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Common Genetic Variants and Modification of Penetrance of BRCA2-Associated Breast Cancer

  1. Author:
    Gaudet, M. M.
    Kirchhoff, T.
    Green, T.
    Vijai, J.
    Korn, J. M.
    Guiducci, C.
    Segre, A. V.
    McGee, K.
    McGuffog, L.
    Kartsonaki, C.
    Morrison, J.
    Healey, S.
    Sinilnikova, O. M.
    Stoppa-Lyonnet, D.
    Mazoyer, S.
    Gauthier-Villars, M.
    Sobol, H.
    Longy, M.
    Frenay, M.
    Hogervorst, F. B. L.
    Rookus, M. A.
    Collee, J. M.
    Hoogerbrugge, N.
    van Roozendaal, K. E. P.
    Piedmonte, M.
    Rubinstein, W.
    Nerenstone, S.
    Van Le, L.
    Blank, S. V.
    Caldes, T.
    de la Hoya, M.
    Nevanlinna, H.
    Aittomaki, K.
    Lazaro, C.
    Blanco, I.
    Arason, A.
    Johannsson, O. T.
    Barkardottir, R. B.
    Devilee, P.
    Olopade, O. I.
    Neuhausen, S. L.
    Wang, X. S.
    Fredericksen, Z. S.
    Peterlongo, P.
    Manoukian, S.
    Barile, M.
    Viel, A.
    Radice, P.
    Phelan, C. M.
    Narod, S.
    Rennert, G.
    Lejbkowicz, F.
    Flugelman, A.
    Andrulis, I. L.
    Glendon, G.
    Ozcelik, H.
    Tol, A. E.
    Montagna, M.
    D'Andrea, E.
    Friedman, E.
    Laitman, Y.
    Borg, A.
    Beattie, M.
    Ramus, S. J.
    Domchek, S. M.
    Nathanson, K. L.
    Rebbeck, T.
    Spurdle, A. B.
    Chen, X. Q.
    Holl, H.
    John, E. M.
    Hopper, J. L.
    Buys, S. S.
    Daly, M. B.
    Southey, M. C.
    Terry, M. B.
    Tung, N.
    Hansen, T. V. O.
    Nielsen, F. C.
    Greene, M. I.
    Mai, P. L.
    Osorio, A.
    Duran, M.
    Andres, R.
    Benitez, J.
    Weitzel, J. N.
    Garber, J.
    Hamann, U.
    Peock, S.
    Cook, M.
    Oliver, C.
    Frost, D.
    Platte, R.
    Evans, D. G.
    Lalloo, F.
    Eeles, R.
    Izatt, L.
    Walker, L.
    Eason, J.
    Barwell, J.
    Godwin, A. K.
    Schmutzler, R. K.
    Wappenschmidt, B.
    Engert, S.
    Arnold, N.
    Gadzicki, D.
    Dean, M.
    Gold, B.
    Klein, R. J.
    Couch, F. J.
    Chenevix-Trench, G.
    Easton, D. F.
    Daly, M. J.
    Antoniou, A. C.
    Altshuler, D. M.
    Offit, K.
    kConFab, G. S. C. H. S. C. O.

