Common variants at 12p11, 12q24, 9p21, 9q31.2 and in ZNF365 are associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers

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Abstract

Introduction: Several common alleles have been shown to be associated with breast and/or ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. Recent genome-wide association studies of breast cancer have identified eight additional breast cancer susceptibility loci: rs1011970 (9p21, CDKN2A/B), rs10995190 (ZNF365), rs704010 (ZMIZ1), rs2380205 (10p15), rs614367 (11q13), rs1292011 (12q24), rs10771399 (12p11 near PTHLH) and rs865686 (9q31.2). Methods: To evaluate whether these single nucleotide polymorphisms (SNPs) are associated with breast cancer risk for BRCA1 and BRCA2 carriers, we genotyped these SNPs in 12,599 BRCA1 and 7,132 BRCA2 mutation carriers and analysed the associations with breast cancer risk within a retrospective likelihood framework. Results: Only SNP rs10771399 near PTHLH was associated with breast cancer risk for BRCA1 mutation carriers (per-allele hazard ratio (HR) = 0.87, 95% CI: 0.81 to 0.94, P-trend = 3 x 10(-4)). The association was restricted to mutations proven or predicted to lead to absence of protein expression (HR = 0.82, 95% CI: 0.74 to 0.90, P-trend = 3.1 x 10(-5), P-difference = 0.03). Four SNPs were associated with the risk of breast cancer for BRCA2 mutation carriers: rs10995190, P-trend = 0.015; rs1011970, P-trend = 0.048; rs865686, 2df P = 0.007; rs1292011 2df P = 0.03. rs10771399 (PTHLH) was predominantly associated with estrogen receptor (ER)-negative breast cancer for BRCA1 mutation carriers (HR = 0.81, 95% CI: 0.74 to 0.90, P-trend = 4 x 10(-5)) and there was marginal evidence of association with ER- negative breast cancer for BRCA2 mutation carriers (HR = 0.78, 95% CI: 0.62 to 1.00, P-trend = 0.049). Conclusions: The present findings, in combination with previously identified modifiers of risk, will ultimately lead to more accurate risk prediction and an improved understanding of the disease etiology in BRCA1 and BRCA2 mutation carriers.

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Authors
  • Antonis C. Antoniou
  • Karoline B. Kuchenbaecker
  • Penny Soucy
  • Jonathan Beesley
  • Xiaoqing Chen
  • Lesley McGuffog
  • Andrew Lee
  • Daniel Barrowdale
  • Sue Healey
  • Olga M. Sinilnikova
  • Maria A. Caligo
  • Annika Lindblom
  • Brita Arver
  • Richard Rosenquist
  • Per Karlsson
  • Kate Nathanson
  • Susan Domchek
  • Tim Rebbeck
  • Anna Jakubowska
  • Jan Lubinski
  • Katarzyna Jaworska
  • Katarzyna Durda
  • Elzbieta Zlowowcka-Perlowska
  • Ana Osorio
  • Mercedes Duran
  • Raquel Andres
  • Javier Benitez
  • Ute Hamann
  • Frans B. Hogervorst
  • Theo A. van Os
  • Senno Verhoef
  • Hanne E. J. Meijers-Heijboer
  • Juul Wijnen
  • Encarna B. Gomez Garcia
  • Marjolijn J. Ligtenberg
  • Mieke Kriege
  • Margriet Collee
  • Margreet G. E. M. Ausems
  • Jan C. Oosterwijk
  • Susan Peock
  • Debra Frost
  • Steve D. Ellis
  • Radka Platte
  • Elena Fineberg
  • D. Gareth Evans
  • Fiona Lalloo
  • Chris Jacobs
  • Ros Eeles
  • Julian Adlard
  • Rosemarie Davidson
  • Trevor Cole
  • Jackie Cook
  • Joan Paterson
  • Fiona Douglas
  • Carole Brewer
  • Shirley Hodgson
  • Patrick J. Morrison
  • Lisa Walker
  • Mark T. Rogers
  • Alan Donaldson
  • Huw Dorkins
  • Andrew K. Godwin
  • Betsy Bove
  • Dominique Stoppa-Lyonnet
  • Claude Houdayer
  • Bruno Buecher
  • Antoine de Pauw
  • Sylvie Mazoyer
  • Alain Calender
  • Melanie Leone
  • Brigitte Bressac-de Paillerets
  • Olivier Caron
  • Hagay Sobol
  • Marc Frenay
  • Fabienne Prieur
  • Sandra Fert Ferrer
  • Isabelle Mortemousque
  • Saundra Buys
  • Mary Daly
  • Alexander Miron
  • Mary Beth Terry
  • John L. Hopper
  • Esther M. John
  • Melissa Southey
  • David Goldgar
  • Christian F. Singer
  • Anneliese Fink-Retter
  • Muy-Kheng Tea
  • Daphne Geschwantler Kaulich
  • Thomas V. O. Hansen
  • Finn C. Nielsen
  • Rosa B. Barkardottir
  • Mia Gaudet
  • Tomas Kirchhoff
  • Vijai Joseph
  • Ana Dutra-Clarke
  • Kenneth Offit
  • Marion Piedmonte
  • Judy Kirk
  • David Cohn
  • Jean Hurteau
  • John Byron
  • James Fiorica
  • Amanda E. Toland
  • Marco Montagna
  • Cristina Oliani
  • Evgeny Imyanitov
  • Claudine Isaacs
  • Laima Tihomirova
  • Ignacio Blanco
  • Conxi Lazaro
  • Alex Teule
  • J. Del Valle
  • Simon A. Gayther
  • Kunle Odunsi
  • Jenny Gross
  • Beth Y. Karlan
  • Edith Olah
  • Soo-Hwang Teo
  • Patricia A. Ganz
  • Mary S. Beattie
  • Cecelia M. Dorfling
  • Elizabeth Jansen van Rensburg
  • 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
  • Dieter Schaefer
  • Trinidad Caldes
  • Miguel de la Hoya
  • Heli Nevanlinna
  • Taru A. Muranen
  • Bernard Lesperance
  • Amanda B. Spurdle
  • Susan L. Neuhausen
  • Yuan C. Ding
  • Xianshu Wang
  • Zachary Fredericksen
  • Vernon S. Pankratz
  • Noralane M. Lindor
  • Paolo Peterlongo
  • Siranoush Manoukian
  • Bernard Peissel
  • Daniela Zaffaroni
  • Bernardo Bonanni
  • Loris Bernard
  • Riccardo Dolcetti
  • Laura Papi
  • Laura Ottini
  • Paolo Radice
  • Mark H. Greene
  • Jennifer T. Loud
  • Irene L. Andrulis
  • Hilmi Ozcelik
  • Anna Marie Mulligan
  • Gord Glendon
  • Mads Thomassen
  • Anne-Marie Gerdes
  • Uffe B. Jensen
  • Anne-Bine Skytte
  • Torben A. Kruse
  • Georgia Chenevix-Trench
  • Fergus J. Couch
  • Jacques Simard
  • Douglas F. Easton
Organisations
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Cancer and Oncology
Original languageEnglish
JournalBreast Cancer Research
Volume14
Issue number1
Publication statusPublished - 2012
Publication categoryResearch
Peer-reviewedYes

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