Poster Presentation 30th Lorne Cancer Conference 2018

Modifier locus mapping of a transgenic F2 mouse population identifies CCDC115 as a novel aggressive prostate cancer modifier gene in humans. (#283)

Jean M Winter 1 2 , Natasha L Curry 2 , Derek M Gildea 3 , Kendra A Williams 2 , Minnkyong Lee 2 , Ying Hu 4 , Nigel PS Crawford 2 5
  1. Dame Roma Mitchell Cancer Research Laboratories, Adelaide Health and Medical Sciences, The University of Adelaide, Adelaide, SA, Australia
  2. Metastasis Genetics Section, Genetics and Molecular Biology Branch, National Human Genome Research Institute, Bethesda, MD, USA
  3. Computational and Statistical Genomics Branch, National Human Genome Research Institute, Bethesda, MD, USA
  4. Center for Biomedical Informatics and Information Technology, National Cancer Institute, Rockville, MD, USA
  5. Sanofi, Bridgewater, NJ, USA

It is well known that development of prostate cancer (PC) can be attributed to somatic mutations acquired within proto-oncogenes or tumour-suppressor genes. What is less well understood is how germline variation contributes to PC aggressiveness. To map germline modifiers of aggressive neuroendocrine PC, we generated genetically diverse F2 inter-cross mice using the transgenic TRAMP mouse model and the wild-derived WSB/EiJ (WSB) strain. The relevance of candidate genes identified in these mice was extensively validated in human PC datasets and cell lines. Aggressive PC traits were quantified in 30 week old (TRAMP x WSB) F2 mice (n=307). Correlation of germline genotype with disease phenotype revealed seven modifier loci that were significantly associated with aggressive disease. RNA-seq analysis of 92 (TRAMP x WSB) F2 prostates revealed 25 candidate genes that harboured both a significant cis-eQTL and mRNA expression correlations with aggressive PC. We further delineated these genes based on their clinical relevance, by interrogating human PC GWAS and tumour gene expression datasets. We identified four genes (CCDC115, DNAJC10, RNF149, and STYXL1), which encompassed all of the following characteristics: 1) one or more germline variants associated with aggressive PC traits; 2) differential mRNA levels associated with aggressive PC traits; and 3) differential mRNA expression between normal and tumour tissue. Functional studies in LNCaP prostate cancer cells revealed ectopic overexpression of CCDC115 can significantly impede cell growth in vitro and tumour growth in vivo. CCDC115 expression in human prostate tumour was associated with better survival outcomes. We have demonstrated how modifier locus mapping in mouse models of PC, coupled with in silico analyses of human PC datasets, reveal novel germline modifier genes of aggressive PC. We have characterized CCDC115 as being associated with less aggressive PC in humans, placing it as a potential prognostic marker of aggressive PC.