Aim of study
The aim of the study was to investigate the role of individual susceptibility factors on the aetiology of brain tumours. The study was a part of the INTERPHONE study.
Implementation
In this study we examined the possible associations between genotypes of different gene polymorphisms and the risk of primary adult brain tumours (glioma, glioblastoma or meningioma). The study was conducted as an international collaboration forming a part of the INTERPHONE study so that genotypes of the DNA-repair genes XRCC1 and XRCC3 were studied at STUK. We genotyped DNA collected for an international population-based case-control study of 725 glioma cases (containing 329 glioblastoma cases), 546 meningioma cases and 1612 controls. Study participants were residents of Denmark, Finland, Sweden, and southeast England. Genotypes of xenobiotic metabolism, DNA-damage repair, apoptosis and folate metabolism genes were genotyped in three other laboratories using these same DNA samples.
Polymorphisms of xenobiotic metabolism genes were found not to be associated with the risk of brain tumours (1). Polymorphims of important DNA-damage repair genes (p53 and ATM) were shown to both increase and decrease the risk of brain tumours depending on the combination of the inherited genotypes (2).
The combination of the rare variants of the DNA-repair genes XRCC1 and XRCC3 indicated possible increase in the risk of glioma and meningioma (3). When 1459 polymorphisms in the DNA-damage repair genes were studied, it was shown that glioma risk was increased most prominently in association with a certain polymorphism at the CHAF1-gene (4). Polymorphism at the BRIP1-gene was consistently associated with an increased risk of developing meningioma (5).
A rare variant of the apoptosis gene CASP8 was shown to increase the glioma risk (6). However, the same variant was not associated with a statistically significantly increased risk of meningioma (7). Variant genotypes of folate metabolism genes MTHFR and MTRR were associated with increased risk of both glioma and meningioma (8).
Exploitation
Results of the study have been published in the following articles:
(1) Schwartzbaum JA, Ahlbom A, Lönn S, Warholm M, Rannug A, Auvinen A, Christensen HC, Henriksson R, Johansen C, Lindholm C, Malmer B, Salminen T, Schoemaker MJ, Swerdlow AJ, Feychting M. An international case-control study of glutathione transferase and functionally related polymorphisms and risk of primary adult brain tumors. Cancer Epidemiology Biomarkers Prev. 2007; 16(3): 559-565.
(2) Malmer B, Feychting M, Lönn, S, Lindström S, Grönberg H, Ahlbom A, Schwartzbaum J, Auvinen A, Collatz Christensen H, Johansen C, Kiuru A, Mudie N, Salminen T, Schoemaker MJ, Swerdlow AJ, Henriksson R. Genetic variation in p53 and ATM haplotypes and risk of glioma and meningioma. J. Neurooncology 2007; 82: 229-237.
(3)Kiuru A, Lindholm C, Heinävaara S, Ilus T, Jokinen P, Haapasalo H, Salminen T, Collatz Christensen H, Feychting M, Johansen C, Lönn S, Malmer B, Schoemaker MJ, Swerdlow AJ, and Auvinen A. XRCC1 and XRCC3 variants and risk of glioma and meningioma. J. Neurooncology 2008; 88(2): 135-142.
(4) Bethke L, Murray A, Webb E, Schoemaker M, Muir K, McKinney P, Hepworth S, Dimitropoulou P, Lophatananon A, Feychting M, Lönn S, Ahlbom A, Malmer B, Henriksson R, Auvinen A, Kiuru A, Salminen T, Johansen C, Collatz Christensen H, Kosteljanetz M, Swerdlow A, and Houlston R. Comprehensive analysis of the role of DNA repair gene polymorphisms on risk of glioma. Hum. Mol. Genet. 2008; 17(6): 800-805.
(5) Bethke L, Murray A, Webb E, Schoemaker M, Muir K, McKinney P, Hepworth S, Dimitropoulou P, Lophatananon A, Feychting M, Lönn S, Ahlbom A, Malmer B, Henriksson R, Auvinen A, Kiuru A, Salminen T, Johansen C, Collatz Christensen H, Kosteljanetz M, Swerdlow A, and Houlston R. Comprehensive analysis of DNA repair gene variants and risk of meningioma. J. Natl. Cancer Inst. 2008; 100(4): 270-276.
(6) Bethke L, Sullivan K, Webb E, Murray A, Schoemaker M, Auvinen A, Kiuru A, Salminen T, Johansen C, Christensen HC, Muir K, McKinney P, Hepworth S, Dimitropoulou P, Lophatananon A, Feychting M, Lönn S, Ahlbom A, Malmer B, Henriksson R, Swerdlow A, and Houlston R. The common D302H variant of CASP8 is associated with risk of glioma. Cancer Epidemiol. Biomarkers Prev. 2008; 17(4): 987-989.
(7) Bethke L, Sullivan K, Webb E, Murray A, Schoemaker M, Auvinen A, Kiuru A, Salminen T, Johansen C, Collatz Christensen H, Muir K, McKinney P, Hepworth S, Dimitropoulou P, Lophatananon A, Feychting M, Lönn S, Ahlbom A, Malmer B, Henriksson R, Swerdlow A, and Houlston R. CASP8 D302H and meningioma risk: An analysis of five case-control series. Cancer Letters 2009; 273: 312-315.
(8) Bethke L, Murray A, Webb E, Schoemaker M, Muir K, McKinney P, Hepworth S, Dimitropoulou P, Lophatananon A, Feychting M, Lönn S, Ahlbom A, Malmer B, Henriksson R, Auvinen A, Kiuru A, Salminen T, Johansen C, Collatz Christensen H, Kosteljanetz M, Swerdlow A, and Houlston R. Functional polymorphisms in folate metabolism genes influence the risk of meningioma and glioma. Cancer Epidemiol. Biomarkers Prev. 2008; 17(5): 1195-1202.
Collaborators
Danish Cancer Society; Department of Neurology, Helsinki University Hospital; Department of Neurology, Kuopio University Hospital; Department of Neurology, Oulu University Hospital; Department of Neurology, Tampere University Hospital; Department of Neurology, Turku University Hospital; Department of Pathology, Tampere University Hospital; Institute of Cancer Research (UK); Karolinska Institutet (Sweden); The Finnish Cancer Registry, and Umeå University Hospital (Sweden).
Timetable
2000 - 2007
Responsible scientist
Anne Kiuru
