Data from Common Variants at the 19p13.1 and <i>ZNF365</i> Loci Are Associated with ER Subtypes of Breast Cancer and Ovarian Cancer Risk in <i>BRCA1</i> and <i>BRCA2</i> 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 2023

<div>Abstract<p><b>Background:</b> Genome-wide association studies (GWAS) identified variants at 19p13.1 and <i>ZNF365</i> (10q21.2) as risk factors for breast cancer among <i>BRCA1</i> and <i>BRCA2</i> 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 <i>BRCA1/2</i> (CIMBA).</p><p><b>Methods:</b> Genotyping data for 12,599 <i>BRCA1</i> and 7,132 <i>BRCA2</i> mutation carriers from 40 studies were combined.</p><p><b>Results:</b> We confirmed associations between rs8170 at 19p13.1 and breast cancer risk for <i>BRCA1</i> mutation carriers [HR, 1.17; 95% confidence interval (CI), 1.07–1.27; <i>P</i> = 7.42 × 10<sup>−4</sup>] and between rs16917302 at <i>ZNF365</i> (HR, 0.84; 95% CI, 0.73–0.97; <i>P</i> = 0.017) but not rs311499 at 20q13.3 (HR, 1.11; 95% CI, 0.94–1.31; <i>P</i> = 0.22) and breast cancer risk for <i>BRCA2</i> mutation carriers. Analyses based on tumor histopathology showed that 19p13 variants were predominantly associated with estrogen receptor (ER)-negative breast cancer for both <i>BRCA1</i> and <i>BRCA2</i> mutation carriers, whereas rs16917302 at <i>ZNF365</i> was mainly associated with ER-positive breast cancer for both <i>BRCA1</i> and <i>BRCA2</i> mutation carriers. We also found for the first time that rs67397200 at 19p13.1 was associated with an increased risk of ovarian cancer for <i>BRCA1</i> (HR, 1.16; 95% CI, 1.05–1.29; <i>P</i> = 3.8 × 10<sup>−4</sup>) and <i>BRCA2</i> mutation carriers (HR, 1.30; 95% CI, 1.10–1.52; <i>P</i> = 1.8 × 10<sup>−3</sup>).</p><p><b>Conclusions:</b> 19p13.1 and <i>ZNF365</i> are susceptibility loci for ovarian cancer and ER subtypes of breast cancer among <i>BRCA1</i> and <i>BRCA2</i> mutation carriers.</p><p><b>Impact:</b> These findings can lead to an improved understanding of tumor development and may prove useful for breast and ovarian cancer risk prediction for <i>BRCA1</i> and <i>BRCA2</i> mutation carriers. <i>Cancer Epidemiol Biomarkers Prev; 21(4); 645–57. ©2012 AACR</i>.</p></div>