The landscape of somatic chromosomal copy number aberrations in GEM models of prostate carcinoma

Abstract

Human prostate cancer is known to harbor recurrent genomic aberrations consisting of chromosomal losses, gains, rearrangements, and mutations that involve oncogenes and tumor suppressors. Genetically engineered mouse (GEM) models have been constructed to assess the causal role of these putative oncogenic events and provide molecular insight into disease pathogenesis. WhileGEMmodels generally initiate neoplasia by manipulating a single gene, expression profiles ofGEMtumors typically comprise hundreds of transcript alterations. It is unclear whether these transcriptional changes represent the pleiotropic effects of single oncogenes, and/or cooperating genomic or epigenomic events. Therefore, it was determined whether structural chromosomal alterations occur in GEM models of prostate cancer and whether the changes are concordant with human carcinomas. Whole genome array-based comparative genomic hybridization (CGH) was used to identify somatic chromosomal copy number aberrations (SCNA) in the widely used TRAMP, Hi-Myc, Pten-null, and LADY GEM models. Interestingly, very few SCNAs were identified and the genomic architecture of Hi-Myc, Pten-null, and LADY tumors were essentially identical to the germline. TRAMP neuroendocrine carcinomas contained SCNAs, which comprised three recurrent aberrations including a single copy loss of chromosome 19 (encoding Pten). In contrast, cell lines derived from the TRAMP, Hi-Myc, and Pten-null tumors were notable for numerous SCNAs that included copy gains of chromosome 15 (encoding Myc) and losses of chromosome 11 (encoding p53). Implications: Chromosomal alterations are not a prerequisite for events do not tumor formation inGEMprostate cancer models and cooperating naturally occur by mechanisms that recapitulate changes in genomic integrity as observed in human prostate cancer.