Association of breast cancer risk in BRCA1 and BRCA2 mutation carriers with genetic variants showing differential allelic expression: identification of a modifier of breast cancer risk at locus 11q22.3.
Yosr Hamdi,
Penny Soucy,
Karoline B Kuchenbaeker,
Tomi Pastinen,
Arnaud Droit,
Audrey Lemaçon,
Julian Adlard,
Kristiina Aittomäki,
Irene L Andrulis,
Adalgeir Arason,
Norbert Arnold,
Banu K Arun,
Jacopo Azzollini,
Anita Bane,
Laure Barjhoux,
Daniel Barrowdale,
Javier Benitez,
Pascaline Berthet,
Marinus J Blok,
Kristie Bobolis,
Valérie Bonadona,
Bernardo Bonanni,
Angela R Bradbury,
Carole Brewer,
Bruno Buecher,
Saundra S Buys,
Maria A Caligo,
Jocelyne Chiquette,
Wendy K Chung,
Kathleen B M Claes,
Mary B Daly,
Francesca Damiola,
Rosemarie Davidson,
Miguel De la Hoya,
Kim De Leeneer,
Orland Diez,
Yuan Chun Ding,
Riccardo Dolcetti,
Susan M Domchek,
Cecilia M Dorfling,
Diana Eccles,
Ros Eeles,
Zakaria Einbeigi,
Bent Ejlertsen,
,
Christoph Engel,
D Gareth Evans,
Lidia Feliubadalo,
Lenka Foretova,
Florentia Fostira,
William D Foulkes,
George Fountzilas,
Eitan Friedman,
Debra Frost,
Pamela Ganschow,
Patricia A Ganz,
Judy Garber,
Simon A Gayther,
,
Anne-Marie Gerdes,
Gord Glendon,
Andrew K Godwin,
David E Goldgar,
Mark H Greene,
Jacek Gronwald,
Eric Hahnen,
Ute Hamann,
Thomas V O Hansen,
Steven Hart,
John L Hays,
,
Frans B L Hogervorst,
Peter J Hulick,
Evgeny N Imyanitov,
Claudine Isaacs,
Louise Izatt,
Anna Jakubowska,
Paul James,
Ramunas Janavicius,
Uffe Birk Jensen,
Esther M John,
Vijai Joseph,
Walter Just,
Katarzyna Kaczmarek,
Beth Y Karlan,
,
Carolien M Kets,
Judy Kirk,
Mieke Kriege,
Yael Laitman,
Maïté Laurent,
Conxi Lazaro,
Goska Leslie,
Jenny Lester,
Fabienne Lesueur,
Annelie Liljegren,
Niklas Loman,
Jennifer T Loud,
Siranoush Manoukian,
Milena Mariani,
Sylvie Mazoyer,
Lesley McGuffog,
Hanne E J Meijers-Heijboer,
Alfons Meindl,
Austin Miller,
Marco Montagna,
Anna Marie Mulligan,
Katherine L Nathanson,
Susan L Neuhausen,
Heli Nevanlinna,
Robert L Nussbaum,
Edith Olah,
Olufunmilayo I Olopade,
Kai-Ren Ong,
Jan C Oosterwijk,
Ana Osorio,
Laura Papi,
Sue Kyung Park,
Inge Sokilde Pedersen,
Bernard Peissel,
Pedro Perez Segura,
Paolo Peterlongo,
Catherine M Phelan,
Paolo Radice,
Johanna Rantala,
Christine Rappaport-Fuerhauser,
Gad Rennert,
Andrea Richardson,
Mark Robson,
Gustavo C Rodriguez,
Matti A Rookus,
Rita Katharina Schmutzler,
Nicolas Sevenet,
Payal D Shah,
Christian F Singer,
Thomas P Slavin,
Katie Snape,
Johanna Sokolowska,
Ida Marie Heeholm Sønderstrup,
Melissa Southey,
Amanda B Spurdle,
Zsofia Stadler,
Dominique Stoppa-Lyonnet,
Grzegorz Sukiennicki,
Christian Sutter,
Yen Tan,
Muy-Kheng Tea,
Manuel R Teixeira,
Alex Teulé,
Soo-Hwang Teo,
Mary Beth Terry,
Mads Thomassen,
Laima Tihomirova,
Marc Tischkowitz,
Silvia Tognazzo,
Amanda Ewart Toland,
Nadine Tung,
Ans M W van den Ouweland,
Rob B van der Luijt,
Klaartje van Engelen,
Elizabeth J van Rensburg,
Raymonda Varon-Mateeva,
Barbara Wappenschmidt,
Juul T Wijnen,
Timothy Rebbeck,
Georgia Chenevix-Trench,
Kenneth Offit,
Fergus J Couch,
Silje Nord,
Douglas F Easton,
Antonis C Antoniou,
Jacques Simard
Abstract
METHODS
Using data from a genome-wide map of SNPs associated with allelic expression, we assessed the association of ~320 SNPs located in the vicinity of these genes with breast and ovarian cancer risks in 15,252 BRCA1 and 8211 BRCA2 mutation carriers ascertained from 54 studies participating in the Consortium of Investigators of Modifiers of BRCA1/2.
CONCLUSION
We identified 11q22.3 as a new modifier locus in BRCA1 carriers. Replication in larger studies using estrogen receptor (ER)-negative or triple-negative (i.e., ER-, progesterone receptor-, and HER2-negative) cases could therefore be helpful to confirm the association of this locus with breast cancer risk.
RESULTS
We identified a region on 11q22.3 that is significantly associated with breast cancer risk in BRCA1 mutation carriers (most significant SNP rs228595 p = 7 × 10-6). This association was absent in BRCA2 carriers (p = 0.57). The 11q22.3 region notably encompasses genes such as ACAT1, NPAT, and ATM. Expression quantitative trait loci associations were observed in both normal breast and tumors across this region, namely for ACAT1, ATM, and other genes. In silico analysis revealed some overlap between top risk-associated SNPs and relevant biological features in mammary cell data, which suggests potential functional significance.
PURPOSE
Cis-acting regulatory SNPs resulting in differential allelic expression (DAE) may, in part, explain the underlying phenotypic variation associated with many complex diseases. To investigate whether common variants associated with DAE were involved in breast cancer susceptibility among BRCA1 and BRCA2 mutation carriers, a list of 175 genes was developed based of their involvement in cancer-related pathways.