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Jakubowska A , Rozkrut D , Antoniou A , Hamann U , Scott RJ , McGuffog L , Healy S , Sinilnikova OM , Rennert G , Lejbkowicz F , Flugelman A , Andrulis IL , Glendon G , Ozcelik H , Thomassen M , Paligo M , Aretini P , Kantala J , Aroer B , Von Wachenfeldt A , Liljegren A , Loman N , Herbst K , Kristoffersson U , Rosenquist R , Karlsson P , Stenmark-Askmalm M , Melin B , Nathanson KL , Domchek SM , Byrski T , Huzarski T , Gronwald J , Menkiszak J , Cybulski C , Serrano P , Osorio A , Cajal TR , Tsitlaidou M , Benitez J , Gilbert M , Rookus M , Aalfs CM , Kluijt I , Boessenkool-Pape JL , Meijers-Heijboer HEJ , Oosterwijk JC , van Asperen CJ , Blok MJ , Nelen MR , van den Ouweland AMW , Seynaeve C , van der Luijt RB , Devilee P , Easton DF , Peock S , Frost D , Platte R , Ellis SD , Fineberg E , Evans DG , Lalloo F , Eeles R , Jacobs C , Adlard J , Davidson R , Eccles D , Cole T , Cook J , Godwin A , Bove B , Stoppa-Lyonnet D , Caux-Moncoutier V , Belotti M , Tirapo C , Mazoyer S , Barjhoux L , Boutry-Kryza N , Pujol P , Coupier I , Peyrat JP , Vennin P , Muller D , Fricker JP , Venat-Bouvet L , Johannsson O , Isaacs C , Schmutzler R , Wappenschmidt B , Meindl A , Arnold N , Varon-Mateeva R , Niederacher D , Sutter C , Deissler H , Preisler-Adams S , Simard J , Soucy P , Durocher F , Chenevix-Trench G , Beesley J , Chen X , Rebbeck T , Couch F , Wang X , Lindor N , Fredericksen Z , Pankratz VS , Peterlongo P , Bonanni B , Fortuzzi S , Peissel B , Szabo C , Mai PL , Loud JT , Lubinski J
Association of PHB 1630 C > T and MTHFR 677 C > T polymorphisms with breast and ovarian cancer risk in BRCA1/2 mutation carriers: results from a multicenter study
British Journal of Cancer. 2012 Jun;106(12) :2016-2024
PMID: WOS:000305011100018    PMCID: PMC3388557   
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Abstract
BACKGROUND: The variable penetrance of breast cancer in BRCA1/2 mutation carriers suggests that other genetic or environmental factors modify breast cancer risk. Two genes of special interest are prohibitin (PHB) and methylene-tetrahydrofolate reductase (MTHFR), both of which are important either directly or indirectly in maintaining genomic integrity. METHODS: To evaluate the potential role of genetic variants within PHB and MTHFR in breast and ovarian cancer risk, 4102 BRCA1 and 2093 BRCA2 mutation carriers, and 6211 BRCA1 and 2902 BRCA2 carriers from the Consortium of Investigators of Modifiers of BRCA1 and BRCA2 (CIMBA) were genotyped for the PHB 1630 C>T (rs6917) polymorphism and the MTHFR 677 C>T (rs1801133) polymorphism, respectively. RESULTS: There was no evidence of association between the PHB 1630 C>T and MTHFR 677 C>T polymorphisms with either disease for BRCA1 or BRCA2 mutation carriers when breast and ovarian cancer associations were evaluated separately. Analysis that evaluated associations for breast and ovarian cancer simultaneously showed some evidence that BRCA1 mutation carriers who had the rare homozygote genotype (TT) of the PHB 1630 C>T polymorphism were at increased risk of both breast and ovarian cancer (HR 1.50, 95% CI 1.10-2.04 and HR 2.16, 95% CI 1.24-3.76, respectively). However, there was no evidence of association under a multiplicative model for the effect of each minor allele. CONCLUSION: The PHB 1630TT genotype may modify breast and ovarian cancer risks in BRCA1 mutation carriers. This association need to be evaluated in larger series of BRCA1 mutation carriers. British Journal of Cancer (2012) 106, 2016-2024. doi:10.1038/bjc.2012.160 www.bjcancer.com Published online 15 May 2012 (C) 2012 Cancer Research UK
