grade gliomas. Gross total resection was associated with lower seizure frequency. Additionally, having a history of childhood seizures is not a risk factor ***for developing glioma-related seizures or glioma.

  • 28. Berntsson, Shala Ghaderi
    et al.
    Malmer, Beatrice
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Bondy, Melissa
    Qu, Mingqi
    Smits, Anja
    Tumor-associated epilepsy and glioma: Are there common genetic pathways?2009Inngår i: Acta oncologica (Stockholm, Sweden), ISSN 1651-226X, Vol. 48, nr 7, s. 955-963Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background. Patients with glioma exhibit a great variability in clinical symptoms apart from variations in response to therapy and survival. Many patients present with epileptic seizures at disease onset, especially in case of low-grade gliomas, but not all have seizures. A large proportion of patients develop refractory seizures. It is likely that the variability in epileptic symptoms cannot exclusively be explained by tumor-related factors, but rather reflects complex interaction between tumor-related, environmental and hereditary factors. Material and methods. No data exist on susceptibility genes associated with epileptic symptoms in patients with glioma. However, an increasing number of candidate genes have been proposed for other focal epilepsies such as temporal lobe epilepsy. Some of the susceptibility candidate genes associated with focal epilepsy may contribute to epileptic symptoms also in patients with glioma. Results. This review presents an update on studies on genetic polymorphisms and focal epilepsy and brings forward putative candidate genes for tumor-associated epilepsy, based on the assumption that common etiological pathways may exist for glioma development and glioma-associated seizures. Conclusion. Genes involved in the immune response, in synaptic transmission and in cell cycle control are discussed that may play a role in the pathogenesis of tumor growth as well as epileptic symptoms in patients with gliomas.

  • 29. 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 gliomas2011Inngår i: Journal of Neuro-Oncology, ISSN 0167-594X, E-ISSN 1573-7373, Vol. 105, nr 3, s. 531-538Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 30. Bethke, Lara
    et al.
    Murray, Anne
    Webb, Emily
    Schoemaker, Minouk
    Muir, Kenneth
    McKinney, Patricia
    Hepworth, Sarah
    Dimitropoulou, Polyxeni
    Lophatananon, Artitaya
    Feychting, Maria
    Lönn, Stefan
    Ahlbom, Anders
    Malmer, Beatrice
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Henriksson, Roger
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Auvinen, Anssi
    Kiuru, Anne
    Salminen, Tiina
    Johansen, Christoffer
    Collatz Christensen, Helle
    Kosteljanetz, Michael
    Swerdlow, Anthony
    Houlston, Richard
    Comprehensive analysis of DNA repair gene variants and risk of meningioma2008Inngår i: Journal of the National Cancer Institute, ISSN 0027-8874, E-ISSN 1460-2105, Vol. 100, nr 4, s. 270-276Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Meningiomas account for up to 37% of all primary brain tumors. Genetic susceptibility to meningioma is well established, with the risk among relatives of meningioma patients being approximately threefold higher than that in the general population. A relationship between risk of meningioma and exposure to ionizing radiation is also well known and led us to examine whether variants in DNA repair genes contribute to disease susceptibility.

    Methods: We analyzed 1127 tagging single-nucleotide polymorphisms (SNPs) that were selected to capture most of the common variation in 136 DNA repair genes in five case–control series (631 case patients and 637 control subjects) from four countries in Europe. We also analyzed 388 putative functional SNPs in these genes for their association with meningioma. All statistical tests were two-sided.

    Results: The SNP rs4968451, which maps to intron 4 of the gene that encodes breast cancer susceptibility gene 1–interacting protein 1, was consistently associated with an increased risk of developing meningioma. Across the five studies, the association was highly statistically significant (trend odds ratio = 1.57, 95% confidence interval = 1.28 to 1.93; Ptrend = 8.95 × 10−6; P = .009 after adjusting for multiple testing).

    Conclusions: We have identified a novel association between rs4968451 and meningioma risk. Because approximately 28% of the European population are carriers of at-risk genotypes for rs4968451, the variant is likely to make a substantial contribution to the development of meningioma.

  • 31. Bethke, Lara
    et al.
    Sullivan, Kate
    Webb, Emily
    Murray, Anne
    Schoemaker, Minouk
    Auvinen, Anssi
    Kiuru, Anne
    Salminen, Tiina
    Johansen, Christoffer
    Collatz Christensen, Helle
    Muir, Kenneth
    McKinney, Patricia
    Hepworth, Sarah
    Dimitropoulou, Polyxeni
    Lophatananon, Artitaya
    Feychting, Maria
    Lönn, Stefan
    Ahlbom, Anders
    Malmer, Beatrice
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Henriksson, Roger
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Swerdlow, Anthony
    Houlston, Richard
    CASP8 D302H and meningioma risk: an analysis of five case-control series2009Inngår i: Cancer Letters, ISSN 0304-3835, E-ISSN 1872-7980, Vol. 273, nr 2, s. 312-315Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Caspase 8 (CASP8) is a key regulator of apoptosis or programmed cell death, and hence a defence against cancer. The CASP8 polymorphism D302H has recently been shown to influence the risk of breast cancer. We tested the hypothesis that the CASP8 polymorphism D302H may influence risk of meningioma through analysis of five independent series of case patients and controls (n=631 and 637, respectively). Carrier status for 302H was not associated with a statistically significantly increased risk (OR=1.16; 95% CI: 0.87-1.53; P=0.31) making it unlikely that this variant contributes to the inherited risk of meningioma.

