Abstract 1098: Epistasis analysis of the PTHLH region in European subjects of the iCOGS breast cancer GWAS suggest multiple genes may be implicated in its role in breast cancer

Parathyroid hormone-related protein (PTHrP), the product of the PTHLH gene, has long been implicated in breast cancer. Its expression is thought to favour and, potentially, facilitate metastasis to bone. Paradoxically, a prospective clinical study clinical suggests that its production in primary breast cancers is actually protective, affording a better prognosis than its absence. Multiple recent Genome-Wide Association Studies (GWAS) have confirmed a single susceptibility locus immediately upstream of the PTHLH gene to be associated with breast cancer. This was again reproduced in the recent iCOGS GWAS, which involved over 90,000 European subjects. In spite of a single SNP, rs10771399, being uniquely reported and reproduced by prior studies, comprehensive analysis of the region reveals multiple significant SNPs stretching for hundreds of kbp across the locus. Epistasis analysis of this region versus the entire iCOGS array was performed using Plink!. These results suggest multiple genes may be implicated in the causation of this signal. Many known functional partners of PTHLH were identified, including IPO8, RUNX1, RUNX3, S100P, SOX9, SOX11, and SOX14. Multiple putative functional partners of PTHLH were likewise identified, including PBXIP1, PMVK, KCNN3, STX12, PPP1R8, CAMTA1, PRKCZ, TGIF1, SPHKAP, MYC, and STAT3. When taken together, these results offer novel potential insights into the function of the locus at PTHLH in breast cancer that may be further investigated. Citation Format: Adam N. Freeman, Michael A. Henderson, T John Martin, Enes Makalic, Miroslaw K. Kapuscinski, Daniel Schmidt, John Hopper. Epistasis analysis of the PTHLH region in European subjects of the iCOGS breast cancer GWAS suggest multiple genes may be implicated in its role in breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1098. doi:10.1158/1538-7445.AM2015-1098