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Multicenter Study
. 2012 Apr;21(4):645-57.
doi: 10.1158/1055-9965.EPI-11-0888. Epub 2012 Feb 20.

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

Fergus J Couch  1 , Mia M Gaudet, Antonis C Antoniou, Susan J Ramus, Karoline B Kuchenbaecker, Penny Soucy, Jonathan Beesley, Xiaoqing Chen, Xianshu Wang, Tomas Kirchhoff, Lesley McGuffog, Daniel Barrowdale, Andrew Lee, Sue Healey, Olga M Sinilnikova, Irene L Andrulis; OCGN; Hilmi Ozcelik, Anna Marie Mulligan, Mads Thomassen, Anne-Marie Gerdes, Uffe Birk Jensen, Anne-Bine Skytte, Torben A Kruse, Maria A Caligo, Anna von Wachenfeldt, Gisela Barbany-Bustinza, Niklas Loman, Maria Soller, Hans Ehrencrona, Per Karlsson; SWE-BRCA; Katherine L Nathanson, Timothy R Rebbeck, Susan M Domchek, Ania Jakubowska, Jan Lubinski, Katarzyna Jaworska, Katarzyna Durda, Elzbieta Zlowocka, Tomasz Huzarski, Tomasz Byrski, Jacek Gronwald, Cezary Cybulski, Bohdan Górski, Ana Osorio, Mercedes Durán, María Isabel Tejada, Javier Benitez, Ute Hamann, Frans B L Hogervorst; HEBON; Theo A van Os, Flora E van Leeuwen, Hanne E J Meijers-Heijboer, Juul Wijnen, Marinus J Blok, Marleen Kets, Maartje J Hooning, Rogier A Oldenburg, Margreet G E M Ausems, Susan Peock, Debra Frost, Steve D Ellis, Radka Platte, Elena Fineberg, D Gareth Evans, Chris Jacobs, Rosalind A Eeles, Julian Adlard, Rosemarie Davidson, Diana M Eccles, Trevor Cole, Jackie Cook, Joan Paterson, Carole Brewer, Fiona Douglas, Shirley V Hodgson, Patrick J Morrison, Lisa Walker, Mary E Porteous, M John Kennedy, Lucy E Side; EMBRACE; Betsy Bove, Andrew K Godwin, Dominique Stoppa-Lyonnet; GEMO Study Collaborators; Marion Fassy-Colcombet, Laurent Castera, François Cornelis, Sylvie Mazoyer, Mélanie Léoné, Nadia Boutry-Kryza, Brigitte Bressac-de Paillerets, Olivier Caron, Pascal Pujol, Isabelle Coupier, Capucine Delnatte, Linda Akloul, Henry T Lynch, Carrie L Snyder, Saundra S Buys, Mary B Daly, Marybeth Terry, Wendy K Chung, Esther M John, Alexander Miron, Melissa C Southey, John L Hopper, David E Goldgar, Christian F Singer, Christine Rappaport, Muy-Kheng M Tea, Anneliese Fink-Retter, Thomas V O Hansen, Finn C Nielsen, Aðalgeir Arason, Joseph Vijai, Sohela Shah, Kara Sarrel, Mark E Robson, Marion Piedmonte, Kelly Phillips, Jack Basil, Wendy S Rubinstein, John Boggess, Katie Wakeley, Amanda Ewart-Toland, Marco Montagna, Simona Agata, Evgeny N Imyanitov, Claudine Isaacs, Ramunas Janavicius, Conxi Lazaro, Ignacio Blanco, Lidia Feliubadalo, Joan Brunet, Simon A Gayther, Paul P D Pharoah, Kunle O Odunsi, Beth Y Karlan, Christine S Walsh, Edith Olah, Soo Hwang Teo, Patricia A Ganz, Mary S Beattie, Elizabeth J van Rensburg, Cecelia M Dorfling, Orland Diez, Ava Kwong, Rita K Schmutzler, Barbara Wappenschmidt, Christoph Engel, Alfons Meindl, Nina Ditsch, Norbert Arnold, Simone Heidemann, Dieter Niederacher, Sabine Preisler-Adams, Dorothea Gadzicki, Raymonda Varon-Mateeva, Helmut Deissler, Andrea Gehrig, Christian Sutter, Karin Kast, Britta Fiebig, Wolfram Heinritz, Trinidad Caldes, Miguel de la Hoya, Taru A Muranen, Heli Nevanlinna, Marc D Tischkowitz, Amanda B Spurdle, Susan L Neuhausen, Yuan Chun Ding, Noralane M Lindor, Zachary Fredericksen, V Shane Pankratz, Paolo Peterlongo, Siranoush Manoukian, Bernard Peissel, Daniela Zaffaroni, Monica Barile, Loris Bernard, Alessandra Viel, Giuseppe Giannini, Liliana Varesco, Paolo Radice, Mark H Greene, Phuong L Mai, Douglas F Easton, Georgia Chenevix-Trench; kConFab investigators; Kenneth Offit, Jacques Simard; Consortium of Investigators of Modifiers of BRCA1/2
Affiliations
Multicenter Study

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

Fergus J Couch et al. Cancer Epidemiol Biomarkers Prev. 2012 Apr.

Abstract

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.

PubMed Disclaimer

Conflict of interest statement

Disclosure of Potential Conflicts of Interest

The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the BCFR, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government or the BCFR. No potential conflicts of interest are disclosed.

Figures

Figure 1
Figure 1. Forest plots of the associations by country of residence of BRCA1 and BRCA2 mutation carriers with breast cancer risk overall
(A–C) Squares indicate the country specific per-allele HR estimates for SNPs (A) rs8170 for BRCA1 mutation carriers, (B) rs67397200 for BRCA1 mutation carriers and (C) rs16917302 for BRCA2 mutation carriers. The area of the square is proportional to the inverse of the variance of the estimate. Horizontal lines indicate 95% Confidence Intervals (CIs).
Figure 1
Figure 1. Forest plots of the associations by country of residence of BRCA1 and BRCA2 mutation carriers with breast cancer risk overall
(A–C) Squares indicate the country specific per-allele HR estimates for SNPs (A) rs8170 for BRCA1 mutation carriers, (B) rs67397200 for BRCA1 mutation carriers and (C) rs16917302 for BRCA2 mutation carriers. The area of the square is proportional to the inverse of the variance of the estimate. Horizontal lines indicate 95% Confidence Intervals (CIs).
Figure 1
Figure 1. Forest plots of the associations by country of residence of BRCA1 and BRCA2 mutation carriers with breast cancer risk overall
(A–C) Squares indicate the country specific per-allele HR estimates for SNPs (A) rs8170 for BRCA1 mutation carriers, (B) rs67397200 for BRCA1 mutation carriers and (C) rs16917302 for BRCA2 mutation carriers. The area of the square is proportional to the inverse of the variance of the estimate. Horizontal lines indicate 95% Confidence Intervals (CIs).
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