  • 32. Bethke, Lara
    et al.
    Sullivan, Kate
    Webb, Emily
    Murray, Anne
    Schoemaker, Minouk
    Auvinen, Anssi
    Kiuru, Anne
    Salminen, Tiina
    Johansen, Christoffer
    Collatz Christensen, Helle
    Muir, Kenneth
    McKinney, Patricia
    Hepworth, Sarah
    Dimitropoulou, Polyxeni
    Lophatananon, Artitaya
    Feychting, Maria
    Lönn, Stefan
    Ahlbom, Anders
    Malmer, Beatrice
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Henriksson, Roger
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Swerdlow, Anthony
    Houlston, Richard
    The Common D302H Variant of CASP8 Is Associated with Risk of Glioma2008Inngår i: Cancer Epidemiology, Biomarkers and Prevention, ISSN 1055-9965, E-ISSN 1538-7755, Vol. 17, nr 4, s. 987-989Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Caspase 8 (CASP8) is a key regulator of apoptosis or programmed cell death, and, hence, a defense against cancer. We tested the hypothesis that the CASP8 polymorphism D302H influences risk of glioma through analysis of five series of glioma case patients and controls (n = 1,005 and 1,011, respectively). Carrier status for the rare allele of D302H was associated with a 1.37-fold increased risk (95% confidence interval, 1.10-1.70; P = 0.004). The association of CASP8 D302H with glioma risk indicates the importance of inherited variation in the apoptosis pathway in susceptibility to this form of primary brain tumor.

  • 33. Bethke, Lara
    et al.
    Webb, Emily
    Murray, Anne
    Schoemaker, Minouk
    Feychting, Maria
    Lönn, Stefan
    Ahlbom, Anders
    Malmer, Beatrice
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Henriksson, Roger
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Auvinen, Anssi
    Kiuru, Anne
    Salminen, Tiina
    Johansen, Christoffer
    Collatz Christensen, Helle
    Muir, Kenneth
    McKinney, Patricia
    Hepworth, Sarah
    Dimitropoulou, Polyxeni
    Lophatananon, Artitaya
    Swerdlow, Anthony
    Houlston, Richard
    Functional polymorphisms in folate metabolism genes influence the risk of meningioma and glioma2008Inngår i: Cancer Epidemiology, Biomarkers and Prevention, ISSN 1055-9965, E-ISSN 1538-7755, Vol. 17, nr 5, s. 1195-1202Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Folate metabolism plays an important role in carcinogenesis. To test the hypothesis that polymorphic variation in the folate metabolism genes 5,10-methylenetetrahydrofolate reductase (MTHFR), methionine synthase (MTRR), and methionine synthase reductase (MTR) influences the risk of primary brain tumors, we genotyped 1,005 glioma cases, 631 meningioma cases, and 1,101 controls for the MTHFR C677A and A1298C, MTRR A66G, and MTR A2756G variants. MTHFR C677T-A1298C diplotypes were associated with risk of meningioma (P = 0.002) and glioma (P = 0.02); risks were increased with genotypes associated with reduced MTHFR activity. The highest risk of meningioma was associated with heterozygosity for both MTHFR variants [odds ratio (OR), 2.11; 95% confidence interval (95% CI), 1.42-3.12]. The corresponding OR for glioma was 1.23 (95% CI, 0.91-1.66). A significant association between risk of meningioma and homozygosity for MTRR 66G was also observed (OR, 1.41; 95% CI, 1.02-1.94). Our findings provide support for the role of folate metabolism in the development of primary brain tumors. In particular, genotypes associated with increased 5,10-methylenetetrahydrofolate levels are associated with elevated risk.

  • 34. Bethke, Lara
    et al.
    Webb, Emily
    Murray, Anne
    Schoemaker, Minouk
    Johansen, Christoffer
    Collatz Christensen, Helle
    Muir, Kenneth
    McKinney, Patricia
    Hepworth, Sarah
    Dimitropoulou, Polyxeni
    Lophatananon, Artitaya
    Feychting, Maria
    Lönn, Stefan
    Ahlbom, Anders
    Malmer, Beatrice
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Henriksson, Roger
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Auvinen, Anssi
    Kiuru, Anne
    Salminen, Tiina
    Swerdlow, Anthony
    Houlston, Richard
    Comprehensive analysis of the role of DNA repair gene polymorphisms on risk of glioma2008Inngår i: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 17, nr 6, s. 800-805Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Much of the variation in inherited risk of glioma is likely to be explained by combinations of common low risk variants. The established relationship between glioma risk and exposure to ionizing radiation led us to examine whether variants in the DNA repair genes contribute to disease susceptibility. We evaluated 1127 haplotype-tagging single-nucleotide polymorphisms (SNPs) supplemented with 388 putative functional SNPs to capture most of the common variation in 136 DNA repair genes, in five unique case–control series from four different countries (1013 cases, 1016 controls). We identified 16 SNPs associated with glioma risk at the 1% significance level. The highest association observed across the five independent case–control datasets involved rs243356, which maps to intron 3 of CHAF1A (trend odds ratio, 1.32; 95% confidence interval 1.14–1.54; P = 0.0002; false-positive report probability = 0.055, based on a prior probability of 0.01). Our results provide additional support for the hypothesis that low penetrance variants contribute to the risk of developing glioma and suggest that a genetic variant located in or around the CHAF1A gene contributes to disease risk.

