Common variants at 12p11, 12q24, 9p21, 9q31.2 and in ZNF365 are associated with breast cancer risk for BRCA1 and/or BRCA2mutation carriers
Authors: Antoniou Antonis C , Kuchenbaecker Karoline B , Soucy Penny , Beesley Jonathan , Chen Xiaoqing , McGuffog Lesley , Lee Andrew , Barrowdale Daniel , Healey Sue , Sinilnikova Olga M , Caligo Maria A , Loman Niklas , Harbst Katja , Lindblom Annika , Arver Brita , Rosenquist Richard , Karlsson Per , Nathanson Kate , Domchek Susan , Rebbeck Tim , Jakubowska Anna , Lubinski Jan , Jaworska Katarzyna , Durda Katarzyna , Złowowcka-Perłowska Elżbieta , Osorio Ana , Durán Mercedes , Andrés Raquel , Benítez Javier , Hamann Ute , Hogervorst Frans B , van Os Theo A , Verhoef Senno , Meijers-Heijboer Hanne EJ , Wijnen Juul , Gómez Garcia Encarna B , Ligtenberg Marjolijn J , Kriege Mieke , Collée J Margriet , Ausems Margreet GEM , Oosterwijk Jan C , Peock Susan , Frost Debra , Ellis Steve D , Platte Radka , Fineberg Elena , Evans D Gareth , Lalloo Fiona , Jacobs Chris , Eeles Ros , Adlard Julian , Davidson Rosemarie , Cole Trevor , Cook Jackie , Paterson Joan , Douglas Fiona , Brewer Carole , Hodgson Shirley , Morrison Patrick J , Walker Lisa , Rogers Mark T , Donaldson Alan , Dorkins Huw , Godwin Andrew K , Bove Betsy , Stoppa-Lyonnet Dominique , Houdayer Claude , Buecher Bruno , de Pauw Antoine , Mazoyer Sylvie , Calender Alain , Léoné Mélanie , Bressac- de Paillerets Brigitte , Caron Olivier , Sobol Hagay , Frenay Marc , Prieur Fabienne , Ferrer Sandra Fert , Mortemousque Isabelle , Buys Saundra , Daly Mary , Miron Alexander , Terry Mary Beth , Hopper John L , John Esther M , Southey Melissa , Goldgar David , Singer Christian F , Fink-Retter Anneliese , Tea Muy-Kheng , Kaulich Daphne Geschwantler , Hansen Thomas VO , Nielsen Finn C , Barkardottir Rosa B , Gaudet Mia , Kirchhoff Tomas , Joseph Vijai , Dutra-Clarke Ana , Offit Kenneth , Piedmonte Marion , Kirk Judy , Cohn David , Hurteau Jean , Byron John , Fiorica James , Toland Amanda E , Montagna Marco , Oliani Cristina , Imyanitov Evgeny , Isaacs Claudine , Tihomirova Laima , Blanco Ignacio , Lazaro Conxi , Teulé Alex , Valle J Del , Gayther Simon A , Odunsi Kunle , Gross Jenny , Karlan Beth Y , Olah Edith , Teo Soo-Hwang , Ganz Patricia A , Beattie Mary S , Dorfling Cecelia M , van Rensburg Elizabeth Jansen , 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 , Schäfer Dieter , Caldes Trinidad , de la Hoya Miguel , Nevanlinna Heli , Muranen Taru A , Lespérance Bernard , Spurdle Amanda B , Neuhausen Susan L , Ding Yuan C , Wang Xianshu , Fredericksen Zachary , Pankratz Vernon S , Lindor Noralane M , Peterlongo Paolo , Manoukian Siranoush , Peissel Bernard , Zaffaroni Daniela , Bonanni Bernardo , Bernard Loris , Dolcetti Riccardo , Papi Laura , Ottini Laura , Radice Paolo , Greene Mark H , Loud Jennifer T , Andrulis Irene L , Ozcelik Hilmi , Mulligan Anna Marie , Glendon Gord , Thomassen Mads , Gerdes Anne-Marie , Jensen Uffe B , Skytte Anne-Bine , Kruse Torben A , Chenevix-Trench Georgia , Couch Fergus J , Simard Jacques , Easton Douglas F ,   CIMBA, SWE-BRCA,   HEBON,   EMBRACE,   GEMO Collaborators Study,   kConFab Investigators
Published: February 2012

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 × 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 × 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 × 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.