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Exome sequencing identifies a spectrum of mutation frequencies in advanced and lethal prostate cancers
- Source :
- Proceedings of the National Academy of Sciences. 108:17087-17092
- Publication Year :
- 2011
- Publisher :
- Proceedings of the National Academy of Sciences, 2011.
-
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.
- Subjects :
- Male
Transplantation, Heterologous
Biology
medicine.disease_cause
Germline
Mice
Prostate cancer
Glypicans
Prostate
Cell Line, Tumor
medicine
Animals
Humans
Point Mutation
Exome
Neoplasm Metastasis
Wnt Signaling Pathway
Exome sequencing
Glycoproteins
Genetics
Mutation
Multidisciplinary
Calcium-Binding Proteins
Genetic Variation
Prostatic Neoplasms
Cancer
Androgen Antagonists
Chromoplexy
Biological Sciences
Genes, p53
medicine.disease
medicine.anatomical_structure
Orchiectomy
Neoplasm Transplantation
Subjects
Details
- ISSN :
- 10916490 and 00278424
- Volume :
- 108
- Database :
- OpenAIRE
- Journal :
- Proceedings of the National Academy of Sciences
- Accession number :
- edsair.doi.dedup.....0b78e8988414d92d74dd7d7415561b9b
- Full Text :
- https://doi.org/10.1073/pnas.1108745108