  • 35.
    Bhattacharjee, Samsiddhi
    et al.
    Biostatistics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, 6120 Executive Boulevard, Rockville, Maryland 20852, USA.
    Rajaraman, Preetha
    Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, 6120 Executive Boulevard, Rockville, Maryland 20852, USA.
    Jacobs, Kevin B
    Core Genotyping Facility, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, 8717 Grovemont Circle, Gaithersburg, Maryland 20877, USA.
    Wheeler, William A
    Information Management Services, Rockville, MD 20852, USA.
    Melin, Beatrice S
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Hartge, Patricia
    Epidemiology and Biostatistics Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20892, USA.
    GliomaScan Consortium,
    GliomaScan Consortium investigators and affiliations are available in the Supplemental Data.
    Yeager, Meredith
    Core Genotyping Facility, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, 8717 Grovemont Circle, Gaithersburg, Maryland 20877, USA.
    Chung, Charles C
    Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20892, USA.
    Chanock, Stephen J
    Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20892, USA.
    Chatterjee, Nilanjan
    Biostatistics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, 6120 Executive Boulevard, Rockville, Maryland 20852, USA.
    A subset-based approach improves power and interpretation for the combined analysis of genetic association studies of heterogeneous traits2012Inngår i: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 90, nr 5, s. 821-835Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Pooling genome-wide association studies (GWASs) increases power but also poses methodological challenges because studies are often heterogeneous. For example, combining GWASs of related but distinct traits can provide promising directions for the discovery of loci with small but common pleiotropic effects. Classical approaches for meta-analysis or pooled analysis, however, might not be suitable for such analysis because individual variants are likely to be associated with only a subset of the traits or might demonstrate effects in different directions. We propose a method that exhaustively explores subsets of studies for the presence of true association signals that are in either the same direction or possibly opposite directions. An efficient approximation is used for rapid evaluation of p values. We present two illustrative applications, one for a meta-analysis of separate case-control studies of six distinct cancers and another for pooled analysis of a case-control study of glioma, a class of brain tumors that contains heterogeneous subtypes. Both the applications and additional simulation studies demonstrate that the proposed methods offer improved power and more interpretable results when compared to traditional methods for the analysis of heterogeneous traits. The proposed framework has applications beyond genetic association studies.

  • 36.
    Björkblom, Benny
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Jonsson, Pär
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Späth, Florentin
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Melin, Beatrice S.
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper.
    Antti, Henrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    PRE-DIAGNOSTIC PLASMA METABOLITES LINKED TO FUTURE BRAIN TUMOR DEVELOPMENT2018Inngår i: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 20, s. 288-289Artikkel i tidsskrift (Annet vitenskapelig)
    Abstract [en]

    BACKGROUND: The Northern Sweden Health and Disease Study is a unique population-based biobank linked to the clinical data registries. The samples originate from over 133 000 individuals living in the northern part of Sweden, and primarily collected during health checkups from the age of 40 years. Our project aims to investigate alterations in metabolite signatures in blood plasma of healthy blood donors that later in life developed a tumor. Brain tumors, especially glioblastoma is associated with poor prognosis. To explore early events of metabolic reprograming linked to future diagnosis, we investigated alterations in metabolite concentrations in plasma collected several years before diagnosis with matched healthy controls. MATERIALS AND METHODS: In total 392 analytical samples (256 repeated timepoint and 136 single timepoint, case-control samples) were analyzed using GCTOFMS. Constrained randomization of run order was utilized to maximize information output and minimize the false discovery rate. By use of reference databases, we could with high confidence quantify and identify 150 plasma metabolites. We detected metabolites with significant alterations in concertation between pre-clinical glioma cases and healthy controls by the effect projection approach based on orthogonal partial least squares (OPLSEP). RESULTS AND CONCLUSIONS: For the repeated blood samples, we designed and applied a novel multivariate strategy for high resolution biomarker pattern discovery. We utilize the fact that we have available samples from two repeated time points prior to diagnosis for each future glioma case and their matched controls to construct a small design of experiment (DoE) of four samples for each match pair. The data for each individual DoE was evaluated by OPLS-EP to determine the effect of each individual metabolite in relation to control-case, time and their interaction. Finally, latent significance calculations by means of OPLS were used to extract and evaluate the correct latent biomarker and highlight true significance of individual metabolites. Our study presents an approach to minimize confounding effects due to systematic noise from sampling, the analytical method, as well as take into account personalized metabolic levels over time, enabling biomarker detection within a smaller sample group. We will present and discuss the latest results and biomarkers from this exploratory metabolomics study at the meeting

