title: 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 tumor-normal pairs.
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, WA 98105, USA.
authors.forename: Akash
authors.initials: A
authors.lastname: Kumar
authors.forename: Thomas A
authors.initials: TA
authors.lastname: White
authors.forename: Alexandra P
authors.initials: AP
authors.lastname: MacKenzie
authors.forename: Nigel
authors.initials: N
authors.lastname: Clegg
authors.forename: Choli
authors.initials: C
authors.lastname: Lee
authors.forename: Ruth F
authors.initials: RF
authors.lastname: Dumpit
authors.forename: Ilsa
authors.initials: I
authors.lastname: Coleman
authors.forename: Sarah B
authors.initials: SB
authors.lastname: Ng
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Salipante
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Rieder
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Nickerson
authors.forename: Eva
authors.initials: E
authors.lastname: Corey
authors.forename: Paul H
authors.initials: PH
authors.lastname: Lange
authors.forename: Colm
authors.initials: C
authors.lastname: Morrissey
authors.forename: Robert L
authors.initials: RL
authors.lastname: Vessella
authors.forename: Peter S
authors.initials: PS
authors.lastname: Nelson
authors.forename: Jay
authors.initials: J
authors.lastname: Shendure
mesh_terms: D000726:Androgen Antagonists / Q000627:therapeutic use; D000818:Animals; D002135:Calcium-Binding Proteins / Q000235:genetics; D045744:Cell Line, Tumor; D059472:Exome; D016158:Genes, p53; D014644:Genetic Variation; D006023:Glycoproteins / Q000235:genetics; D053673:Glypicans / Q000235:genetics; D006801:Humans; D008297:Male; D051379:Mice; D009154:Mutation; D009362:Neoplasm Metastasis / Q000235:genetics; D009368:Neoplasm Transplantation; D009919:Orchiectomy; D017354:Point Mutation; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000628:therapy; D014183:Transplantation, Heterologous; D060449:Wnt Signaling Pathway / Q000235:genetics
chemical_list: D000726:Androgen Antagonists; D002135:Calcium-Binding Proteins; C120300:GPC6 protein, human; D006023:Glycoproteins; D053673:Glypicans; C099100:SDF4 protein, human