  2. Author Address

    [Gaudet, Mia M.] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, New York, NY USA. [Gaudet, Mia M.] Albert Einstein Coll Med, Dept Obstet & Gynecol & Womens Hlth, New York, NY USA. [Kirchhoff, Tomas; Vijai, Joseph; Offit, Kenneth] Mem Sloan Kettering Canc Ctr, Dept Med, Sloan Kettering Inst, Clin Genet Serv, New York, NY 10021 USA. [Kirchhoff, Tomas] Mem Sloan Kettering Canc Ctr, Sloan Kettering Inst, Canc Biol & Genet Program, New York, NY 10021 USA. [Green, Todd; Korn, Joshua M.; Guiducci, Candace; Daly, Mark J.; Altshuler, David M.] Harvard Univ, Sch Med, Broad Inst Harvard, Boston, MA USA. [Green, Todd; Korn, Joshua M.; Guiducci, Candace; Daly, Mark J.; Altshuler, David M.] Harvard Univ, Sch Med, MIT, Boston, MA USA. [Segre, Ayellet V.] Broad Inst Harvard, Program Med & Populat Genet, Cambridge, MA USA. [Segre, Ayellet V.] MIT, Cambridge, MA 02139 USA. [Segre, Ayellet V.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Segre, Ayellet V.] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [McGee, Kate; Dean, Michael; Gold, Bert] NCI, Ctr Canc Res, Canc Inflammat Program, Human Genet Sect, Frederick, MD 21701 USA. [McGuffog, Lesley; Kartsonaki, Christiana; Morrison, Jonathan; Healey, Sue; Peock, Susan; Cook, Margaret; Oliver, Clare; Frost, Debra; Platte, Radka; Easton, Douglas F.; Antoniou, Antonis C.] Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge, England. [Sinilnikova, Olga M.] CHU Lyon, Ctr Leon Berard, Unite Mixte Genet Constitut Canc Frequents, Lyon, France. [Sinilnikova, Olga M.; Mazoyer, Sylvie] Univ Lyon, Ctr Leon Berard, CNRS UMR5201, Equipe Labellisee LIGUE 2008, Lyon, France. [Stoppa-Lyonnet, Dominique] Univ Paris 05, INSERM U830, Serv Genet, Inst Curie, F-75248 Paris, France. [Stoppa-Lyonnet, Dominique; Gauthier-Villars, Marion] Inst Curie, Serv Genet Oncol, Paris, France. [Sobol, Hagay] Univ Aix Marseille 2, Inst J Paoli I Calmettes, INSERM CIC P9502, Dept Oncol Genet Prevent & Depistage, F-13284 Marseille 07, France. [Longy, Michel] Inst Bergonie, Bordeaux, France. [Frenay, Marc] Ctr Antoine Lacassagne, F-06054 Nice, France. [GEMO Study Collaborators] Fed Natl Ctr Lutte Contre Canc, GEMO Study Canc Genet Network Grp Genet & Canc, Paris, France. [Hogervorst, Frans B. L.; HEBON Study Collaborators] Netherlands Canc Inst, Family Canc Clin, Amsterdam, Netherlands. [Rookus, Matti A.] Netherlands Canc Inst, Dept Epidemiol, Amsterdam, Netherlands. [Collee, J. Margriet] Erasmus Univ, Med Ctr, Rotterdam Family Canc Clin, Dept Med Oncol, Rotterdam, Netherlands. [Hoogerbrugge, Nicoline] Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, NL-6525 ED Nijmegen, Netherlands. [van Roozendaal, Kees E. P.] Univ Med Ctr, Dept Clin Genet, Maastricht, Netherlands. [Piedmonte, Marion] Roswell Pk Canc Inst, Gynecol Oncol Grp Stat, Buffalo, NY 14263 USA. [Piedmonte, Marion] Roswell Pk Canc Inst, Ctr Data, Buffalo, NY 14263 USA. [Rubinstein, Wendy] NorthShore Univ Hlth Syst, Evanston, IL USA. [Nerenstone, Stacy] Hartford Hosp, Cent Connecticut Canc Consortium, Hartford, CT 06115 USA. [Van Le, Linda] Univ N Carolina, Chapel Hill, NC USA. [Blank, Stephanie V.] NYU, Sch Med, New York, NY USA. [Caldes, Trinidad; de la Hoya, Miguel] Hosp Clin San Carlos, Mol Oncol Lab, Madrid, Spain. [Nevanlinna, Heli] Univ Helsinki, Cent Hosp, Dept Obstet & Gynecol, FIN-00290 Helsinki, Finland. [Aittomaki, Kristiina] Univ Helsinki, Cent Hosp, Dept Clin Genet, Helsinki, Finland. [Lazaro, Conxi; Blanco, Ignacio] Catalan Inst Oncol, Hereditary Canc Program, Barcelona, Spain. [Arason, Adalgeir; Johannsson, Oskar T.; Barkardottir, Rosa B.] Landspitali LSH, Dept Oncol, Reykjavik, Iceland. [Arason, Adalgeir; Barkardottir, Rosa B.] Landspitali LSH, Dept Pathol, Reykjavik, Iceland. [Arason, Adalgeir; Johannsson, Oskar T.; Barkardottir, Rosa B.] Univ Iceland, Fac Med, Reykjavik, Iceland. [Devilee, Peter] Leiden Univ, Dept Human Genet, Med Ctr, NL-2300 RA Leiden, Netherlands. [Devilee, Peter] Leiden Univ, Dept Pathol, Med Ctr, Leiden, Netherlands. [Olopade, Olofunmilayo I.] Univ Chicago, Med Ctr, Dept Med, Ctr Clin Canc Genet & Global Hlth, Chicago, IL 60637 USA. [Neuhausen, Susan L.] Beckman Res Inst City Hope, Dept Populat Sci, Duarte, CA USA. [Wang, Xianshu; Couch, Fergus J.] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA. [Fredericksen, Zachary S.] Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA. [Peterlongo, Paolo] Fdn IRCCS Ist Nazl Tumori INT, Dept Expt Oncol & Mol Med, Unit Genet Susceptibil Canc, Milan, Italy. [Peterlongo, Paolo; Radice, Paolo] Fdn Ist FIRC Oncol Mol, IFOM, Milan, Italy. [Manoukian, Siranoush] Fdn IRCCS Ist Nazl Tumori INT, Dept Prevent & Predict Med, Unit Med Genet, Milan, Italy. [Barile, Monica] IEO, Div Canc Prevent & Genet, Milan, Italy. [Viel, Alessandra] IRCCS, CRO, Div Expt Oncol 1, Aviano, PN, Italy. [Phelan, Catherine M.] H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL USA. [Narod, Steven] Womens Coll Res Inst, Toronto, ON, Canada. [Rennert, Gad; Lejbkowicz, Flavio; Flugelman, Anath] CHS Natl Canc Control Ctr, Haifa, Israel. [Rennert, Gad; Lejbkowicz, Flavio; Flugelman, Anath] Carmel Hosp, Dept Community Med & Epidemiol, Haifa, Israel. [Andrulis, Irene L.; Ozcelik, Hilmi] Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Toronto, ON M5G 1X5, Canada. [Andrulis, Irene L.; Glendon, Gord; Ozcelik, Hilmi; OCGN] Univ Toronto, Ontario Canc Genet Network, Toronto, ON, Canada. [Toland, Amanda E.] Ohio State Univ, Dept Mol Virol, Columbus, OH 43210 USA. [Toland, Amanda E.] Ohio State Univ, Dept Immunol, Columbus, OH 43210 USA. [Toland, Amanda E.] Ohio State Univ, Dept Med Genet & Internal Med, Columbus, OH 43210 USA. [Montagna, Marco; D'Andrea, Emma] IRCCS, Ist Oncol Veneto, Immunol & Mol Oncol Unit, Padua, Italy. [D'Andrea, Emma] Univ Padua, Dept Oncol & Surg Sci, Padua, Italy. [Friedman, Eitan; Laitman, Yael] Sheba Med Ctr, Inst Genet, Susan Levy Gertner Oncogenet Unit, Tel Hashomer, Israel. [Borg, Ake] Lund Univ, Dept Oncol, Lund, Sweden. [Beattie, Mary] Univ Calif San Francisco, Dept Med, Div Gen Internal Med, San Francisco, CA 94143 USA. [Ramus, Susan J.] UCL, UCL EGA Inst Womens Hlth, Gynaecol Oncol Unit, London WC1E 6BT, England. [Domchek, Susan M.] Hosp Univ Penn, Dept Oncol, Philadelphia, PA 19104 USA. [Nathanson, Katherine L.] Univ Penn, Sch Med, Dept Cell & Mol Biol, Philadelphia, PA 19104 USA. [Rebbeck, Tim] Univ Penn, Sch Med, Dept Biostat & Epidemiol, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Spurdle, Amanda B.; Chen, Xiaoqing; Holland, Helene] Queensland Inst Med Res, Genet & Populat Hlth Div, Brisbane, Qld 4006, Australia. [Chenevix-Trench, Georgia; kConFab] Peter MacCallum Canc Ctr, Melbourne, Australia. [John, Esther M.] Canc Prevent Inst Calif, Fremont, CA USA. [Hopper, John L.] Univ Melbourne, Ctr Genet Epidemiol, Melbourne, Vic, Australia. [Buys, Saundra S.] Univ Utah, Huntsman Canc Inst, Salt Lake City, UT USA. [Daly, Mary B.] Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. [Southey, Melissa C.] Univ Melbourne, Ctr Genet Epidemiol, Melbourne, Vic, Australia. [Terry, Mary Beth] Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, New York, NY USA. [Tung, Nadine] Beth Israel Deaconess Med Ctr, Div Hematol Oncol, Boston, MA 02215 USA. [Hansen, Thomas V. Overeem; Nielsen, Finn C.] Copenhagen Univ Hosp, Rigshosp, Dept Clin Biochem, Copenhagen, Denmark. [Greene, Mark I.; Mai, Phuong L.] NCI, Clin Genet Branch, Rockville, MD USA. [Osorio, Ana; Benitez, Javier] Spanish Natl Canc Res Ctr, Human Canc Genet Programme, Human Genet Grp, Madrid, Spain. [Duran, Mercedes] Univ Valladolid IBGM UVA, Inst Biol & Mol Genet, Valladolid, Spain. [Andres, Raquel] Hosp Clin Univ Lozano Blesa, Oncol Serv, Zaragoza, Spain. [Benitez, Javier] Spanish Natl Canc Res Ctr, Human Canc Genet Programme, Genotyping Unit, Madrid, Spain. [Weitzel, Jeffrey N.] City Hope Canc Ctr, Duarte, CA USA. [Garber, Judy] Harvard Univ, Dana Farber Canc Inst, Boston, MA 02115 USA. [Hamann, Ute] Deutsch Krebsforschungszentrum, D-6900 Heidelberg, Germany. [Evans, D. Gareth; Lalloo, Fiona] Cent Manchester Univ Hosp NHS Fdn Trust, Manchester Acad Hlth Sci Ctr, Manchester, Lancs, England. [Eeles, Ros] Inst Canc Res, Oncogenet Team, London SW3 6JB, England. [Eeles, Ros] Royal Marsden NHS Fdn Trust, London, England. [Izatt, Louise] Guys & St Thomas NHS Fdn Trust, London, England. [Walker, Lisa] Churchill Hosp, Oxford Reg Genet Serv, Oxford OX3 7LJ, England. [Eason, Jacqueline] Nottingham Univ Hosp NHS Trust, Nottingham Clin Genet Serv, Nottingham, England. [Barwell, Julian] Univ Hosp Leicester NHS Trust, Leicestershire Clin Genet Serv, Leicester, Leics, England. [Godwin, Andrew K.] Fox Chase Canc Ctr, Dept Med Oncol, Womens Canc Program, Philadelphia, PA 19111 USA. [Schmutzler, Rita K.; Wappenschmidt, Barbara] Univ Hosp Cologne, Ctr Familial Breast & Ovarian Canc, Dept Obstet & Gynaecol, Cologne, Germany. [Schmutzler, Rita K.; Wappenschmidt, Barbara] Univ Hosp Cologne, CIO, Cologne, Germany. [Engert, Stefanie] Tech Univ Munich, Klinikum Rechts Isar, Div Tumor Genet, Dept Obstet & Gynaecol, D-8000 Munich, Germany. [Arnold, Norbert] Univ Kiel, Univ Hosp Schleswig Holstein, Dept Obstet & Gynaecol, Kiel, Germany. [Gadzicki, Dorothea] Hannover Med Sch, Inst Cell & Mol Pathol, D-3000 Hannover, Germany.\\Gaudet, MM, Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, New York, NY USA.\\offitk@mskcc.org
    1. Year: 2010
    2. Date: Oct
  2. Journal: Plos Genetics
    1. 6
    2. 10
    3. Pages: 12
  4. Type of Article: Article
  5. Article Number: e1001183
  6. ISSN: 1553-7390
  1. Abstract:

