A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers
Authors: Coignard Juliette , Lush Michael , Beesley Jonathan , O’Mara Tracy A. , Dennis Joe , Tyrer Jonathan P. , Barnes Daniel R. , McGuffog Lesley , Leslie Goska , Bolla Manjeet K. , Adank Muriel A. , Agata Simona , Ahearn Thomas , Aittomäki Kristiina , Andrulis Irene L. , Anton-Culver Hoda , Arndt Volker , Arnold Norbert , Aronson Kristan J. , Arun Banu K. , Augustinsson Annelie , Azzollini Jacopo , Barrowdale Daniel , Baynes Caroline , Becher Heiko , Bermisheva Marina , Bernstein Leslie , Białkowska Katarzyna , Blomqvist Carl , Bojesen Stig E. , Bonanni Bernardo , Borg Ake , Brauch Hiltrud , Brenner Hermann , Burwinkel Barbara , Buys Saundra S. , Caldés Trinidad , Caligo Maria A. , Campa Daniele , Carter Brian D. , Castelao Jose E. , Chang-Claude Jenny , Chanock Stephen J. , Chung Wendy K. , Claes Kathleen B. M. , Clarke Christine L. ,   GEMO Study Collaborators, Bertrand Ophélie , Caputo Sandrine , Dupré Anaïs , Le Mentec Marine , Belotti Muriel , Birot Anne-Marie , Buecher Bruno , Fourme Emmanuelle , Gauthier-Villars Marion , Golmard Lisa , Houdayer Claude , Moncoutier Virginie , de Pauw Antoine , Saule Claire , Sinilnikova Olga , Mazoyer Sylvie , Damiola Francesca , Barjhoux Laure , Verny-Pierre Carole , Léone Mélanie , Boutry-Kryza Nadia , Calender Alain , Giraud Sophie , Caron Olivier , Guillaud-Bataille Marine , Bressac-de-Paillerets Brigitte , Bignon Yves- Jean , Uhrhammer Nancy , Lasset Christine , Bonadona Valérie , Berthet Pascaline , Vaur Dominique , Castera Laurent , Noguchi Tetsuro , Popovici Cornel , Sobol Hagay , Bourdon Violaine , Noguchi Tetsuro , Remenieras Audrey , Noguès Catherine , Coupier Isabelle , Pujol Pascal , Dumont Aurélie , Révillion Françoise , Adenis Claude , Muller Danièle , Barouk-Simonet Emmanuelle , Bonnet Françoise , Bubien Virginie , Sevenet Nicolas , Longy Michel , Toulas Christine , Guimbaud Rosine , Gladieff Laurence , Feillel Viviane , Leroux Dominique , Dreyfus Hélène , Rebischung Christine , Peysselon Magalie , Coron Fanny , Faivre Laurence , Baurand Amandine , Jacquot Caroline , Bertolone Geoffrey , Lizard Sarab , Prieur Fabienne , Lebrun Marine , Kientz Caroline , Ferrer Sandra Fert , Mari Véronique , Vénat-Bouvet Laurence , Delnatte Capucine , Bézieau Stéphane , Mortemousque Isabelle , Coulet Florence , Colas Chrystelle , Soubrier Florent , Warcoin Mathilde , Sokolowska Johanna , Bronner Myriam , Collonge-Rame Marie-Agnès , Damette Alexandre , Gesta Paul , Lallaoui Hakima , Chiesa Jean , Molina-Gomes Denise , Ingster Olivier ,   EMBRACE Collaborators, Gregory Helen , Miedzybrodzka Zosia , Morrison Patrick J. , Ong Kai-ren , Donaldson Alan , Rogers Mark T. , Kennedy M. John , Porteous Mary E. , Brewer Carole , Davidson Rosemarie , Izatt Louise , Brady Angela , Barwell Julian , Adlard Julian , Foo Claire , Lalloo Fiona , Side Lucy E. , Eason Jacqueline , Henderson Alex , Walker Lisa , Eeles Rosalind A. , Cook Jackie , Snape Katie , Eccles Diana , Murray Alex , McCann Emma , Collée J. Margriet , Conroy Don M. , Czene Kamila , Daly Mary B. , Devilee Peter , Diez Orland , Ding Yuan Chun , Domchek Susan M. , Dörk Thilo , dos-Santos-Silva Isabel , Dunning Alison M. , Dwek Miriam , Eccles Diana M. , Eliassen A. Heather , Engel Christoph , Eriksson Mikael , Evans D. Gareth , Fasching Peter A. , Flyger Henrik , Fostira Florentia , Friedman Eitan , Fritschi Lin , Frost Debra , Gago-Dominguez Manuela , Gapstur Susan M. , Garber Judy , Garcia-Barberan Vanesa , García-Closas Montserrat , García-Sáenz José A. , Gaudet Mia M. , Gayther Simon A. , Gehrig Andrea , Georgoulias Vassilios , Giles Graham G. , Godwin Andrew K. , Goldberg Mark S. , Goldgar David E. , González-Neira Anna , Greene Mark H. , Guénel Pascal , Haeberle Lothar , Hahnen Eric , Haiman Christopher A. , Håkansson Niclas , Hall Per , Hamann Ute , Harrington Patricia A. , Hart Steven N. , He Wei , Hogervorst Frans B. L. , Hollestelle Antoinette , Hopper John L. , Horcasitas Darling J. , Hulick Peter J. , Hunter David J. , Imyanitov Evgeny N. ,   KConFab Investigators, Fox Stephen , Campbell Ian , Spurdle Amanda , Webb Penny , de Fazio Anna , Tassell