  • 37.
    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 risk2016Inngår i: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 7, nr 24, s. 37043-37053Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 38. Blein, Sophie
    et al.
    Bardel, Claire
    Danjean, Vincent
    McGuffog, Lesley
    Healey, Sue
    Barrowdale, Daniel
    Lee, Andrew
    Dennis, Joe
    Kuchenbaecker, Karoline B.
    Soucy, Penny
    Terry, Mary Beth
    Chung, Wendy K.
    Goldgar, David E.
    Buys, Saundra S.
    Janavicius, Ramunas
    Tihomirova, Laima
    Tung, Nadine
    Dorfling, Cecilia M.
    van Rensburg, Elizabeth J.
    Neuhausen, Susan L.
    Ding, Yuan Chun
    Gerdes, Anne-Marie
    Ejlertsen, Bent
    Nielsen, Finn C.
    Hansen, Thomas V. O.
    Osorio, Ana
    Benitez, Javier
    Andres Conejero, Raquel
    Segota, Ena
    Weitzel, Jeffrey N.
    Thelander, Margo
    Peterlongo, Paolo
    Radice, Paolo
    Pensotti, Valeria
    Dolcetti, Riccardo
    Bonanni, Bernardo
    Peissel, Bernard
    Zaffaroni, Daniela
    Scuvera, Giulietta
    Manoukian, Siranoush
    Varesco, Liliana
    Capone, Gabriele L.
    Papi, Laura
    Ottini, Laura
    Yannoukakos, Drakoulis
    Konstantopoulou, Irene
    Garber, Judy
    Hamann, Ute
    Donaldson, Alan
    Brady, Angela
    Brewer, Carole
    Foo, Claire
    Evans, D. Gareth
    Frost, Debra
    Eccles, Diana
    Douglas, Fiona
    Cook, Jackie
    Adlard, Julian
    Barwell, Julian
    Walker, Lisa
    Izatt, Louise
    Side, Lucy E.
    Kennedy, M. John
    Tischkowitz, Marc
    Rogers, Mark T.
    Porteous, Mary E.
    Morrison, Patrick J.
    Platte, Radka
    Eeles, Ros
    Davidson, Rosemarie
    Hodgson, Shirley
    Cole, Trevor
    Godwin, Andrew K.
    Isaacs, Claudine
    Claes, Kathleen
    De Leeneer, Kim
    Meindl, Alfons
    Gehrig, Andrea
    Wappenschmidt, Barbara
    Sutter, Christian
    Engel, Christoph
    Niederacher, Dieter
    Steinemann, Doris
    Plendl, Hansjoerg
    Kast, Karin
    Rhiem, Kerstin
    Ditsch, Nina
    Arnold, Norbert
    Varon-Mateeva, Raymonda
    Schmutzler, Rita K.
    Preisler-Adams, Sabine
    Markov, Nadja Bogdanova
    Wang-Gohrke, Shan
    de Pauw, Antoine
    Lefol, Cedrick
    Lasset, Christine
    Leroux, Dominique
    Rouleau, Etienne
    Damiola, Francesca
    Dreyfus, Helene
    Barjhoux, Laure
    Golmard, Lisa
    Uhrhammer, Nancy
    Bonadona, Valerie
    Sornin, Valerie
    Bignon, Yves-Jean
    Carter, Jonathan
    Van Le, Linda
    Piedmonte, Marion
    DiSilvestro, Paul A.
    de la Hoya, Miguel
    Caldes, Trinidad
    Nevanlinna, Heli
    Aittomaki, Kristiina
    Jager, Agnes
    van den Ouweland, Ans M. W.
    Kets, Carolien M.
    Aalfs, Cora M.
    van Leeuwen, Flora E.
    Hogervorst, Frans B. L.
    Meijers-Heijboer, Hanne E. J.
    Oosterwijk, Jan C.
    van Roozendaal, Kees E. P.
    Rookus, Matti A.
    Devilee, Peter
    van der Luijt, Rob B.
    Olah, Edith
    Diez, Orland
    Teule, Alex
    Lazaro, Conxi
    Blanco, Ignacio
    Del Valle, Jesus
    Jakubowska, Anna
    Sukiennicki, Grzegorz
    Gronwald, Jacek
    Lubinski, Jan
    Durda, Katarzyna
    Jaworska-Bieniek, Katarzyna
    Agnarsson, Bjarni A.
    Maugard, Christine
    Amadori, Alberto
    Montagna, Marco
    Teixeira, Manuel R.
    Spurdle, Amanda B.
    Foulkes, William
    Olswold, Curtis
    Lindor, Noralane M.
    Pankratz, Vernon S.
    Szabo, Csilla I.
    Lincoln, Anne
    Jacobs, Lauren
    Corines, Marina
    Robson, Mark
    Vijai, Joseph
    Berger, Andreas
    Fink-Retter, Anneliese
    Singer, Christian F.
    Rappaport, Christine
    Kaulich, Daphne Geschwantler
    Pfeiler, Georg
    Tea, Muy-Kheng
    Greene, Mark H.
    Mai, Phuong L.
    Rennert, Gad
    Imyanitov, Evgeny N.
    Mulligan, Anna Marie
    Glendon, Gord
    Andrulis, Irene L.
    Tchatchou, Sandrine
    Toland, Amanda Ewart
    Pedersen, Inge Sokilde
    Thomassen, Mads
    Kruse, Torben A.
    Jensen, Uffe Birk
    Caligo, Maria A.
    Friedman, Eitan
    Zidan, Jamal
    Laitman, Yael
    Lindblom, Annika
    Melin, Beatrice
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Arver, Brita
    Loman, Niklas
    Rosenquist, Richard
    Olopade, Olufunmilayo I.
    Nussbaum, Robert L.
    Ramus, Susan J.
    Nathanson, Katherine L.
    Domchek, Susan M.
    Rebbeck, Timothy R.
    Arun, Banu K.
    Mitchell, Gillian
    Karlan, Beth Y.
    Lester, Jenny
    Orsulic, Sandra
    Stoppa-Lyonnet, Dominique
    Thomas, Gilles
    Simard, Jacques
    Couch, Fergus J.
    Offit, Kenneth
    Easton, Douglas F.
    Chenevix-Trench, Georgia
    Antoniou, Antonis C.
    Mazoyer, Sylvie
    Phelan, Catherine M.
    Sinilnikova, Olga M.
    Cox, David G.
    An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers2015Inngår i: Breast Cancer Research, ISSN 1465-5411, E-ISSN 1465-542X, Vol. 17, artikkel-id 61Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Introduction: Individuals carrying pathogenic mutations in the BRCA1 and BRCA2 genes have a high lifetime risk of breast cancer. BRCA1 and BRCA2 are involved in DNA double-strand break repair, DNA alterations that can be caused by exposure to reactive oxygen species, a main source of which are mitochondria. Mitochondrial genome variations affect electron transport chain efficiency and reactive oxygen species production. Individuals with different mitochondrial haplogroups differ in their metabolism and sensitivity to oxidative stress. Variability in mitochondrial genetic background can alter reactive oxygen species production, leading to cancer risk. In the present study, we tested the hypothesis that mitochondrial haplogroups modify breast cancer risk in BRCA1/2 mutation carriers. Methods: We genotyped 22,214 (11,421 affected, 10,793 unaffected) mutation carriers belonging to the Consortium of Investigators of Modifiers of BRCA1/2 for 129 mitochondrial polymorphisms using the iCOGS array. Haplogroup inference and association detection were performed using a phylogenetic approach. ALTree was applied to explore the reference mitochondrial evolutionary tree and detect subclades enriched in affected or unaffected individuals. Results: We discovered that subclade T1a1 was depleted in affected BRCA2 mutation carriers compared with the rest of clade T (hazard ratio (HR) = 0.55; 95% confidence interval (CI), 0.34 to 0.88; P = 0.01). Compared with the most frequent haplogroup in the general population (that is, H and T clades), the T1a1 haplogroup has a HR of 0.62 (95% CI, 0.40 to 0.95; P = 0.03). We also identified three potential susceptibility loci, including G13708A/rs28359178, which has demonstrated an inverse association with familial breast cancer risk. Conclusions: This study illustrates how original approaches such as the phylogeny-based method we used can empower classical molecular epidemiological studies aimed at identifying association or risk modification effects.

