Abstract A1-10: The iCOGS breast cancer GWAS reveals 4 unique signals in the PTHLH region in patients of European origin

Parathyroid hormone-related protein (PTHrP), the product of the PTHLH gene, has long been implicated in breast cancer. Its expression is thought to favor 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, we demonstrate 4 discrete overlapping signals by utilizing forward selection logistic regression and LASSO techniques. Two of these signals are centered and superimposed around rs10771399, ~40kbp upstream of PTHLH, a third lies a further 100kbp upstream, and the fourth lies a further 250kbp upstream over the next gene, CCDC91. While the causation of this signal remains elusive, multiple putatively contributory variations are captured by these signals. Citation Format: Adam N. Freeman, T John Martin, Michael A. Henderson, Enes Makalic, Miroslaw K. Kapuscinski, Daniel F. Schmidt, John Hopper. The iCOGS breast cancer GWAS reveals 4 unique signals in the PTHLH region in patients of European origin. [abstract]. In: Proceedings of the AACR Special Conference on Translation of the Cancer Genome; Feb 7-9, 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 1):Abstract nr A1-10.