Common Variants at the 19p13.1 and ZNF365 Loci Are Associated with ER Subtypes of Breast Cancer and Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation Carriers
Authors: Couch Fergus J. , Gaudet Mia M. , Antoniou Antonis C. , Ramus Susan J. , Kuchenbaecker Karoline B. , Soucy Penny , Beesley Jonathan , Chen Xiaoqing , Wang Xianshu , Kirchhoff Tomas , McGuffog Lesley , Barrowdale Daniel , Lee Andrew , Healey Sue , Sinilnikova Olga M. , Andrulis Irene L. , Ozcelik Hilmi , Mulligan Anna Marie , Thomassen Mads , Gerdes Anne-Marie , Jensen Uffe Birk , Skytte Anne-Bine , Kruse Torben A. , Caligo Maria A. , von Wachenfeldt Anna , Barbany-Bustinza Gisela , Loman Niklas , Soller Maria , Ehrencrona Hans , Karlsson Per , Nathanson Katherine L. , Rebbeck Timothy R. , Domchek Susan M. , Jakubowska Ania , Lubinski Jan , Jaworska Katarzyna , Durda Katarzyna , Złowocka Elżbieta , Huzarski Tomasz , Byrski Tomasz , Gronwald Jacek , Cybulski Cezary , Górski Bohdan , Osorio Ana , Durán Mercedes , Tejada María Isabel , Benitez Javier , Hamann Ute , Hogervorst Frans B.L. , van Os Theo A. , van Leeuwen Flora E. , Meijers-Heijboer Hanne E.J. , Wijnen Juul , Blok Marinus J. , Kets Marleen , Hooning Maartje J. , Oldenburg Rogier A. , Ausems Margreet G.E.M. , Peock Susan , Frost Debra , Ellis Steve D. , Platte Radka , Fineberg Elena , Evans D. Gareth , Jacobs Chris , Eeles Rosalind A. , Adlard Julian , Davidson Rosemarie , Eccles Diana M. , Cole Trevor , Cook Jackie , Paterson Joan , Brewer Carole , Douglas Fiona , Hodgson Shirley V. , Morrison Patrick J. , Walker Lisa , Porteous Mary E. , Kennedy M. John , Side Lucy E. , Bove Betsy , Godwin Andrew K. , Stoppa-Lyonnet Dominique , Fassy-Colcombet Marion , Castera Laurent , Cornelis François , Mazoyer Sylvie , Léoné Mélanie , Boutry-Kryza Nadia , Bressac-de Paillerets Brigitte , Caron Olivier , Pujol Pascal , Coupier Isabelle , Delnatte Capucine , Akloul Linda , Lynch Henry T. , Snyder Carrie L. , Buys Saundra S. , Daly Mary B. , Terry MaryBeth , Chung Wendy K. , John Esther M. , Miron Alexander , Southey Melissa C. , Hopper John L. , Goldgar David E. , Singer Christian F. , Rappaport Christine , Tea Muy-Kheng M. , Fink-Retter Anneliese , Hansen Thomas V.O. , Nielsen Finn C. , Arason Aðalgeir , Vijai Joseph , Shah Sohela , Sarrel Kara , Robson Mark E. , Piedmonte Marion , Phillips Kelly , Basil Jack , Rubinstein Wendy S. , Boggess John , Wakeley Katie , Ewart-Toland Amanda , Montagna Marco , Agata Simona , Imyanitov Evgeny N. , Isaacs Claudine , Janavicius Ramunas , Lazaro Conxi , Blanco Ignacio , Feliubadalo Lidia , Brunet Joan , Gayther Simon A. , Pharoah Paul P.D. , Odunsi Kunle O. , Karlan Beth Y. , Walsh Christine S. , Olah Edith , Teo Soo Hwang , Ganz Patricia A. , Beattie Mary S. , van Rensburg Elizabeth J. , Dorfling Cecelia M. , Diez Orland , Kwong Ava , Schmutzler Rita K. , Wappenschmidt Barbara , Engel Christoph , Meindl Alfons , Ditsch Nina , Arnold Norbert , Heidemann Simone , Niederacher Dieter , Preisler-Adams Sabine , Gadzicki Dorothea , Varon-Mateeva Raymonda , Deissler Helmut , Gehrig Andrea , Sutter Christian , Kast Karin , Fiebig Britta , Heinritz Wolfram , Caldes Trinidad , de la Hoya Miguel , Muranen Taru A. , Nevanlinna Heli , Tischkowitz Marc D. , Spurdle Amanda B. , Neuhausen Susan L. , Ding Yuan Chun , Lindor Noralane M. , Fredericksen Zachary , Pankratz V. Shane , Peterlongo Paolo , Manoukian Siranoush , Peissel Bernard , Zaffaroni Daniela , Barile Monica , Bernard Loris , Viel Alessandra , Giannini Giuseppe , Varesco Liliana , Radice Paolo , Greene Mark H. , Mai Phuong L. , Easton Douglas F. , Chenevix-Trench Georgia , Offit Kenneth , Simard Jacques 
Published: March 2012

Background: Genome-wide association studies (GWAS) identified variants at 19p13.1 and ZNF365 (10q21.2) as risk factors for breast cancer among BRCA1 and BRCA2 mutation carriers, respectively. We explored associations with ovarian cancer and with breast cancer by tumor histopathology for these variants in mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA).

Methods: Genotyping data for 12,599 BRCA1 and 7,132 BRCA2 mutation carriers from 40 studies were combined.

Results: We confirmed associations between rs8170 at 19p13.1 and breast cancer risk for BRCA1 mutation carriers [HR, 1.17; 95% confidence interval (CI), 1.07–1.27; P = 7.42 × 10−4] and between rs16917302 at ZNF365 (HR, 0.84; 95% CI, 0.73–0.97; P = 0.017) but not rs311499 at 20q13.3 (HR, 1.11; 95% CI, 0.94–1.31; P = 0.22) and breast cancer risk for BRCA2 mutation carriers. Analyses based on tumor histopathology showed that 19p13 variants were predominantly associated with estrogen receptor (ER)-negative breast cancer for both BRCA1 and BRCA2 mutation carriers, whereas rs16917302 at ZNF365 was mainly associated with ER-positive breast cancer for both BRCA1 and BRCA2 mutation carriers. We also found for the first time that rs67397200 at 19p13.1 was associated with an increased risk of ovarian cancer for BRCA1 (HR, 1.16; 95% CI, 1.05–1.29; P = 3.8 × 10−4) and BRCA2 mutation carriers (HR, 1.30; 95% CI, 1.10–1.52; P = 1.8 × 10−3).

Conclusions: 19p13.1 and ZNF365 are susceptibility loci for ovarian cancer and ER subtypes of breast cancer among BRCA1 and BRCA2 mutation carriers.

Impact: These findings can lead to an improved understanding of tumor development and may prove useful for breast and ovarian cancer risk prediction for BRCA1 and BRCA2 mutation carriers. Cancer Epidemiol Biomarkers Prev; 21(4); 645–57. ©2012 AACR.