Fine-Scale Mapping of the 4q24 Locus Identifies Two Independent Loci Associated with Breast Cancer Risk

Abstract

Background A recent association study identified a common variant (rs9790517) at 4q24 to be associated with breast cancer risk. Independent association signals and potential functional variants in this locus have not been explored. Methods We conducted a fine-mapping analysis in 55,540 breast cancer cases and 51,168 controls from the Breast Cancer Association Consortium. Results Conditional analyses identified two independent association signals among women of European ancestry, represented by rs9790517 (conditional p = 2.51 × 10−4; OR = 1.04; 95% CI 1.02–1.07) and rs77928427 (p = 1.86 × 10−4; OR = 1.04; 95% CI 1.02–1.07). Functional annotation using data from the Encyclopedia of DNA Elements (ENCODE) project revealed two putative functional variants, rs62331150 and rs73838678 in linkage disequilibrium (LD) with rs9790517 (r2 ≥ 0.90) residing in the active promoter or enhancer, respectively, of the nearest gene, TET2. Both variants are located in DNase I hypersensitivity and transcription factor binding sites. Using data from both The Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC), we showed that rs62331150 was associated with level of expression of TET2 in breast normal and tumor tissue. Conclusion Our study identified two independent association signals at 4q24 in relation to breast cancer risk and suggested that observed association in this locus may be mediated through the regulation of TET2. Impact Fine-mapping study with large sample size warranted for identification of independent loci for breast cancer risk.

Genetic Variants in Epigenetic Pathways and Risks of Multiple Cancers in the GAME-ON Consortium

“…Previous studies reported significant associations of variants at the TET2 locus with risk of cancer including ovarian and breast cancer (9, 21, 34). A large number of functional variants were identified in this region forming multiple pleiotropic linkage blocks that support the role of TET2 and its germline variants in the development of multiple cancer types.…”

“…A large number of functional variants were identified in this region forming multiple pleiotropic linkage blocks that support the role of TET2 and its germline variants in the development of multiple cancer types. Furthermore, an association between rs62331150 and TET2 gene expression in breast normal and tumor tissue was recently shown (9). The bidirectional association of the rs62331150 variant allele implies that the effect of TET2 genetic variation may be of a different nature for distinct cancers, increasing the risk of breast cancer, but decreasing the risk of prostate cancer.…”

“…Important mutations have been shown for example in DNMTs , IDH1 , IDH2 and TETs (as important players of DNA methylation), in EZH2 and KDM1A (involved in histone modifications) and in ARID1A (participant of chromatin remodeling) (reviewed in (2)). In addition, inherited genetic variants related to epigenetic regulatory processes were described in association with multiple cancers (9, 10). Given the fundamentality of epigenetic processes, germline variants in genes related to epigenetic pathways presumably have pleiotropic effects on the initiation of different cancers.…”

“…2007;39(5):645–649), Colon CGEMS pancreatic cancer scan (PanScan) (Amundadottir L, et al Nat Genet. 2009;41(9):986–990 and Petersen GM, et al Nat Genet. 2010;42(3):224–228), and the Lung Cancer and Smoking study.…”

Fine‐mapping of a novel premenopausal breast cancer susceptibility locus at Chr4q31.22 in Caucasian women and validation in African and Chinese women

“…While fine‐mapping approaches are well described in the literature, it is challenging to elucidate the functional relevance of GWAS SNPs, which are predominantly from noncoding regions conferring potential gene regulatory roles. Thus far, 15 breast cancer associated GWAS variants have been fine‐mapped and characterized for putative biological roles …”