A locus on 19p13 modifies risk of breast cancer in BRCA1 mutation carriers and is associated with hormone receptor-negative breast cancer in the general population.

Authors:
Antonis C Antoniou Xianshu Wang Zachary S Fredericksen Lesley McGuffog Robert Tarrell Olga M Sinilnikova Sue Healey Jonathan Morrison Christiana Kartsonaki Timothy Lesnick Maya Ghoussaini Daniel Barrowdale Susan Peock Margaret Cook Clare Oliver Debra Frost Diana Eccles D Gareth Evans Ros Eeles Louise Izatt Carol Chu Fiona Douglas Joan Paterson Dominique Stoppa-Lyonnet Claude Houdayer Sylvie Mazoyer Sophie Giraud Christine Lasset Audrey Remenieras Olivier Caron Agnès Hardouin Pascaline Berthet Frans B L Hogervorst Matti A Rookus Agnes Jager Ans van den Ouweland Nicoline Hoogerbrugge Rob B van der Luijt Hanne Meijers-Heijboer Encarna B Gómez García Peter Devilee Maaike P G Vreeswijk Jan Lubinski Anna Jakubowska Jacek Gronwald Tomasz Huzarski Tomasz Byrski Bohdan Górski Cezary Cybulski Amanda B Spurdle Helene Holland David E Goldgar Esther M John John L Hopper Melissa Southey Saundra S Buys Mary B Daly Mary-Beth Terry Rita K Schmutzler Barbara Wappenschmidt Christoph Engel Alfons Meindl Sabine Preisler-Adams Norbert Arnold Dieter Niederacher Christian Sutter Susan M Domchek Katherine L Nathanson Timothy Rebbeck Joanne L Blum Marion Piedmonte Gustavo C Rodriguez Katie Wakeley John F Boggess Jack Basil Stephanie V Blank Eitan Friedman Bella Kaufman Yael Laitman Roni Milgrom Irene L Andrulis Gord Glendon Hilmi Ozcelik Tomas Kirchhoff Joseph Vijai Mia M Gaudet David Altshuler Candace Guiducci Niklas Loman Katja Harbst Johanna Rantala Hans Ehrencrona Anne-Marie Gerdes Mads Thomassen Lone Sunde Paolo Peterlongo Siranoush Manoukian Bernardo Bonanni Alessandra Viel Paolo Radice Trinidad Caldes Miguel de la Hoya Christian F Singer Anneliese Fink-Retter Mark H Greene Phuong L Mai Jennifer T Loud Lucia Guidugli Noralane M Lindor Thomas V O Hansen Finn C Nielsen Ignacio Blanco Conxi Lazaro Judy Garber Susan J Ramus Simon A Gayther Catherine Phelan Stephen Narod Csilla I Szabo Javier Benitez Ana Osorio Heli Nevanlinna Tuomas Heikkinen Maria A Caligo Mary S Beattie Ute Hamann Andrew K Godwin Marco Montagna Cinzia Casella Susan L Neuhausen Beth Y Karlan Nadine Tung Amanda E Toland Jeffrey Weitzel Olofunmilayo Olopade Jacques Simard Penny Soucy Wendy S Rubinstein Adalgeir Arason Gad Rennert Nicholas G Martin Grant W Montgomery Jenny Chang-Claude Dieter Flesch-Janys Hiltrud Brauch Gianluca Severi Laura Baglietto Angela Cox Simon S Cross Penelope Miron Sue M Gerty William Tapper Drakoulis Yannoukakos George Fountzilas Peter A Fasching Matthias W Beckmann Isabel Dos Santos Silva Julian Peto Diether Lambrechts Robert Paridaens Thomas Rüdiger Asta Försti Robert Winqvist Katri Pylkäs Robert B Diasio Adam M Lee Jeanette Eckel-Passow Celine Vachon Fiona Blows Kristy Driver Alison Dunning Paul P D Pharoah Kenneth Offit V Shane Pankratz Hakon Hakonarson Georgia Chenevix-Trench Douglas F Easton Fergus J Couch

Nat Genet 2010 Oct 19;42(10):885-92. Epub 2010 Sep 19.

Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.

Germline BRCA1 mutations predispose to breast cancer. To identify genetic modifiers of this risk, we performed a genome-wide association study in 1,193 individuals with BRCA1 mutations who were diagnosed with invasive breast cancer under age 40 and 1,190 BRCA1 carriers without breast cancer diagnosis over age 35. We took forward 96 SNPs for replication in another 5,986 BRCA1 carriers (2,974 individuals with breast cancer and 3,012 unaffected individuals). Five SNPs on 19p13 were associated with breast cancer risk (P(trend) = 2.3 × 10⁻⁹ to P(trend) = 3.9 × 10⁻⁷), two of which showed independent associations (rs8170, hazard ratio (HR) = 1.26, 95% CI 1.17-1.35; rs2363956 HR = 0.84, 95% CI 0.80-0.89). Genotyping these SNPs in 6,800 population-based breast cancer cases and 6,613 controls identified a similar association with estrogen receptor-negative breast cancer (rs2363956 per-allele odds ratio (OR) = 0.83, 95% CI 0.75-0.92, P(trend) = 0.0003) and an association with estrogen receptor-positive disease in the opposite direction (OR = 1.07, 95% CI 1.01-1.14, P(trend) = 0.016). The five SNPs were also associated with triple-negative breast cancer in a separate study of 2,301 triple-negative cases and 3,949 controls (P(trend) = 1 × 10⁻⁷) to P(trend) = 8 × 10⁻⁵; rs2363956 per-allele OR = 0.80, 95% CI 0.74-0.87, P(trend) = 1.1 × 10⁻⁷

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http://dx.doi.org/10.1038/ng.669DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3130795PMC
October 2010
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