Newly discovered breast cancer susceptibility loci on 3p24 and 17q23.2

Abstract

Genome-wide association studies (GWAS) have identified seven breast cancer susceptibility loci, but these explain only a small fraction of the familial risk of the disease. Five of these loci were identified through a two-stage GWAS involving 390 familial cases and 364 controls in the first stage, and 3,990 cases and 3,916 controls in the second stage. To identify additional loci, we tested over 800 promising associations from this GWAS in a further two stages involving 37,012 cases and 40,069 controls from 33 studies in the CGEMS collaboration and Breast Cancer Association Consortium. We found strong evidence for additional susceptibility loci on 3p (rs4973768: per-allele OR = 1.11, 95% CI = 1.08-1.13, P = 4.1 × 10-23) and 17q (rs6504950: per-allele OR = 0.95, 95% CI = 0.92-0.97, P = 1.4 × 10 -8). Potential causative genes include SLC4A7 and NEK10 on 3p and COX11 on 17q. © 2009 Nature America, Inc. All rights reserved

Breast cancer genome-wide association studies: there is strength in numbers

“…Moreover, in this study additional association analyses showed that another SNP rs1357245 is located in the same LD block as rs4973768 in the 3p24 region (Ahmed et al, 2009). Genotyping the 28 SNPs, known to be present in this region, in 2301 cases and 2256 controls, it presents a further SNP rs2307032 that was correlated with both SNPs.…”

“…Allele frequency studies in European populations have revealed that rs4973768 and rs6504950 could explain respectively 0.4% and 0.07% of the familial risk of BC. These susceptibility loci together with those previously identified in original GWAS would give rise to 5.9% of BC familial risk (Ahmed et al, 2009). Further genomewide linkage studies have revealed three putative BC susceptibility regions of interest, located on 3q25, 6q24 and 21q22.…”

“…Recently, a further GWAS study confirmed the correspondence between FGFR2 susceptibility loci and BC risk. In particular, the perallele odds ratio was higher for ER-positive rather than for ER-negative BC (Ahmed et al, 2009). This finding is consistent with the involvement of FGFR2 in estrogenrelated breast carcinogenesis (Tamaru et al, 2004), and with higher levels of FGFR2 expression in ER þ than ERÀ cell lines and tumors (Zhang et al, 1999).…”

Interactions of ion transporters and channels with cancer cell metabolism and the tumour microenvironment

“…Genome-wide association studies have shown correlation between a single nucleotide polymorphism in the NBCn1 gene and breast cancer susceptibility [91], suggesting that NBCn1 plays a role in breast cancer biology. This is supported by our recent finding that NBCn1 plasma membrane density was increased in primary breast carcinomas and metastases compared with matched normal breast tissue [81].…”

Polygenic susceptibility to breast cancer: current state-of-the-art

“…Four of the SNPs were within known genes. More recently, 814 promising associations from the original two-staged genome scan have been tested by Ahmed et al in a further sample of 37,012 cases and 40,069 controls from 33 BCAC studies, evidence has been found for association of two additional loci (3p24 and 17q22) [32].Hunter and colleagues conducted a GWAS, as a part of the Cancer Genetic Markers of Susceptibility (CGEMS) project, by genotyping over 500,000 SNPs using the Illumina HumanHap500 array in 1145 women of European ancestry with postmenopausal invasive breast cancer and 1142 controls [29]. Of the six SNPs with most extreme p-values, two were at the 10q26 locus/intron 2 of FGFR2 and the associations were replicated in a further cohort comprising 1776 cases and 2072 controls.…”