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

A. Jakubowska; D. Rozkrut; A. Antoniou; U. Hamann; R. J. Scott; L. McGuffog; S. Healy; O. M. Sinilnikova; G. Rennert; F. Lejbkowicz; A. Flugelman; I. L. Andrulis; G. Glendon; H. Ozcelik; M. Thomassen; M. Paligo; P. Aretini; J. Kantala; B. Aroer; A. Von Wachenfeldt; A. Liljegren; N. Loman; K. Herbst; U. Kristoffersson; R. Rosenquist; P. Karlsson; M. Stenmark-Askmalm; B. Melin; K. L. Nathanson; S. M. Domchek; T. Byrski; T. Huzarski; J. Gronwald; J. Menkiszak; C. Cybulski; P. Serrano; A. Osorio; T. R. Cajal; M. Tsitlaidou; J. Benítez; M. Gilbert; M. Rookus; C. M. Aalfs; I. Kluijt; J. L. Boessenkool-Pape; H. E.J. Meijers-Heijboer; J. C. Oosterwijk; C. J. Van Asperen; M. J. Blok; M. R. Nelen; A. M.W. Van Den Ouweland; C. Seynaeve; R. B. Van Der Luijt; P. Devilee; D. F. Easton; S. Peock; D. Frost; R. Platte; S. D. Ellis; E. Fineberg; D. G. Evans; F. Lalloo; R. Eeles; C. Jacobs; J. Adlard; R. Davidson; D. Eccles; T. Cole; J. Cook; A. Godwin; B. Bove; D. Stoppa-Lyonnet; V. Caux-Moncoutier; M. Belotti; C. Tirapo; S. Mazoyer; L. Barjhoux; N. Boutry-Kryza; P. Pujol; I. Coupier; J. P. Peyrat; P. Vennin; D. Muller; J. P. Fricker; L. Venat-Bouvet; O. Th Johannsson; C. Isaacs; R. Schmutzler; B. Wappenschmidt; A. Meindl; N. Arnold; R. Varon-Mateeva; D. Niederacher; C. Sutter; H. Deissler; S. Preisler-Adams; J. Simard; P. Soucy; F. Durocher; G. Chenevix-Trench; J. Beesley; X. Chen; T. Rebbeck; F. Couch; X. Wang; N. Lindor; Z. Fredericksen; V. S. Pankratz; P. Peterlongo; B. Bonanni; S. Fortuzzi; B. Peissel; C. Szabo; P. L. Mai; J. T. Loud; J. Lubinski

doi:10.1038/bjc.2012.160

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

A. Jakubowska, D. Rozkrut, A. Antoniou, U. Hamann, R. J. Scott, L. McGuffog, S. Healy, O. M. Sinilnikova, G. Rennert, F. Lejbkowicz, A. Flugelman, I. L. Andrulis, G. Glendon, H. Ozcelik, M. Thomassen, M. Paligo, P. Aretini, J. Kantala, B. Aroer, A. Von WachenfeldtA. Liljegren, N. Loman, K. Herbst, U. Kristoffersson, R. Rosenquist, P. Karlsson, M. Stenmark-Askmalm, B. Melin, K. L. Nathanson, S. M. Domchek, T. Byrski, T. Huzarski, J. Gronwald, J. Menkiszak, C. Cybulski, P. Serrano, A. Osorio, T. R. Cajal, M. Tsitlaidou, J. Benítez, M. Gilbert, M. Rookus, C. M. Aalfs, I. Kluijt, J. L. Boessenkool-Pape, H. E.J. Meijers-Heijboer, J. C. Oosterwijk, C. J. Van Asperen, M. J. Blok, M. R. Nelen, A. M.W. Van Den Ouweland, C. Seynaeve, R. B. Van Der Luijt, P. Devilee, D. F. Easton, S. Peock, D. Frost, R. Platte, S. D. Ellis, E. Fineberg, D. G. Evans, F. Lalloo, R. Eeles, C. Jacobs, J. Adlard, R. Davidson, D. Eccles, T. Cole, J. Cook, A. Godwin, B. Bove, D. Stoppa-Lyonnet, V. Caux-Moncoutier, M. Belotti, C. Tirapo, S. Mazoyer, L. Barjhoux, N. Boutry-Kryza, P. Pujol, I. Coupier, J. P. Peyrat, P. Vennin, D. Muller, J. P. Fricker, L. Venat-Bouvet, O. Th Johannsson, C. Isaacs, R. Schmutzler, B. Wappenschmidt, A. Meindl, N. Arnold, R. Varon-Mateeva, D. Niederacher, C. Sutter, H. Deissler, S. Preisler-Adams, J. Simard, P. Soucy, F. Durocher, G. Chenevix-Trench, J. Beesley, X. Chen, T. Rebbeck, F. Couch, X. Wang, N. Lindor, Z. Fredericksen, V. S. Pankratz, P. Peterlongo, B. Bonanni, S. Fortuzzi, B. Peissel, C. Szabo, P. L. Mai, J. T. Loud, J. Lubinski

