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

Abstract

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

Combination OX40 agonism/CTLA-4 blockade with HER2 vaccination reverses T-cell anergy and promotes survival in tumor-bearing mice

“…Indeed, recent studies suggest that checkpoint blockade using PD-1 or CTLA-4 blockade is more effective in tumors with a higher somatic mutation load (48,49). However, the mutational burden in prostate cancer is low relative to other cancer types and is more often associated with chromosomal rearrangements or deletions (50)(51)(52)(53). Our data support these studies, because combination therapy in the TRAMP model of spontaneous prostate adenocarcinoma was effective only when administered with a vaccine against a tumor-associated antigen.…”

Genetics and genomics of prostate cancer

“…Three studies [45][46][47] have been published to date with genome/exome sequence of more than 10 prostate tumors. One challenge with PCa is the high proportion of normal cells and heterogeneity in the primary tumor.…”

“…To address this, some groups have either passaged xenografts in mice or sequenced metastatic tumors. Kumar et al 45 performed exome capture and sequenced xenografts from 16 lethal metastatic tumors and three primary tumors. They did not have corresponding normal DNA, but used filters to identify the most likely somatic variants and identified recurrent mutations in the TP53, DLK2, GPC6, SDF4 and 19 other genes.…”

Uncovering the genetic landscape driving castration-resistant prostate cancer

“…7 Gene deregulations sometimes occur via mutation, however in the case of ETS2, the TMPRSS2: ERG fusion is the cause of this gene deletion. 3,8 Another significantly mutated pathway was observed in the PTEN network. Loss…”