A meta-analysis of genome-wide association studies of breast cancer identifies two novel susceptibility loci at 6q14 and 20q11

Abstract

Genome-wide association studies (GWAS) of breast cancer defined by hormone receptor status have revealed loci contributing to susceptibility of estrogen receptor (ER)-negative subtypes. To identify additional genetic variants for ER-negative breast cancer, we conducted the largest meta-analysis of ER-negative disease to date, comprising 4754 ER-negative cases and 31 663 controls from three GWAS: NCI Breast and Prostate Cancer Cohort Consortium (BPC3) (2188 ER-negative cases; 25 519 controls of European ancestry), Triple Negative Breast Cancer Consortium (TNBCC) (1562 triple negative cases; 3399 controls of European ancestry) and African American Breast Cancer Consortium (AABC) (1004 ER-negative cases; 2745 controls). We performed in silico replication of 86 SNPs at P ≤ 1 × 10(-5) in an additional 11 209 breast cancer cases (946 with ER-negative disease) and 16 057 controls of Japanese, Latino and European ancestry. We identified two novel loci for breast cancer at 20q11 and 6q14. SNP rs2284378 at 20q11 was associated with ER-negative breast cancer (combined two-stage OR = 1.16; P = 1.1 × 10(-8)) but showed a weaker association with overall breast cancer (OR = 1.08, P = 1.3 × 10(-6)) based on 17 869 cases and 43 745 controls and no association with ER-positive disease (OR = 1.01, P = 0.67) based on 9965 cases and 22 902 controls. Similarly, rs17530068 at 6q14 was associated with breast cancer (OR = 1.12; P = 1.1 × 10(-9)), and with both ER-positive (OR = 1.09; P = 1.5 × 10(-5)) and ER-negative (OR = 1.16, P = 2.5 × 10(-7)) disease. We also confirmed three known loci associated with ER-negative (19p13) and both ER-negative and ER-positive breast cancer (6q25 and 12p11). Our results highlight the value of large-scale collaborative studies to identify novel breast cancer risk loci.

Modifiers of breast and ovarian cancer risks for BRCA1 and BRCA2 mutation carriers

“…Genotypes at many millions of common variants across the genome can be genotyped or imputed with high accuracy using largescale genotyping arrays, using reference panels from the 1000 Genomes Project (Auton et al 2015). This approach has been applied with great success in cancer epidemiology in the general population, with GWAS having identified more than 100 common susceptibility variants for breast cancer , Hunter et al 2007, Stacey et al 2007, Ahmed et al 2009, Thomas et al 2009, Antoniou et al 2010b, Turnbull et al 2010, Cai et al 2011, Fletcher et al 2011, Ghoussaini et al 2012, Hein et al 2012, Long et al 2012, Siddiq et al 2012, Bojesen et al 2013, French et al 2013, Garcia-Closas et al 2013, Gaudet et al 2013, Meyer et al 2013, Cai et al 2014, Milne et al 2014a, Orr et al 2015, Couch et al 2016, Dunning et al 2016, Lawrenson et al 2016, Zheng et al 2009) and 22 for ovarian cancer (Song et al 2009, Bolton et al 2010, Goode et al 2010, Bojesen et al 2013, Permuth-Wey et al 2013, Pharoah et al 2013, Kuchenbaecker et al 2015.…”

Breast Cancer Susceptibility Variants and Mammographic Density Phenotypes in Norwegian Postmenopausal Women

“…Genome-wide association studies (GWAS) and candidate gene studies have identified more than 75 SNPs that may be associated with risk of breast cancer in Caucasians (20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34). It has been estimated that there is about a 10% overlap in the genetic factors that influence breast cancer risk and those that determine variation in MD (5).…”

Preimplantation genetic diagnosis using combined strategies on a breast cancer patient with a novel genomic deletion in BRCA2

“…have also been identified [19] to be associated with breast cancer. In addition, more than 40 novel breast cancer susceptibility loci have been found in a most recent meta-analysis of nine GWAS studies [20,21]. As breast cancer involves multiple cancer susceptibility alleles, the patient's mother might carry another breast cancer gene mutation that had not yet be identified.…”