Research output: Contribution to journal › Article › peer-review

20 Scopus citations

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.

Original language	English (US)
Pages (from-to)	2016-2024
Number of pages	9
Journal	British journal of cancer
Volume	106
Issue number	12
DOIs	https://doi.org/10.1038/bjc.2012.160
State	Published - Jun 5 2012

Keywords

BRCA1/2 mutation carriers
MTHFR 677 C>T polymorphism
PHB 1630 C>T polymorphism
breast/ovarian cancer risk

ASJC Scopus subject areas

Oncology
Cancer Research

Access to Document

10.1038/bjc.2012.160

Cite this

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., ... Lubinski, J. (2012). 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, 106(12), 2016-2024. https://doi.org/10.1038/bjc.2012.160

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, Benítez, 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, OT, 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 2012, '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, vol. 106, no. 12, pp. 2016-2024. https://doi.org/10.1038/bjc.2012.160

@article{0a2cc23628d340e3a3314cbd131ce42a,

title = "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",

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.",

keywords = "BRCA1/2 mutation carriers, MTHFR 677 C>T polymorphism, PHB 1630 C>T polymorphism, breast/ovarian cancer risk",

author = "A. Jakubowska and D. Rozkrut and A. Antoniou and U. Hamann and Scott, {R. J.} and L. McGuffog and S. Healy and Sinilnikova, {O. M.} and G. Rennert and F. Lejbkowicz and A. Flugelman and Andrulis, {I. L.} and G. Glendon and H. Ozcelik and M. Thomassen and M. Paligo and P. Aretini and J. Kantala and B. Aroer and {Von Wachenfeldt}, A. and A. Liljegren and N. Loman and K. Herbst and U. Kristoffersson and R. Rosenquist and P. Karlsson and M. Stenmark-Askmalm and B. Melin and Nathanson, {K. L.} and Domchek, {S. M.} and T. Byrski and T. Huzarski and J. Gronwald and J. Menkiszak and C. Cybulski and P. Serrano and A. Osorio and Cajal, {T. R.} and M. Tsitlaidou and J. Ben{\'i}tez and M. Gilbert and M. Rookus and Aalfs, {C. M.} and I. Kluijt and Boessenkool-Pape, {J. L.} and Meijers-Heijboer, {H. E.J.} and Oosterwijk, {J. C.} and {Van Asperen}, {C. J.} and Blok, {M. J.} and Nelen, {M. R.} and {Van Den Ouweland}, {A. M.W.} and C. Seynaeve and {Van Der Luijt}, {R. B.} and P. Devilee and Easton, {D. F.} and S. Peock and D. Frost and R. Platte and Ellis, {S. D.} and E. Fineberg and Evans, {D. G.} and F. Lalloo and R. Eeles and C. Jacobs and J. Adlard and R. Davidson and D. Eccles and T. Cole and J. Cook and A. Godwin and B. Bove and D. Stoppa-Lyonnet and V. Caux-Moncoutier and M. Belotti and C. Tirapo and S. Mazoyer and L. Barjhoux and N. Boutry-Kryza and P. Pujol and I. Coupier and Peyrat, {J. P.} and P. Vennin and D. Muller and Fricker, {J. P.} and L. Venat-Bouvet and Johannsson, {O. Th} and C. Isaacs and R. Schmutzler and B. Wappenschmidt and A. Meindl and N. Arnold and R. Varon-Mateeva and D. Niederacher and C. Sutter and H. Deissler and S. Preisler-Adams and J. Simard and P. Soucy and F. Durocher and G. Chenevix-Trench and J. Beesley and X. Chen and T. Rebbeck and F. Couch and X. Wang and N. Lindor and Z. Fredericksen and Pankratz, {V. S.} and P. Peterlongo and B. Bonanni and S. Fortuzzi and B. Peissel and C. Szabo and Mai, {P. L.} and Loud, {J. T.} and J. Lubinski",