  • 39. Bondy, M L
    et al.
    Scheurer, M E
    Malmer, Beatrice
    Onkologi.
    Barnholtz-Sloan, J S
    Davis, F G
    Il'yasova, D
    Kruchko, C
    McCarthy, B J
    Rajaraman, P
    Schwartzbaum, J A
    Sadetzki, S
    Schlehofer, B
    Tihan, T
    Wiemels, J L
    Wrensch, M
    Buffler, P A
    On behalf of the Brain Tumor Epidemiology Consortium: Brain tumor epidemiology: Consensus from the Brain Tumor Epidemiology Consortium2008Inngår i: Cancer Supplement, Vol. 113, s. 1953-1968Artikkel i tidsskrift (Fagfellevurdert)
  • 40. Bondy, Melissa
    et al.
    Bainbridge, Matthew
    Jhangiani, Shalini
    Jalali, Ali
    Plon, Sharon E.
    Armstrong, Georgina
    Bernstein, Jonine
    Claus, Elizabeth
    Davis, Faith
    Houlston, Richard
    Il'yasova, Dora
    Jenkins, Robert
    Johansen, Christoffer
    Lachance, Daniel
    Lai, Rose
    Lau, Ching
    Merrell, Ryan
    Olson, Sara
    Sadetzki, Siegal
    Schildkraut, Joellen
    Shete, Sanjay
    Barnholtz-Sloan, Jill
    Wrensch, Margaret
    Melin, Beatrice
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Gibbs, Richard A.
    POT1 GERMLINE MUTATIONS MAY EXPLAIN A SUBSET OF FAMILIAL GLIOMA: A REPORT FROM THE GLIOGENE CONSORTIUM2013Inngår i: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 15, nr Supplement: 3, s. 89-89Artikkel i tidsskrift (Annet vitenskapelig)
  • 41. Bondy, Melissa L
    et al.
    Scheurer, Michael E
    Malmer, Beatrice
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Barnholtz-Sloan, Jill S
    Davis, Faith G
    Il'yasova, Dora
    Kruchko, Carol
    McCarthy, Bridget J
    Rajaraman, Preetha
    Schwartzbaum, Judith A
    Sadetzki, Siegal
    Schlehofer, Brigitte
    Tihan, Tarik
    Wiemels, Joseph L
    Wrensch, Margaret
    Buffler, Patricia A
    Brain tumor epidemiology: consensus from the Brain Tumor Epidemiology Consortium.2008Inngår i: Cancer, ISSN 0008-543X, E-ISSN 1097-0142, Vol. 113, nr 7 Suppl, s. 1953-1968Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Epidemiologists in the Brain Tumor Epidemiology Consortium (BTEC) have prioritized areas for further research. Although many risk factors have been examined over the past several decades, there are few consistent findings, possibly because of small sample sizes in individual studies and differences between studies in patients, tumor types, and methods of classification. Individual studies generally have lacked samples of sufficient size to examine interactions. A major priority based on available evidence and technologies includes expanding research in genetics and molecular epidemiology of brain tumors. BTEC has taken an active role in promoting understudied groups, such as pediatric brain tumors; the etiology of rare glioma subtypes, such as oligodendroglioma; and meningioma, which, although it is not uncommon, has only recently been registered systematically in the United States. There also is a pressing need for more researchers, especially junior investigators, to study brain tumor epidemiology. However, relatively poor funding for brain tumor research has made it difficult to encourage careers in this area. In this report, BTEC epidemiologists reviewed the group's consensus on the current state of scientific findings, and they present a consensus on research priorities to identify which important areas the science should move to address.

  • 42. Brandefors, Lena
    et al.
    Kimby, Eva
    Lundqvist, Kristina
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Melin, Beatrice
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Lindh, Jack
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Familial Waldenstrom's macroglobulinemia and relation to immune defects, autoimmune diseases, and haematological malignancies: a population-based study from northern Sweden2016Inngår i: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 55, nr 1, s. 91-98Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Waldenstrom's macroglobulinemia (WM) is a rare lymphoprolipherative disorder with geographic and ethnic disparities in incidence. The cause of WM remains mostly unknown although a role for genetic, immune-related, and environmental factors has been suggested. Most cases of WM are sporadic although familial cases occur. Aim: This study estimated the incidence of WM in northern Sweden and identified and described patients with familial WM in this area. Patients and methods: The Swedish and Northern Lymphoma Registry, the Swedish Cancer Registry (1997-2011), and medical records were used to identify patients with WM in two counties (Norrbotten and Västerbotten) in northern Sweden and to calculate the overall age-adjusted incidence (2000-2012). We identified 12 families with a family history of WM, IgM monoclonal gammophathy (MGUS), and/or multiple myeloma (MM). Results: In Norrbotten and Västerbotten, the age-adjusted incidence of WM/LPL is 1.75 and 1.48 per 100 000 persons per year, respectively (2000-2012), rates that are higher than the overall incidence of WM/LPL in Sweden (1.05 per 100 000 persons per year; 2000-2012). Autoimmune diseases and other haematological malignancies in the medical history (their own or in relatives) were reported in 9/12 and 5/12 families, respectively. A high proportion of abnormal serum protein electrophoresis was found in the relatives; 12/56 (21%) had a MGUS and 13/56 (25%) showed abnormalities in the immunoglobulin levels (i.e. subnormal levels and poly/oligoclonality). Conclusion: The incidence of WM in Norrbotten and Västerbotten counties was higher than expected. We found a strong correlation between autoimmune/inflammatory diseases, other haematological malignancies, and familial WM and a high frequency of serum immunoglobulin abnormalities in the relatives of the WM patients, findings that strengthen the hypothesis that the aetiology of WM depends on both immune-related and genetic factors.

