Rs11977670

rs11977670 is an intergenic SNP associated with predisposition for invasive lobular breast cancer (ILC) and lobular carcinoma in situ (LCIS). rs11977670 is located on chromosome 7q34 (position:139942304, GRCh Build 37).

Invasive lobular breast cancer makes up 10-15% of all breast cancer cases and forms in the milk-producing lobes of breast tissue. ILC often does not form a lump and can therefore be difficult to diagnose using mammogram screenings. While researchers have identified a range of genes associated with breast cancer risk, rs11977670 is the first genetic variant shown to be linked specifically with a predisposition for ILC. LCIS is a type of non-invasive breast cancer that is also difficult to detect. LCIS shares genetic patterns similar to those of ILC, suggesting that LCIS lesions may be precursors to ILC tumors.

Its nearest neighbor, the histone demethylase JHDM1D, lies 65 kb away. BRAF, a proto-oncogene mutated in many melanomas, is 500 kb from rs11977670. There was no evidence of increased somatic mutation in either JHDM1D or BRAF in ILC tumors. ENCODE data shows that rs11977670 is marked by H3K27 acetylation in normal human mammary epithelial cells (HMEC) and breast carcinoma (MCF-7).

rs11977670 was identified by genotyping 6,000 cases of lobular carcinoma and 34,000 controls with an iCOGS chip, a custom Illumina iSelect SNP array designed to test 211,155 genetic variants linked to breast cancers, as well as ovarian and prostate cancers. Cases and controls for phase I were taken from 34 studies from the Breast Cancer Association Consortium and GLACIER (A study to investigate the Genetics of LobulAr Carcinoma In situ in EuRope). Once identified, six novel SNPs (at p<5x10-5) were genotyped in 516 phase II cases and 1,467 controls. All subjects were white and of Western European ancestry.

Of these six SNPs (rs11977670, rs2121783, rs2747652, rs3909680, rs9948182, rs7034265), only rs11977670 was significant at a genome-wide level in phase II. In an analysis of pooled phase I and phase II cases, rs11977670 reached genome-wide significance for ILC (OR=1.13, p=6.0x10-10) and similar significance for LCIS. The risk allele A, had a dominant, rather than additive effect (ORAG=1.21, ORAA=1.27, p for departure from log-additivity=0.009). Allele frequency in the HapMap CEU population is G=0.571 and A=0.429 and from 1000 Genomes is G=0.589 and A=0.411.

Genetic Predisposition to In Situ and Invasive Lobular Carcinoma of the Breast.