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Jakubowska, A. Rozkrut, D. Antoniou, A. Hamann, U. Scott, R. J. McGuffog, L. Healy, S. Sinilnikova, O. M. Rennert, G. Lejbkowicz, F. Flugelman, A. Andrulis, I. L. Glendon, G. Ozcelik, H. Thomassen, M. Paligo, M. Aretini, P. Kantala, J. Aroer, B. Von Wachenfeldt, A. Liljegren, A. Loman, N. Herbst, K. Kristoffersson, U. Rosenquist, R. Karlsson, P. Stenmark-Askmalm, M. Melin, B. Nathanson, K. L. Domchek, S. M. Byrski, T. Huzarski, T. Gronwald, J. Menkiszak, J. Cybulski, C. Serrano, P. Osorio, A. Cajal, T. R. Tsitlaidou, M. Benitez, J. Gilbert, M. Rookus, M. Aalfs, C. M. Kluijt, I. Boessenkool-Pape, J. L. Meijers-Heijboer, H. E. J. Oosterwijk, J. C. van Asperen, C. J. Blok, M. J. Nelen, M. R. van den Ouweland, A. M. W. Seynaeve, C. van der Luijt, R. B. Devilee, P. Easton, D. F. Peock, S. Frost, D. Platte, R. Ellis, S. D. Fineberg, E. Evans, D. G. Lalloo, F. Eeles, R. Jacobs, C. Adlard, J. Davidson, R. Eccles, D. Cole, T. Cook, J. Godwin, A. Bove, B. Stoppa-Lyonnet, D. Caux-Moncoutier, V. Belotti, M. Tirapo, C. Mazoyer, S. Barjhoux, L. Boutry-Kryza, N. Pujol, P. Coupier, I. Peyrat, J-P Vennin, P. Muller, D. Fricker, J-P Venat-Bouvet, L. Johannsson, OTh Isaacs, C. Schmutzler, R. Wappenschmidt, B. Meindl, A. Arnold, N. Varon-Mateeva, R. Niederacher, D. Sutter, C. Deissler, H. Preisler-Adams, S. Simard, J. Soucy, P. Durocher, F. Chenevix-Trench, G. Beesley, J. Chen, X. Rebbeck, T. Couch, F. Wang, X. Lindor, N. Fredericksen, Z. Pankratz, V. S. Peterlongo, P. Bonanni, B. Fortuzzi, S. Peissel, B. Szabo, C. Mai, P. L. Loud, J. T. Lubinski, J. OCGN; SWE BRCA; HEBON; EMBRACE; GEMO Study Collaborators; KConFab; CIMBA Breast Cancer Research Foundation; Susan G Komen Foundation; Istituto Toscano Tumori; Cancer Care Ontario, Canada (ILA); National Cancer Institute, National Institutes of Health[RFA-CA-06-503]; Mayo Rochester Early Career Development Award for Non-Clinician Scientists; Grant Agency of the Czech republic[301/08/P103]; Ministry of Health of the CR[-MZ0 MOU 2005]; Fund for Scientific Research Flanders (FWO)[1.5.150.07]; Ghent university[12051203]; Susan G Komen Foundation Basic, Clinical and Translational; [BCTR0402923] We acknowledge the support by the Breast Cancer Research Foundation to KLN and the Susan G Komen Foundation to SMD.This research was supported by Istituto Toscano Tumori.This work was supported by Cancer Care Ontario, Canada (ILA); and the National Cancer Institute, National Institutes of Health under RFA-CA-06-503 and through cooperative agreements with members of the Breast Cancer Family Registry and P.Is. The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centres in the CFR, nor does mention the trade names, commercial products, or organisations imply endorsement by the US Government or the CFR.Research grant (BCTR0402923) and the Mayo Rochester Early Career Development Award for Non-Clinician Scientists; We acknowledge the contributions of Petr Pohlreich and Zdenek Kleibl (Department of Biochemistry and Experimental Oncology, First Faculty of Medicine, Charles University, Prague, Czech Republic) and the support of the Grant Agency of the Czech republic grant No. 301/08/P103 (to MZ). Lenka Foretova, Machackova Eva and Lukesova Miroslava (Masaryk Memorial Cancer Institute, Brno, Czech Republic) are supported through the Ministry of Health of the CR grant -MZ0 MOU 2005. We acknowledge the contribution of Kim De Leeneer, Kathleen Claes and Anne De Paepe. This research was supported by grant 1.5.150.07 from the Fund for Scientific Research Flanders (FWO) to Kathleen Claes and by grant 12051203 from the Ghent university to Anne De Paepe. Bruce Poppe is Senior Clinical Investigator of the Fund for Scientific Research of Flanders (FWO - Vlaanderen).CI Szabo is supported by Susan G Komen Foundation Basic, Clinical and Translational 35 Nature publishing group London 955im