  • 43. Brandefors, Lena
    et al.
    Melin, Beatrice S.
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Lindh, Jack
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper.
    Lundqvist, Kristina
    Kimby, Eva
    Prognostic factors and primary treatment for Waldenstrom macroglobulinemia: a Swedish Lymphoma Registry study2018Inngår i: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 183, nr 4, s. 564-577Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We present a nationwide prospective Swedish registry-based study of Waldenstrom macroglobulinaemia (WM), that focuses on incidence and survival in relation to clinical prognostic factors and primary systemic therapies. A total of 1511 patients with WM and lymphoplasmocytic lymphoma (LPL) were registered in the Swedish Lymphoma Registry (SLR) between 1 January 2000 and 31 December 2014. The age-adjusted incidence of WM/LPL was 11.5 per million persons per year, three times higher than the reported incidence worldwide. Medical records were retrieved for 1135 patients (75%). A retrospective review showed that 981 (86.1%) of these patients fulfilled the World Health Organization diagnostic criteria for WM and these patients were analysed further. The overall survival (OS) improved between two periods - 2000-2006 and 2007-2014 - with a five-year OS of 61% and 70%, respectively. Significant prognostic factors for OS, evaluated at the time of diagnosis, were age, elevated lactate dehydrogenase level and haemoglobin <= 115 g/l for patients receiving therapy 0-3 months after diagnosis, and age, poor performance status, haemoglobin <= 115 g/l, and female sex in "watch and wait" patients (multivariable analysis). The level of the IgM monoclonal immunoglobulin had no significant prognostic value. Rituximab included in first-line therapy was associated with improved survival.

  • 44. Britton, Julie A
    et al.
    Khan, Aneire E
    Rohrmann, Sabine
    Becker, Nikolaus
    Linseisen, Jakob
    Nieters, Alexandra
    Kaaks, Rudolf
    Tjønneland, Anne
    Halkjaer, Jytte
    Severinsen, Marianne Tang
    Overvad, Kim
    Pischon, Tobias
    Boeing, Heiner
    Trichopoulou, Antonia
    Kalapothaki, Victoria
    Trichopoulos, Dimitrios
    Mattiello, Amalia
    Tagliabue, Giovanna
    Sacerdote, Carlotta
    Peeters, Petra H M
    Bueno-de-Mesquita, H Bas
    Ardanaz, Eva
    Navarro, Carmen
    Jakszyn, Paula
    Altzibar, Jone M
    Hallmans, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Näringsforskning.
    Malmer, Beatrice
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Berglund, Göran
    Manjer, Jonas
    Allen, Naomi
    Key, Timothy
    Bingham, Sheila
    Besson, Hervé
    Ferrari, Pietro
    Jenab, Mazda
    Boffetta, Paolo
    Vineis, Paolo
    Riboli, Elio
    Anthropometric characteristics and non-Hodgkin's lymphoma and multiple myeloma risk in the European Prospective Investigation into Cancer and Nutrition (EPIC).2008Inngår i: Haematologica, ISSN 1592-8721, Vol. 93, nr 11, s. 1666-1677Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND:

    The incidences of non-Hodgkin's lymphoma and multiple myeloma are increasing steadily. It has been hypothesized that this may be due, in part, to the parallel rising prevalence of obesity. It is biologically plausible that anthropometric characteristics can infuence the risk of non-Hodgkin's lymphoma and multiple myeloma.

    DESIGN AND METHODS:

    In the context of the European Prospective Investigation into Cancer and Nutrition (EPIC), anthropometric characteristics were assessed in 371,983 cancer-free individuals at baseline. During the 8.5 years of follow-up, 1,219 histologically confirmed incident cases of non-Hodgkin's lymphoma and multiple myeloma occurred in 609 men and 610 women. Gender-specific proportional hazards models were used to estimate relative risks and 95% confidence intervals (95% CI) of development of non-Hodgkin's lymphoma and multiple myeloma in relation to the anthropometric characteristics.

    RESULTS:

    Height was associated with overall non-Hodgkin's lymphoma and multiple myeloma in women (RR 1.50, 95% CI 1.14-1.98) for highest versus lowest quartile; p-trend < 0.01) but not in men. Neither obesity (weight and body mass index) nor abdominal fat (waist-to-hip ratio, waist or hip circumference) measures were positively associated with overall non-Hodgkin's lymphoma and multiple myeloma. Relative risks for highest versus lowest body mass index quartile were 1.09 (95% CI 0.85-1.38) and 0.92 (95% CI 0.71-1.19) for men and women, respectively. Women in the upper body mass index quartile were at greater risk of diffuse large B-cell lymphoma (RR 2.18, 95% CI 1.05-4.53) and taller women had an elevated risk of follicular lymphoma (RR 1.25, 95% CI 0.59-2.62). Among men, height and body mass index were non-significantly, positively related to follicular lymphoma. Multiple myeloma risk alone was elevated for taller women (RR 2.34, 95% CI 1.29-4.21) and heavier men (RR 1.77, 95% CI 1.02-3.05).

    CONCLUSIONS:

    The EPIC analyses support an association between height and overall non-Hodgkin's lymphoma and multiple myeloma among women and suggest heterogeneous subtype associations. This is one of the first prospective studies focusing on central adiposity and non-Hodgkin's lymphoma subtypes.

