Exome sequencing identifies a spectrum of mutation frequencies in advanced and lethal prostate cancers

摘要: To catalog protein-altering mutations that may drive the development of prostate cancers and their progression to metastatic disease systematically, we performed whole-exome sequencing 23 derived from 16 different lethal tumors three high-grade primary carcinomas. All were propagated in mice as xenografts, designated LuCaP series, model phenotypic variation, such responses cancer-directed therapeutics. Although corresponding normal tissue was not available for most tumors, able take advantage increasingly deep catalogs human genetic variation remove germline variants. On average, each tumor genome contained ∼200 novel nonsynonymous variants, which vast majority specific individual A subset genes recurrently altered across individuals, including TP53, DLK2, GPC6, SDF4. Unexpectedly, cancer genomes exhibited substantially higher mutation frequencies, with 2,000–4,000 coding variants per exome. comparison castration-resistant castration-sensitive pairs lines same highlights Wnt pathway potentially contributing castration resistance. Collectively, our results indicate point arising regions advanced are common but, notable exceptions, very few mutated a substantial fraction tumors. We also report previously undescribed subtype exhibiting “hypermutated” genomes, potential implications resistance Our suggest challenge necessity matched tumor-normal pairs.