Abstract 4952: Germline variation modulates susceptibility to aggressive disease development in a mouse model of prostate tumorigenesis

Abstract

Abstract Although prostate cancer is common, with over 238,000 new cases being diagnosed in the US in 2012, it typically runs an indolent course with most men succumbing to unrelated disease processes. This is reflected in the low prostate cancer-specific mortality, with approximately 29,000 men succumbing in the same period. It is of critical importance to identify modifiers that increase susceptibility to aggressive disease to allow physicians to more accurately identify men at risk of fatal disease forms. The goal of this work is to map prostate tumor progression and metastasis modifier loci mapping using the C57BL/6-Tg(TRAMP)8247Ng/J (TRAMP) mouse model of aggressive neuroendocrine prostate carcinoma. We hypothesize that germline variation influences tumor progression and metastasis in prostate cancer. The effect of germline variation in TRAMP mice was investigated by crossing it to Collaborative Cross progenitor strains and quantifying tumor progression and metastasis in transgene-positive F1 males. Those strains with the greatest phenotypic variation from the wildtype TRAMP C57BL6/J mice were chosen for modifier mapping using an F2 intercross approach. F2 mice were genotyped using a linkage panel consisting of 1,449 SNPs and modifier loci analyzed using j/qtl. The greatest number of loci achieving genomewide significance were observed in the TRAMPxNOD/ShiLtJ F2 cross (n=232). Modifier loci associated with primary tumor growth were observed on chromosomes 4, 7 and 8. Additionally, loci associated with metastasis were observed on chromosomes 1, 11, 13 and 17. We have therefore identified multiple loci associated with aggressive disease development in a mouse model of prostate cancer. Candidate gene identification is ongoing, and focuses upon characterizing cis-eQTLs in TRAMPxNOD/ShiLtJ F2 primary tumors. Additionally, we are performing high resolution modifier mapping in TRAMPxJ:DO F1 mice. Our eventual aim is to confirm the relevance of candidate genes identified in the TRAMP mouse in human association cohorts. Citation Format: Kendra A. Williams, Sujata Bupp, Shashank Patel, Jonathan Andreas, Suiyuan Zhang, Alfredo Molinolo, Silvio Gutkind, Nigel Crawford. Germline variation modulates susceptibility to aggressive disease development in a mouse model of prostate tumorigenesis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4952. doi:10.1158/1538-7445.AM2014-4952