  • 45. Campanella, Gianluca
    et al.
    Gunter, Marc J.
    Polidoro, Silvia
    Krogh, Vittorio
    Palli, Domenico
    Panico, Salvatore
    Sacerdote, Carlotta
    Tumino, Rosario
    Fiorito, Giovanni
    Guarrera, Simonetta
    Iacoviello, Licia
    Bergdahl, Ingvar A.
    Umeå universitet, Medicinska fakulteten, Enheten för biobanksforskning.
    Melin, Beatrice
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Lenner, Per
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    de Kok, Theo M. C. M.
    Georgiadis, Panagiotis
    Kleinjans, Jos C. S.
    Kyrtopoulos, Soterios A.
    Bueno-de-Mesquita, H. Bas
    Lillycrop, Karen A.
    May, Anne M.
    Onland-Moret, N. Charlotte
    Murray, Robert
    Riboli, Elio
    Verschuren, Monique
    Lund, Eiliv
    Mode, Nicolle
    Sandanger, Torkjel M.
    Fiano, Valentina
    Trevisan, Morena
    Matullo, Giuseppe
    Froguel, Philippe
    Elliott, Paul
    Vineis, Paolo
    Chadeau-Hyam, Marc
    Epigenome-wide association study of adiposity and future risk of obesity-related diseases2018Inngår i: International Journal of Obesity, ISSN 0307-0565, E-ISSN 1476-5497, Vol. 42, nr 12, s. 2022-2035Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Obesity is an established risk factor for several common chronic diseases such as breast and colorectal cancer, metabolic and cardiovascular diseases; however, the biological basis for these relationships is not fully understood. To explore the association of obesity with these conditions, we investigated peripheral blood leucocyte (PBL) DNA methylation markers for adiposity and their contribution to risk of incident breast and colorectal cancer and myocardial infarction.

    Methods: DNA methylation profiles (Illumina Infinium® HumanMethylation450 BeadChip) from 1941 individuals from four population-based European cohorts were analysed in relation to body mass index, waist circumference, waist-hip and waist-height ratio within a meta-analytical framework. In a subset of these individuals, data on genome-wide gene expression level, biomarkers of glucose and lipid metabolism were also available. Validation of methylation markers associated with all adiposity measures was performed in 358 individuals. Finally, we investigated the association of obesity-related methylation marks with breast, colorectal cancer and myocardial infarction within relevant subsets of the discovery population.

    Results: We identified 40 CpG loci with methylation levels associated with at least one adiposity measure. Of these, one CpG locus (cg06500161) in ABCG1 was associated with all four adiposity measures (P = 9.07×10−8 to 3.27×10−18) and lower transcriptional activity of the full-length isoform of ABCG1 (P = 6.00×10−7), higher triglyceride levels (P = 5.37×10−9) and higher triglycerides-to-HDL cholesterol ratio (P = 1.03×10−10). Of the 40 informative and obesity-related CpG loci, two (in IL2RB and FGF18) were significantly associated with colorectal cancer (inversely, P < 1.6×10−3) and one intergenic locus on chromosome 1 was inversely associated with myocardial infarction (P < 1.25×10−3), independently of obesity and established risk factors.

    Conclusion: Our results suggest that epigenetic changes, in particular altered DNA methylation patterns, may be an intermediate biomarker at the intersection of obesity and obesity-related diseases, and could offer clues as to underlying biological mechanisms.

  • 46. Campanella, Gianluca
    et al.
    Gunter, Marc J.
    Polidoro, Silvia
    Krogh, Vittorio
    Palli, Domenico
    Panico, Salvatore
    Sacerdote, Carlotta
    Tumino, Rosario
    Fiorito, Giovanni
    Guarrera, Simonetta
    Iacoviello, Licia
    Bergdahl, Ingvar
    Umeå universitet, Medicinska fakulteten, Enheten för biobanksforskning.
    Melin, Beatrice
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Lenner, Per
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    de Kok, Theo M. C. M.
    Georgiadis, Panagiotis
    Kleinjans, Jos C. S.
    Kyrtopoulos, Soterios A.
    Bueno-de-Mesquita, H. Bas
    Lillycrop, Karen A.
    May, Anne M.
    Onland-Moret, N. Charlotte
    Murray, Robert
    Riboli, Elio
    Verschuren, Monique
    Lund, Eiliv
    Mode, Nicolle
    Sandanger, Torkjel M.
    Fiano, Valentina
    Trevisan, Morena
    Matullo, Giuseppe
    Froguel, Philippe
    Elliott, Paul
    Vineis, Paolo
    Chadeau-Hyam, Marc
    Epigenome-wide association study of adiposity and future risk of obesity-related diseases2018Inngår i: International Journal of Obesity, ISSN 0307-0565, E-ISSN 1476-5497, Vol. 42, nr 12, s. 2022-2035Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background Obesity is an established risk factor for several common chronic diseases such as breast and colorectal cancer, metabolic and cardiovascular diseases; however, the biological basis for these relationships is not fully understood. To explore the association of obesity with these conditions, we investigated peripheral blood leucocyte (PBL) DNA methylation markers for adiposity and their contribution to risk of incident breast and colorectal cancer and myocardial infarction. Methods DNA methylation profiles (Illumina Infinium® HumanMethylation450 BeadChip) from 1941 individuals from four population-based European cohorts were analysed in relation to body mass index, waist circumference, waist-hip and waistheight ratio within a meta-analytical framework. In a subset of these individuals, data on genome-wide gene expression level, biomarkers of glucose and lipid metabolism were also available. Validation of methylation markers associated with all adiposity measures was performed in 358 individuals. Finally, we investigated the association of obesity-related methylation marks with breast, colorectal cancer and myocardial infarction within relevant subsets of the discovery population. Results We identified 40 CpG loci with methylation levels associated with at least one adiposity measure. Of these, one CpG locus (cg06500161) in ABCG1 was associated with all four adiposity measures (P=9.07×10−8 to 3.27×10−18) and lower transcriptional activity of the full-length isoform of ABCG1 (P=6.00×10−7), higher triglyceride levels (P=5.37×10−9) and higher triglycerides-to-HDL cholesterol ratio (P=1.03×10−10). Of the 40 informative and obesity-related CpG loci, two (in IL2RB and FGF18) were significantly associated with colorectal cancer (inversely, P<1.6×10−3) and one intergenic locus on chromosome 1 was inversely associated with myocardial infarction (P<1.25×10−3), independently of obesity and established risk factors. Conclusion Our results suggest that epigenetic changes, in particular altered DNA methylation patterns, may be an intermediate biomarker at the intersection of obesity and obesity-related diseases, and could offer clues as to underlying biological mechanisms.