    The considerable uncertainty regarding cancer risks associated with inherited mutations of BRCA2 is due to unknown factors. To investigate whether common genetic variants modify penetrance for BRCA2 mutation carriers, we undertook a two-staged genome-wide association study in BRCA2 mutation carriers. In stage 1 using the Affymetrix 6.0 platform, 592,163 filtered SNPs genotyped were available on 899 young (, 40 years) affected and 804 unaffected carriers of European ancestry. Associations were evaluated using a survival-based score test adjusted for familial correlations and stratified by country of the study and BRCA2*6174delT mutation status. The genomic inflation factor (lambda) was 1.011. The stage 1 association analysis revealed multiple variants associated with breast cancer risk: 3 SNPs had p-values, 10 25 and 39 SNPs had p-values<10(-4). These variants included several previously associated with sporadic breast cancer risk and two novel loci on chromosome 20 (rs311499) and chromosome 10 (rs16917302). The chromosome 10 locus was in ZNF365, which contains another variant that has recently been associated with breast cancer in an independent study of unselected cases. In stage 2, the top 85 loci from stage 1 were genotyped in 1,264 cases and 1,222 controls. Hazard ratios (HR) and 95% confidence intervals (CI) for stage 1 and 2 were combined and estimated using a retrospective likelihood approach, stratified by country of residence and the most common mutation, BRCA2*6174delT. The combined per allele HR of the minor allele for the novel loci rs16917302 was 0.75 (95% CI 0.66-0.86, p = 3: 8 x 10(-5)) and for rs311499 was 0.72 (95% CI 0.61-0.85, p = 6: 6 x 10(-5)). FGFR2 rs2981575 had the strongest association with breast cancer risk (per allele HR = 1.28, 95% CI 1.18-1.39, p = 1: 2 x 10(-8)). These results indicate that SNPs that modify BRCA2 penetrance identified by an agnostic approach thus far are limited to variants that also modify risk of sporadic BRCA2 wild-type breast cancer.

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External Sources

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  2. DOI: 10.1371/journal.pgen.1001183
  3. View record in Web of Science®
  4. WOS: 000283647800014

Library Notes

  1. Fiscal Year: FY2010-2011
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