note = "Funding Information: EMBRACE is supported by Cancer Research UK grants C1287/ A10118 and C1287/A11990. D Gareth Evans and Fiona Lalloo are supported by an NIHR grant to the Biomedical Research Centre, Manchester. The Investigators at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust are supported by an NIHR grant to the Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust. Ros Eeles, Elizabeth Bancroft and Lucia D{\textquoteright}Mello are also supported by Cancer Research UK Grant C5047/A8385. Fox Chase Cancer Center (FCCC) Andrew Godwin was funded by U01CA69631, 5U01CA113916, the Ovarian Cancer Research Fund, the Eileen Stein Jacoby Fund. The author acknowledges the support from The University of Kansas Cancer Center and the Kansas Bioscience Authority Eminent Scholar Program. AKG is the Chancellors Distinguished Chair in Biomedical Sciences endowed Professor. Funding Information: The Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer (kConFab) We wish to thank Heather Thorne, Eveline Niedermayr, all the kConFab research nurses and staff, the heads and staff of the Family Cancer Clinics, and the Clinical Follow-Up Study (funded 2001-2009 by NHMRC and currently by the National Breast Cancer Foundation and Cancer Australia #628333) for their contributions to this resource, and the many families who contributed to kConFab. kConFab is supported by grants from the National Breast Cancer Foundation, the National Health and Medical Research Council (NHMRC) and by the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania and South Australia, and the Cancer Foundation of Western Australia. Modifiers and Genetics in Cancer (MAGIC) NIH grants R01-CA083855 and R01-CA102776. Mayo Clinic (MAYO) MAYO was supported by a National Institutes of Health Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201) to the Mayo Clinic and R01 CA128978, and grants from the Komen Foundation for the Cure and the Breast Cancer Research Foundation. Milan Breast Cancer Study Group (MBCSG) MBCSG thanks Paolo Radice, Bernard Peissel, Daniela Zaffaroni and Marco A: Pierotti of the Fondazione IRCCS Istituto Nazionale Tumori and Monica Barile of the Istituto Europeo di Oncologia, Milano, Italy. Funding Information: The HEBON study is supported by the Dutch Cancer Society grants NKI1998-1854, NKI2004-3088, NKI2007-3756 and the ZonMW grant 91109024. International Hereditary Cancer Centre (IHCC) Iceland, Landspitali - University Hospital (ILUH) The ILUH was supported by Landspitali University Hospital Research Fund, Walking Together Research Fund. Funding Information: The study was supported by the Ligue National Contre le Cancer; Association for International Cancer Research Grant (AICR-07-0454); and the Association {\textquoteleft}Le cancer du sein, parlons-en!{\textquoteright} Award. Georgetown Claudine Isaacs received support from the Familial Cancer Registry and the Tissue Culture Shared Resource at Georgetown University (NIH/NCI grant P30-CA051008), the Cancer Genetics Network (HHSN261200744000C), and Swing Fore the Cure. Funding Information: This work was supported by the Canadian Institutes of Health Research for the {\textquoteleft}CIHR Team in Familial Risks of Breast Cancer{\textquoteright} program and by the Canadian Breast Cancer Research Alliance-grant #019511. Funding Information: Paolo Peterlongo is supported by funds from Italian citizens who allocated the 5 ⨯ 1000 share of their tax payment to the Fondazione IRCCS Istituto Nazionale Tumori, according to Italian laws (INT-Institutional strategic projects {\textquoteleft}5 ⨯ 1000{\textquoteright}). Funding Information: CI Szabo is supported by Susan G Komen Foundation Basic, Clinical and Translational 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). National Cancer Institute (NCI) National Israeli Cancer Control Center (NICCC) The NICCC cohort is supported by the Breast Cancer Research Foundation (BCRF). Ontario Cancer Genetics