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:
Fergus J Couch 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 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 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 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 Betsy Bove Andrew K Godwin Dominique Stoppa-Lyonnet 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 Kenneth Offit Jacques Simard

Cancer Epidemiol Biomarkers Prev 2012 Apr 20;21(4):645-57. Epub 2012 Feb 20.

Departments of Laboratory Medicine and Pathology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.

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.

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http://dx.doi.org/10.1158/1055-9965.EPI-11-0888DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3319317PMC
April 2012
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