Common variants on chromosomes 2q35 and 16q12 confer susceptibility to estrogen receptor–positive breast cancer

Abstract

Familial clustering studies indicate that breast cancer risk has a substantial genetic component. To identify new breast cancer risk variants, we genotyped approximately 300,000 SNPs in 1,600 Icelandic individuals with breast cancer and 11,563 controls using the Illumina Hap300 platform. We then tested selected SNPs in five replication sample sets. Overall, we studied 4,554 affected individuals and 17,577 controls. Two SNPs consistently associated with breast cancer: approximately 25% of individuals of European descent are homozygous for allele A of rs13387042 on chromosome 2q35 and have an estimated 1.44-fold greater risk than noncarriers, and for allele T of rs3803662 on 16q12, about 7% are homozygous and have a 1.64-fold greater risk. Risk from both alleles was confined to estrogen receptor-positive tumors. At present, no genes have been identified in the linkage disequilibrium block containing rs13387042. rs3803662 is near the 5' end of TNRC9 , a high mobility group chromatin-associated protein whose expression is implicated in breast cancer metastasis to bone.

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

“…In the LD block where lies rs13387042 there are no known genes, but there are proximally and distally TNP1, IGFBP5, IGFBP2 and TNS1 genes (Stacey et al, 2007).…”

A family-based, genome-wide association study of young-onset breast cancer: inherited variants and maternally mediated effects

“…35 The other highly ranked TOX3 SNP, rs3803662:G4A, was also originally identified in a GWAS study 36 and the association was successfully replicated. [37][38][39][40] The top two ranked SNPs from the maternal effects analysis, rs12919267:C4T and rs12926526:A4G, are in RBFOX1, which encodes the FOX1 RNA-binding protein. The identified SNPs have no known associations with breast cancer or with the prenatal environment specifically.…”

Surveying germline genomic landscape of breast cancer

“…Among germline mutations predisposing to breast cancer several variants have also been described, whereby the germline landscape of breast cancer susceptibility is taking form [2]. Along with the previously characterized high-penetrance genes, such as BRCA1 and BRCA2, moderate-penetrance and low-penetrance susceptibility alleles have recently been detected [3][4][5][6][7]. The level of penetrance is defined by the relative risk that the alleles inflict in mutation carriers.…”

“…PAFs have been used extensively for environmental risk factors of diseases in order to rank them and to assess the prospective gains in disease prevention. Their use in cancer genetics is relatively new [5,6,9,10], probably because the mutant variants of the 'classical' high-penetrance cancer genes are so rare that their contribution to the population burden is low compared to the high individual risks [7]. Some recent studies on low-penetrance genes do cite PAFs, referring to the high population burden conferred by the variants in spite of their low relative risks.…”

“…1). Among low-penetrance alleles, PAF for TGFbeta1 and CASP8 may account for 5.7 and 3.2%, respectively [3]; the five loci described by Easton et al [4] (close to genes/loci FGFR2, TNRC9, MAP3K1, LSP1, 8q) can be calculated to confer a joint PAF of 36%, assuming independence and multiplicative epistatic interactions; the two loci described by Stacey et al on chromosomes 2q35 and 16q12 confer PAFs of 5.3 and 7.1%, assuming that estrogen receptor-positive breast cancers accounted for 50% of all breast cancer [5]. Assuming that the low-penetrance loci act independently and multiplicatively, their joint PAF can be estimated at 58% (Fig.…”