Network (OCGN) We wish to thank Mona Gill, Lucine Collins, Nalan Gokgoz, Teresa Selander, Nayana Weerasooriya and members of the Ontario Cancer Genetics Network for their contributions to the study. Funding Information: The CIMBA data management and analysis are supported by Cancer Research – UK. Antonis C Antoniou is a Cancer Research – UK Senior Cancer Research Fellow. Spanish National Cancer Centre (CNIO) The research leading to these results has been partially funded by Mutua Madrile{\~n}a Foundation, {\textquoteleft}Red de Investigaci{\'o}n en C{\'a}ncer RD06/0020/1160{\textquoteright} and Spanish Ministry of Science and Innovation (FIS PI08 1120 and SAF2010-20493). Deutsches Krebsforschungszentrum (DKFZ) The DKFZ study was supported by the DKFZ Epidemiological study of BRCA1 and BRCA2 mutation carriers (EMBRACE) Douglas F Easton is the PI of the study. EMBRACE Collaborating Centres are: Coordinating Centre, Cambridge: Susan Peock, Debra Frost, Radka Platte, Steve D Ellis, Elena Fineberg. North of Scotland Regional Genetics Service, Aberdeen: Zosia Miedzybrodzka, Helen Gregory. Northern Ireland Regional Genetics Service, Belfast: Patrick Morrison, Lisa Jeffers. West Midlands Regional Clinical Genetics Service, Birmingham: Trevor Cole, Kai-ren Ong, Jonathan Hoffman. South West Regional Genetics Service, Bristol: Alan Donaldson, Margaret James. East Anglian Regional Genetics Service, Cambridge: Joan Paterson, Sarah Downing, Amy Taylor. Medical Genetics Services for Wales, Cardiff: Alexandra Murray, Mark T Rogers, Emma McCann. St James{\textquoteright}s Hospital, Dublin and National Centre for Medical Genetics, Dublin: M John Kennedy, David Barton. South East of Scotland Regional Genetics Service, Edinburgh: Mary Porteous, Sarah Drummond. Peninsula Clinical Genetics Service, Exeter: Carole Brewer, Emma Kivuva, Anne Searle, Selina Goodman, Kathryn Hill. West of Scotland Regional Genetics Service, Glasgow: Rosemarie Davidson, Victoria Murday, Nicola Bradshaw, Lesley Snadden, Mark Longmuir, Catherine Watt, Sarah Gibson, Eshika Haque, Ed Tobias, Alexis Duncan. South East Thames Regional Genetics Service, Guy{\textquoteright}s Hospital London: Louise Izatt, Chris Jacobs, Caroline Langman, Anna Whaite. North West Thames Regional Genetics Service, Harrow: Huw Dorkins. Leicestershire Clinical Genetics Service, Leicester: Julian Barwell. Yorkshire Regional Genetics Service, Leeds: Julian Adlard, Carol Chu, Julie Miller. Cheshire and Merseyside Clinical Genetics Service, Liverpool: Ian Ellis, Catherine Houghton. Manchester Regional Genetics Service, Manchester: D Gareth Evans, Fiona Lalloo, Jane Taylor. North East Thames Regional Genetics Service, NE Thames, London: Lucy Side, Alison Male, Cheryl Berlin. Nottingham Centre for Medical Genetics, Nottingham: Jacqueline Eason, Rebecca Collier. Northern Clinical Genetics Service, Newcastle: Fiona Douglas, Oonagh Claber, Irene Jobson. Oxford Regional Genetics Service, Oxford: Lisa Walker, Diane McLeod, Dorothy Halliday, Sarah Durell, Barbara Stayner. The Institute of Cancer Research and Royal Marsden NHS Foundation Trust: Ros Eeles, Susan Shanley, Nazneen Rahman, Richard Houlston, Elizabeth Bancroft, Lucia D{\textquoteright}Mello, Elizabeth Page, Audrey Ardern-Jones, Kelly Kohut, Jennifer Wiggins, Elena Castro, Anita Mitra, Lisa Robertson. North Trent Clinical Genetics Service, Sheffield: Jackie Cook, Oliver Quarrell, Cathryn Bardsley. South West Thames Regional Genetics Service, London: Shirley Hodgson, Sheila Goff, Glen Brice, Lizzie Winchester, Charlotte Eddy, Vishakha Tripathi, Virginia Attard. Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton: Diana Eccles, Anneke Lucassen, Gillian Crawford, Donna McBride, Sarah Smalley. Funding Information: The German Consortium of Hereditary Breast and Ovarian Cancer (GC-HBOC) GC-HBOC is supported by a grant of the German Cancer Aid (grant 109076) and by the Centre of Molecular Medicine Cologne (CMMC).",