Margaret , Kirk Judy , Lindeman Geoff , Price Melanie , Southey Melissa , Milne Roger , Deb Sid , Bowtell David ,   HEBON Investigators, van der Hout Annemieke H. , van den Ouweland Ans M. W. , Mensenkamp Arjen R. , van Deurzen Carolien H. M. , Kets Carolien M. , Seynaeve Caroline , van Asperen Christi J. , Aalfs Cora M. , Gómez Garcia Encarna B. , van Leeuwen Flora E. , de Bock G. H. , Meijers-Heijboer Hanne E. J. , Obdeijn Inge M. , Collée J. Margriet , Gille J. J. P. , Oosterwijk Jan C. , Wijnen Juul T. , van der Kolk Lizet E. , Hooning Maartje J. , Ausems Margreet G. E. M. , Mourits Marian J. E. , Blok Marinus J. , Rookus Matti A. , Adank Muriel A. , van der Luijt Rob B. , van Cronenburg T. C. T. E. F. , van der Pol Carmen C. , Russell Nicola S. , Siesling Sabine , Overbeek Lucy , Wijnands R. , de Lange Judith L. ,   ABCTB Investigators, Clarke Christine , Graham Dinny , Sachchithananthan Mythily , Marsh Deborah , Scott Rodney , Baxter Robert , Yip Desmond , Carpenter Jane , Davis Alison , Pathmanathan Nirmala , Simpson Peter , Jager Agnes , Jakubowska Anna , James Paul A. , Jensen Uffe Birk , John Esther M. , Jones Michael E. , Kaaks Rudolf , Kapoor Pooja Middha , Karlan Beth Y. , Keeman Renske , Khusnutdinova Elza , Kiiski Johanna I. , Ko Yon-Dschun , Kosma Veli-Matti , Kraft Peter , Kurian Allison W. , Laitman Yael , Lambrechts Diether , Le Marchand Loic , Lester Jenny , Lesueur Fabienne , Lindstrom Tricia , Lopez-Fernández Adria , Loud Jennifer T. , Luccarini Craig , Mannermaa Arto , Manoukian Siranoush , Margolin Sara , Martens John W. M. , Mebirouk Noura , Meindl Alfons , Miller Austin , Milne Roger L. , Montagna Marco , Nathanson Katherine L. , Neuhausen Susan L. , Nevanlinna Heli , Nielsen Finn C. , O’Brien Katie M. , Olopade Olufunmilayo I. , Olson Janet E. , Olsson Håkan , Osorio Ana , Ottini Laura , Park-Simon Tjoung-Won , Parsons Michael T. , Pedersen Inge Sokilde , Peshkin Beth , Peterlongo Paolo , Peto Julian , Pharoah Paul D. P. , Phillips Kelly-Anne , Polley Eric C. , Poppe Bruce , Presneau Nadege , Pujana Miquel Angel , Punie Kevin , Radice Paolo , Rantala Johanna , Rashid Muhammad U. , Rennert Gad , Rennert Hedy S. , Robson Mark , Romero Atocha , Rossing Maria , Saloustros Emmanouil , Sandler Dale P. , Santella Regina , Scheuner Maren T. , Schmidt Marjanka K. , Schmidt Gunnar , Scott Christopher , Sharma Priyanka , Soucy Penny , Southey Melissa C. , Spinelli John J. , Steinsnyder Zoe , Stone Jennifer , Stoppa-Lyonnet Dominique , Swerdlow Anthony , Tamimi Rulla M. , Tapper William J. , Taylor Jack A. , Terry Mary Beth , Teulé Alex , Thull Darcy L. , Tischkowitz Marc , Toland Amanda E. , Torres Diana , Trainer Alison H. , Truong Thérèse , Tung Nadine , Vachon Celine M. , Vega Ana , Vijai Joseph , Wang Qin , Wappenschmidt Barbara , Weinberg Clarice R. , Weitzel Jeffrey N. , Wendt Camilla , Wolk Alicja , Yadav Siddhartha , Yang Xiaohong R. , Yannoukakos Drakoulis , Zheng Wei , Ziogas Argyrios , Zorn Kristin K. , Park Sue K. , Thomassen Mads , Offit Kenneth , Schmutzler Rita K. , Couch Fergus J. , Simard Jacques , Chenevix-Trench Georgia , Easton Douglas F. , Andrieu Nadine , Antoniou Antonis C. 
Published: February 2021

Breast cancer (BC) risk forBRCA1andBRCA2mutation carriers varies by genetic and familial factors. About 50 common variants have been shown to modify BC risk for mutation carriers. All but three, were identified in general population studies. Other mutation carrier-specific susceptibility variants may exist but studies of mutation carriers have so far been underpowered. We conduct a novel case-only genome-wide association study comparing genotype frequencies between 60,212 general population BC cases and 13,007 cases withBRCA1orBRCA2mutations. We identify robust novel associations for 2 variants with BC forBRCA1and 3 forBRCA2mutation carriers,P < 10−8, at 5 loci, which are not associated with risk in the general population. They include rs60882887 at 11p11.2 whereMADD,SP11andEIF1, genes previously implicated in BC biology, are predicted as potential targets. These findings will contribute towards customising BC polygenic risk scores forBRCA1andBRCA2mutation carriers.