Candidate Genetic Modifiers for Breast and Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation Carriers
Authors: Peterlongo Paolo , Chang-Claude Jenny , Moysich Kirsten B. , Rudolph Anja , Schmutzler Rita K. , Simard Jacques , Soucy Penny , Eeles Rosalind A. , Easton Douglas F. , Hamann Ute , Wilkening Stefan , Chen Bowang , Rookus Matti A. , Schmidt Marjanka K. , van der Baan Frederieke H. , Spurdle Amanda B. , Walker Logan C. , Lose Felicity , Maia Ana-Teresa , Montagna Marco , Matricardi Laura , Lubinski Jan , Jakubowska Anna , Gómez Garcia Encarna B. , Olopade Olufunmilayo I. , Nussbaum Robert L. , Nathanson Katherine L. , Domchek Susan M. , Rebbeck Timothy R. , Arun Banu K. , Karlan Beth Y. , Orsulic Sandra , Lester Jenny , Chung Wendy K. , Miron Alex , Southey Melissa C. , Goldgar David E. , Buys Saundra S. , Janavicius Ramunas , Dorfling Cecilia M. , van Rensburg Elizabeth J. , Ding Yuan Chun , Neuhausen Susan L. , Hansen Thomas V.O. , Gerdes Anne-Marie , Ejlertsen Bent , Jønson Lars , Osorio Ana , Martínez-Bouzas Cristina , Benitez Javier , Conway Edye E. , Blazer Kathleen R. , Weitzel Jeffrey N. , Manoukian Siranoush , Peissel Bernard , Zaffaroni Daniela , Scuvera Giulietta , Barile Monica , Ficarazzi Filomena , Mariette Frederique , Fortuzzi Stefano , Viel Alessandra , Giannini Giuseppe , Papi Laura , Martayan Aline , Tibiletti Maria Grazia , Radice Paolo , Vratimos Athanassios , Fostira Florentia , Garber Judy E. , Donaldson Alan , Brewer Carole , Foo Claire , Evans D. Gareth R. , Frost Debra , Eccles Diana , Brady Angela , Cook Jackie , Tischkowitz Marc , Adlard Julian , Barwell Julian , Walker Lisa , Izatt Louise , Side Lucy E. , Kennedy M. John , Rogers Mark T. , Porteous Mary E. , Morrison Patrick J. , Platte Radka , Davidson Rosemarie , Hodgson Shirley V. , Ellis Steve , Cole Trevor ,   on behalf of EMBRACE, Godwin Andrew K. , Claes Kathleen , Van Maerken Tom , Meindl Alfons , Gehrig Andrea , Sutter Christian , Engel Christoph , Niederacher Dieter , Steinemann Doris , Plendl Hansjoerg , Kast Karin , Rhiem Kerstin , Ditsch Nina , Arnold Norbert , Varon-Mateeva Raymonda , Wappenschmidt Barbara , Wang-Gohrke Shan , Bressac-de Paillerets Brigitte , Buecher Bruno , Delnatte Capucine , Houdayer Claude , Stoppa-Lyonnet Dominique , Damiola Francesca , Coupier Isabelle , Barjhoux Laure , Venat-Bouvet Laurence , Golmard Lisa , Boutry-Kryza Nadia , Sinilnikova Olga M. , Caron Olivier , Pujol Pascal , Mazoyer Sylvie , Belotti Muriel ,   on behalf of GEMO Study Collaborators, Piedmonte Marion , Friedlander Michael L. , Rodriguez Gustavo C. , Copeland Larry J. , de la Hoya Miguel , Segura Pedro Perez , Nevanlinna Heli , Aittomäki Kristiina , van Os Theo A.M. , Meijers-Heijboer Hanne E.J. , van der Hout Annemarie H. , Vreeswijk Maaike P.G. , Hoogerbrugge Nicoline , Ausems Margreet G.E.M. , van Doorn Helena C. , Collée J. Margriet ,   on behalf of HEBON, Olah Edith , Diez Orland , Blanco Ignacio , Lazaro Conxi , Brunet Joan , Feliubadalo Lidia , Cybulski Cezary , Gronwald Jacek , Durda Katarzyna , Jaworska-Bieniek Katarzyna , Sukiennicki Grzegorz , Arason Adalgeir , Chiquette Jocelyne , Teixeira Manuel R. , Olswold Curtis , Couch Fergus J. , Lindor Noralane M. , Wang Xianshu , Szabo Csilla I. , Offit Kenneth , Corines Marina , Jacobs Lauren , Robson Mark E. , Zhang Liying , Joseph Vijai , Berger Andreas , Singer Christian F. , Rappaport Christine , Kaulich Daphne Geschwantler , Pfeiler Georg , Tea Muy-Kheng M. , Phelan Catherine M. , Greene Mark H. , Mai Phuong L. , Rennert Gad , Mulligan Anna Marie , Glendon Gord , Tchatchou Sandrine , Andrulis Irene L. , Toland Amanda Ewart , Bojesen Anders , Pedersen Inge Sokilde , Thomassen Mads , Jensen Uffe Birk , Laitman Yael , Rantala Johanna , von Wachenfeldt Anna , Ehrencrona Hans , Askmalm Marie Stenmark , Borg Åke , Kuchenbaecker Karoline B. , McGuffog Lesley , Barrowdale Daniel , Healey Sue , Lee Andrew , Pharoah Paul D.P. , Chenevix-Trench Georgia ,   on behalf of KConFab Investigators, Antoniou Antonis C. , Friedman Eitan 
Published: October 2014

Abstract
Background:BRCA1 and BRCA2 mutation carriers are at substantially increased risk for developing breast and ovarian cancer. The incomplete penetrance coupled with the variable age at diagnosis in carriers of the same mutation suggests the existence of genetic and nongenetic modifying factors. In this study, we evaluated the putative role of variants in many candidate modifier genes.
Methods: Genotyping data from 15,252 BRCA1 and 8,211 BRCA2 mutation carriers, for known variants (n = 3,248) located within or around 445 candidate genes, were available through the iCOGS custom-designed array. Breast and ovarian cancer association analysis was performed within a retrospective cohort approach.
Results: The observed P values of association ranged between 0.005 and 1.000. None of the variants was significantly associated with breast or ovarian cancer risk in either BRCA1 or BRCA2 mutation carriers, after multiple testing adjustments.
Conclusion: There is little evidence that any of the evaluated candidate variants act as modifiers of breast and/or ovarian cancer risk in BRCA1 or BRCA2 mutation carriers.
Impact: Genome-wide association studies have been more successful at identifying genetic modifiers of BRCA1/2 penetrance than candidate gene studies. Cancer Epidemiol Biomarkers Prev; 24(1); 308–16. ©2014 AACR.