year = "2012",

month = jun,

day = "5",

doi = "10.1038/bjc.2012.160",

language = "English (US)",

volume = "106",

pages = "2016--2024",

journal = "British Journal of Cancer",

issn = "0007-0920",

publisher = "Nature Publishing Group",

number = "12",

}

TY - JOUR

T1 - Association of PHB 1630 C>T and MTHFR 677 C>T polymorphisms with breast and ovarian cancer risk in BRCA1/2 mutation carriers

T2 - Results from a multicenter study

AU - Jakubowska, A.

AU - Rozkrut, D.

AU - Antoniou, A.

AU - Hamann, U.

AU - Scott, R. J.

AU - McGuffog, L.

AU - Healy, S.

AU - Sinilnikova, O. M.

AU - Rennert, G.

AU - Lejbkowicz, F.

AU - Flugelman, A.

AU - Andrulis, I. L.

AU - Glendon, G.

AU - Ozcelik, H.

AU - Thomassen, M.

AU - Paligo, M.

AU - Aretini, P.

AU - Kantala, J.

AU - Aroer, B.

AU - Von Wachenfeldt, A.

AU - Liljegren, A.

AU - Loman, N.

AU - Herbst, K.

AU - Kristoffersson, U.

AU - Rosenquist, R.

AU - Karlsson, P.

AU - Stenmark-Askmalm, M.

AU - Melin, B.

AU - Nathanson, K. L.

AU - Domchek, S. M.

AU - Byrski, T.

AU - Huzarski, T.

AU - Gronwald, J.

AU - Menkiszak, J.

AU - Cybulski, C.

AU - Serrano, P.

AU - Osorio, A.

AU - Cajal, T. R.

AU - Tsitlaidou, M.

AU - Benítez, J.

AU - Gilbert, M.

AU - Rookus, M.

AU - Aalfs, C. M.

AU - Kluijt, I.

AU - Boessenkool-Pape, J. L.

AU - Meijers-Heijboer, H. E.J.

AU - Oosterwijk, J. C.

AU - Van Asperen, C. J.

AU - Blok, M. J.

AU - Nelen, M. R.

AU - Van Den Ouweland, A. M.W.

AU - Seynaeve, C.

AU - Van Der Luijt, R. B.

AU - Devilee, P.

AU - Easton, D. F.

AU - Peock, S.

AU - Frost, D.

AU - Platte, R.

AU - Ellis, S. D.

AU - Fineberg, E.

AU - Evans, D. G.

AU - Lalloo, F.

AU - Eeles, R.

AU - Jacobs, C.

AU - Adlard, J.

AU - Davidson, R.

AU - Eccles, D.

AU - Cole, T.

AU - Cook, J.

AU - Godwin, A.

AU - Bove, B.

AU - Stoppa-Lyonnet, D.

AU - Caux-Moncoutier, V.

AU - Belotti, M.

AU - Tirapo, C.

AU - Mazoyer, S.

AU - Barjhoux, L.

AU - Boutry-Kryza, N.

AU - Pujol, P.

AU - Coupier, I.

AU - Peyrat, J. P.

AU - Vennin, P.

AU - Muller, D.

AU - Fricker, J. P.

AU - Venat-Bouvet, L.

AU - Johannsson, O. Th

AU - Isaacs, C.

AU - Schmutzler, R.

AU - Wappenschmidt, B.

AU - Meindl, A.

AU - Arnold, N.

AU - Varon-Mateeva, R.

AU - Niederacher, D.

AU - Sutter, C.

AU - Deissler, H.

AU - Preisler-Adams, S.

AU - Simard, J.

AU - Soucy, P.

AU - Durocher, F.

AU - Chenevix-Trench, G.

AU - Beesley, J.

AU - Chen, X.

AU - Rebbeck, T.

AU - Couch, F.

AU - Wang, X.

AU - Lindor, N.

AU - Fredericksen, Z.

AU - Pankratz, V. S.

AU - Peterlongo, P.

AU - Bonanni, B.

AU - Fortuzzi, S.

AU - Peissel, B.

AU - Szabo, C.

AU - Mai, P. L.

AU - Loud, J. T.

AU - Lubinski, J.

