Epigenetic analysis of the LSP1-rs3817198 breast cancer risk locus (360G-Wellcome-211573_Z_18_Z)

rs3817198 at 11p15.5 is associated with estrogen receptor-positive breast cancer risk. This locus shows a parent of origin effect and effect modification by parity. Fine-scale mapping of this region identified seven possible single nucleotide polymorphisms (SNPs), all within 11kb of the 5’ end of Lymphocyte Specific Protein (LSP1), any of which could be causally associated with risk. Four of these map within a region that shows differential methylation and one of them (rs686722) co-localises precisely with a CpG methylated site. We hypothesise that rs686722 influences breast cancer risk because both the allele (C/T) and the methylation of the "C" affect expression of LSP1. The mechanism by which LSP1 could influence breast cancer risk is not clear; one possibility is via an effect on the motility of lymphocytes within the breast stroma. For this project we will use lymphocyte DNA from women participating in the Generations Study and CEPH individuals. The key goals are to investigate the methylation of rs686722 with regard to the parental origin of a woman's C allele and her parity. We will also use lymphoblastoid cell lines from heterozygous CEPH individuals to test for allele specific expression of LSP1.