Germline variation modulates susceptibility to metastasis in a mouse model of prostate tumorigenesis

Monday, September 22, 2014 — Poster Session II
4:00 p.m. – 6:00 p.m.	FAES Academic Center	NHGRI	GEN-17

* FARE Award Winner

Authors

• K.A Williams
• S. Bupp
• S. Patel
• J. Andreas
• S. Zhang
• A. Molinolo
• S. Gutkind
• N. Crawford

Abstract

Although prostate cancer is common, it typically runs an indolent course with most men succumbing to unrelated disease processes. The goal of this work is to map prostate metastasis modifier loci mapping using the C57BL/6-Tg(TRAMP)8247Ng/J (TRAMP) mouse model of aggressive prostate carcinoma. We hypothesize that germline variation influences metastasis in prostate cancer. The effect of germline variation in TRAMP mice was investigated by crossing it to different inbred mouse strains and quantifying metastasis in transgene-positive F1 males. Strains with the greatest phenotypic variation from the wildtype TRAMP mice were chosen for modifier mapping using an F2 intercross approach. The greatest number of loci achieving genome-wide significance was observed in the TRAMPxNOD/ShiLtJ F2 cross. Microarray data derived from the TRAMPxNOD/ShiLtJ F2 primary tumors allowed for the identification of novel metastasis susceptibility candidate genes. We have identified novel metastasis susceptibility candidate genes using both quantitative trait locus (QTL) mapping and tumor expression profiling. The relevance of those genes that display a cis-eQTL to aggressive human prostate cancer will be investigated in human prostate cancer genome-wide association study cohorts. This approach will identify novel germline factors driving metastasis susceptibility and allow for new insights into this form of prostate cancer.

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