N1 - Funding Information: EMBRACE is supported by Cancer Research UK grants C1287/ A10118 and C1287/A11990. D Gareth Evans and Fiona Lalloo are supported by an NIHR grant to the Biomedical Research Centre, Manchester. The Investigators at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust are supported by an NIHR grant to the Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust. Ros Eeles, Elizabeth Bancroft and Lucia D’Mello are also supported by Cancer Research UK Grant C5047/A8385. Fox Chase Cancer Center (FCCC) Andrew Godwin was funded by U01CA69631, 5U01CA113916, the Ovarian Cancer Research Fund, the Eileen Stein Jacoby Fund. The author acknowledges the support from The University of Kansas Cancer Center and the Kansas Bioscience Authority Eminent Scholar Program. AKG is the Chancellors Distinguished Chair in Biomedical Sciences endowed Professor. Funding Information: The Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer (kConFab) We wish to thank Heather Thorne, Eveline Niedermayr, all the kConFab research nurses and staff, the heads and staff of the Family Cancer Clinics, and the Clinical Follow-Up Study (funded 2001-2009 by NHMRC and currently by the National Breast Cancer Foundation and Cancer Australia #628333) for their contributions to this resource, and the many families who contributed to kConFab. kConFab is supported by grants from the National Breast Cancer Foundation, the National Health and Medical Research Council (NHMRC) and by the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania and South Australia, and the Cancer Foundation of Western Australia. Modifiers and Genetics in Cancer (MAGIC) NIH grants R01-CA083855 and R01-CA102776. Mayo Clinic (MAYO) MAYO was supported by a National Institutes of Health Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201) to the Mayo Clinic and R01 CA128978, and grants from the Komen Foundation for the Cure and the Breast Cancer Research Foundation. Milan Breast Cancer Study Group (MBCSG) MBCSG thanks Paolo Radice, Bernard Peissel, Daniela Zaffaroni and Marco A: Pierotti of the Fondazione IRCCS Istituto Nazionale Tumori and Monica Barile of the Istituto Europeo di Oncologia, Milano, Italy. Funding Information: The HEBON study is supported by the Dutch Cancer Society grants NKI1998-1854, NKI2004-3088, NKI2007-3756 and the ZonMW grant 91109024. International Hereditary Cancer Centre (IHCC) Iceland, Landspitali - University Hospital (ILUH) The ILUH was supported by Landspitali University Hospital Research Fund, Walking Together Research Fund. Funding Information: The study was supported by the Ligue National Contre le Cancer; Association for International Cancer Research Grant (AICR-07-0454); and the Association ‘Le cancer du sein, parlons-en!’ Award. Georgetown Claudine Isaacs received support from the Familial Cancer Registry and the Tissue Culture Shared Resource at Georgetown University (NIH/NCI grant P30-CA051008), the Cancer Genetics Network (HHSN261200744000C), and Swing Fore the Cure. Funding Information: This work was supported by the Canadian Institutes of Health Research for the ‘CIHR Team in Familial Risks of Breast Cancer’ program and by the Canadian Breast Cancer Research Alliance-grant #019511. Funding Information: Paolo Peterlongo is supported by funds from Italian citizens who allocated the 5 ⨯ 1000 share of their tax payment to the Fondazione IRCCS Istituto Nazionale Tumori, according to Italian laws (INT-Institutional strategic projects ‘5 ⨯ 1000’). Funding Information: CI Szabo is supported by Susan G Komen Foundation Basic, Clinical and Translational 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). National Cancer Institute (NCI) National Israeli Cancer Control Center (NICCC) The NICCC cohort is supported by the Breast Cancer Research Foundation (BCRF). Ontario Cancer Genetics Network (OCGN) We wish to thank Mona Gill, Lucine Collins, Nalan Gokgoz, Teresa Selander, Nayana Weerasooriya and members of the Ontario Cancer Genetics Network for their contributions to the study. Funding Information: The CIMBA data management and analysis are supported by Cancer Research – UK. Antonis C Antoniou is a Cancer Research – UK Senior Cancer Research Fellow. Spanish National Cancer