  • 47. Chadeau-Hyam, M.
    et al.
    Vermeulen, R. C. H.
    Hebels, D. G. A. J.
    Castagne, R.
    Campanella, G.
    Portengen, L.
    Kelly, R. S.
    Bergdahl, Ingvar
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Yrkes- och miljömedicin. Umeå universitet, Medicinska fakulteten, Enheten för biobanksforskning.
    Melin, Beatrice
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper.
    Hallmans, Göran
    Umeå universitet, Medicinska fakulteten, Enheten för biobanksforskning. Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Näringsforskning.
    Palli, D.
    Krogh, V.
    Tumino, R.
    Sacerdote, C.
    Panico, S.
    de Kok, T. M. C. M.
    Smith, M. T.
    Kleinjans, J. C. S.
    Vineis, P.
    Kyrtopoulos, S. A.
    Prediagnostic transcriptomic markers of Chronic lymphocytic leukemia reveal perturbations 10 years before diagnosis2014Inngår i: Annals of Oncology, ISSN 0923-7534, E-ISSN 1569-8041, Vol. 25, nr 5, s. 1065-1072Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND:

    B-cell lymphomas are a diverse group of hematological neoplasms with differential etiology and clinical trajectories. Increased insights in the etiology and the discovery of prediagnostic markers have the potential to improve the clinical course of these neoplasms.

    METHODS:

    We investigated in a prospective study global gene expression in peripheral blood mononuclear cells of 263 incident B-cell lymphoma cases, diagnosed between 1 and 17 years after blood sample collection, and 439 controls, nested within two European cohorts.

    RESULTS:

    Our analyses identified only transcriptomic markers for specific lymphoma subtypes; few markers of multiple myeloma (N = 3), and 745 differentially expressed genes in relation to future risk of chronic lymphocytic leukemia (CLL). The strongest of these associations were consistently found in both cohorts and were related to (B-) cell signaling networks and immune system regulation pathways. CLL markers exhibited very high predictive abilities of disease onset even in cases diagnosed more than 10 years after blood collection.

    CONCLUSIONS:

    This is the first investigation on blood cell global gene expression and future risk of B-cell lymphomas. We mainly identified genes in relation to future risk of CLL that are involved in biological pathways, which appear to be mechanistically involved in CLL pathogenesis. Many but not all of the top hits we identified have been reported previously in studies based on tumor tissues, therefore suggesting that a mixture of preclinical and early disease markers can be detected several years before CLL clinical diagnosis.

  • 48. Costas, Laura
    et al.
    Lujan-Barroso, Leila
    Benavente, Yolanda
    Allen, Naomi E.
    Amiano, Pilar
    Ardanaz, Eva
    Besson, Caroline
    Boeing, Heiner
    Bueno-de-Mesquita, Bas
    Cervenka, Iris
    Fortner, Renee T.
    Fournier, Agnes
    Gunter, Marc
    Harlid, Sophia
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Maria Huerta, Jose
    Jerkeman, Mats
    Jirstrom, Karin
    Kaaks, Rudolf
    Karakatsani, Anna
    Khaw, Kay-Tee
    Kotanidou, Anastasia
    Lund, Eiliv
    Masala, Giovanna
    Mattiello, Amalia
    Melin, Beatrice S.
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Menendez, Virginia
    Murphy, Neil
    Nieters, Alexandra
    Overvad, Kim
    Riboli, Elio
    Sacerdote, Carlotta
    Sanchez, Maria-Jose
    Schmidt, Julie A.
    Sieri, Sabina
    Tjonneland, Anne
    Trichopoulou, Antonia
    Tumino, Rosario
    Vermeulen, Roel
    Weiderpass, Elisabete
    de Sanjose, Silvia
    Agudo, Antonio
    Casabonne, Delphine
    Reproductive Factors, Exogenous Hormone Use, and Risk of B-Cell Non-Hodgkin Lymphoma in a Cohort of Women From the European Prospective Investigation Into Cancer and Nutrition2019Inngår i: American Journal of Epidemiology, ISSN 0002-9262, E-ISSN 1476-6256, Vol. 188, nr 2, s. 274-281Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The role of hormonal factors in the etiology of lymphoid neoplasms remains unclear. Previous studies have yielded conflicting results, have lacked sufficient statistical power to assess many lymphoma subtypes, or have lacked detailed information on relevant exposures. Within the European Prospective Investigation Into Cancer and Nutrition cohort, we analyzed comprehensive data on reproductive factors and exogenous hormone use collected at baseline (1992-2000) among 343,458 women, including data on 1,427 incident cases of B-cell non-Hodgkin lymphoma (NHL) and its major subtypes identified after a mean follow-up period of 14 years (through 2015). We estimated hazard ratios and 95% confidence intervals using multivariable proportional hazards modeling. Overall, we observed no statistically significant associations between parity, age at first birth, breastfeeding, oral contraceptive use, or ever use of postmenopausal hormone therapy and risk of B-cell NHL or its subtypes. Women who had undergone surgical menopause had a 51% higher risk of B-cell NHL (based on 67 cases) than women with natural menopause (hazard ratio = 1.51, 95% confidence interval: 1.17, 1.94). Given that this result may have been due to chance, our results provide little support for the hypothesis that sex hormones play a role in lymphomagenesis.

  • 49.
    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 medulloblastoma2015Inngår i: Journal of Neuro-Oncology, ISSN 0167-594X, E-ISSN 1573-7373, Vol. 125, nr 1, s. 75-78Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 50.
    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 Study2019Inngår i: Cancer Epidemiology, Biomarkers and Prevention, ISSN 1055-9965, E-ISSN 1538-7755, Vol. 28, nr 7, s. 1252-1258Artikkel i tidsskrift (Fagfellevurdert)
    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.

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