Centre (CNIO) The research leading to these results has been partially funded by Mutua Madrileña Foundation, ‘Red de Investigación en Cáncer RD06/0020/1160’ and Spanish Ministry of Science and Innovation (FIS PI08 1120 and SAF2010-20493). Deutsches Krebsforschungszentrum (DKFZ) The DKFZ study was supported by the DKFZ Epidemiological study of BRCA1 and BRCA2 mutation carriers (EMBRACE) Douglas F Easton is the PI of the study. EMBRACE Collaborating Centres are: Coordinating Centre, Cambridge: Susan Peock, Debra Frost, Radka Platte, Steve D Ellis, Elena Fineberg. North of Scotland Regional Genetics Service, Aberdeen: Zosia Miedzybrodzka, Helen Gregory. Northern Ireland Regional Genetics Service, Belfast: Patrick Morrison, Lisa Jeffers. West Midlands Regional Clinical Genetics Service, Birmingham: Trevor Cole, Kai-ren Ong, Jonathan Hoffman. South West Regional Genetics Service, Bristol: Alan Donaldson, Margaret James. East Anglian Regional Genetics Service, Cambridge: Joan Paterson, Sarah Downing, Amy Taylor. Medical Genetics Services for Wales, Cardiff: Alexandra Murray, Mark T Rogers, Emma McCann. St James’s Hospital, Dublin and National Centre for Medical Genetics, Dublin: M John Kennedy, David Barton. South East of Scotland Regional Genetics Service, Edinburgh: Mary Porteous, Sarah Drummond. Peninsula Clinical Genetics Service, Exeter: Carole Brewer, Emma Kivuva, Anne Searle, Selina Goodman, Kathryn Hill. West of Scotland Regional Genetics Service, Glasgow: Rosemarie Davidson, Victoria Murday, Nicola Bradshaw, Lesley Snadden, Mark Longmuir, Catherine Watt, Sarah Gibson, Eshika Haque, Ed Tobias, Alexis Duncan. South East Thames Regional Genetics Service, Guy’s Hospital London: Louise Izatt, Chris Jacobs, Caroline Langman, Anna Whaite. North West Thames Regional Genetics Service, Harrow: Huw Dorkins. Leicestershire Clinical Genetics Service, Leicester: Julian Barwell. Yorkshire Regional Genetics Service, Leeds: Julian Adlard, Carol Chu, Julie Miller. Cheshire and Merseyside Clinical Genetics Service, Liverpool: Ian Ellis, Catherine Houghton. Manchester Regional Genetics Service, Manchester: D Gareth Evans, Fiona Lalloo, Jane Taylor. North East Thames Regional Genetics Service, NE Thames, London: Lucy Side, Alison Male, Cheryl Berlin. Nottingham Centre for Medical Genetics, Nottingham: Jacqueline Eason, Rebecca Collier. Northern Clinical Genetics Service, Newcastle: Fiona Douglas, Oonagh Claber, Irene Jobson. Oxford Regional Genetics Service, Oxford: Lisa Walker, Diane McLeod, Dorothy Halliday, Sarah Durell, Barbara Stayner. The Institute of Cancer Research and Royal Marsden NHS Foundation Trust: Ros Eeles, Susan Shanley, Nazneen Rahman, Richard Houlston, Elizabeth Bancroft, Lucia D’Mello, Elizabeth Page, Audrey Ardern-Jones, Kelly Kohut, Jennifer Wiggins, Elena Castro, Anita Mitra, Lisa Robertson. North Trent Clinical Genetics Service, Sheffield: Jackie Cook, Oliver Quarrell, Cathryn Bardsley. South West Thames Regional Genetics Service, London: Shirley Hodgson, Sheila Goff, Glen Brice, Lizzie Winchester, Charlotte Eddy, Vishakha Tripathi, Virginia Attard. Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton: Diana Eccles, Anneke Lucassen, Gillian Crawford, Donna McBride, Sarah Smalley. Funding Information: The German Consortium of Hereditary Breast and Ovarian Cancer (GC-HBOC) GC-HBOC is supported by a grant of the German Cancer Aid (grant 109076) and by the Centre of Molecular Medicine Cologne (CMMC).

PY - 2012/6/5

Y1 - 2012/6/5

N2 - 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.

AB - 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.

KW - BRCA1/2 mutation carriers

KW - MTHFR 677 C>T polymorphism

KW - PHB 1630 C>T polymorphism

KW - breast/ovarian cancer risk

UR - http://www.scopus.com/inward/record.url?scp=84862017252&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84862017252&partnerID=8YFLogxK

U2 - 10.1038/bjc.2012.160

DO - 10.1038/bjc.2012.160

M3 - Article

C2 - 22669161

AN - SCOPUS:84862017252

SN - 0007-0920

VL - 106

SP - 2016

EP - 2024

JO - British Journal of Cancer

JF - British Journal of Cancer

IS - 12

ER -

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

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