Substantial interindividual and limited intraindividual genomic diversity among tumors from men with metastatic prostate cancer

Akash Kumar, Ilsa Coleman, Colm Morrissey, Xiaotun Zhang, Lawrence D. True, Roman Gulati, Ruth Etzioni, Hamid Bolouri, Bruce Montgomery, Thomas White, Jared M. Lucas, Lisha G. Brown, Ruth F. Dumpit, Navonil DeSarkar, Celestia Higano, Evan Y. Yu, Roger Coleman, Nikolaus Schultz, Min Fang, Paul H. LangeJay Shendure, Robert L. Vessella, Peter S. Nelson

Research output: Contribution to journalArticle

236 Scopus citations

Abstract

Tumor heterogeneity may reduce the efficacy of molecularly guided systemic therapy for cancers that have metastasized. To determine whether the genomic alterations in a single metastasis provide a reasonable assessment of the major oncogenic drivers of other dispersed metastases in an individual, we analyzed multiple tumors from men with disseminated prostate cancer through whole-exome sequencing, array comparative genomic hybridization (CGH) and RNA transcript profiling, and we compared the genomic diversity within and between individuals. In contrast to the substantial heterogeneity between men, there was limited diversity among metastases within an individual. The number of somatic mutations, the burden of genomic copy number alterations and aberrations in known oncogenic drivers were all highly concordant, as were metrics of androgen receptor (AR) activity and cell cycle activity. AR activity was inversely associated with cell proliferation, whereas the expression of Fanconi anemia (FA)-complex genes was correlated with elevated cell cycle progression, expression of the E2F transcription factor 1 (E2F1) and loss of retinoblastoma 1 (RB1). Men with somatic aberrations in FA-complex genes or in ATM serine/threonine kinase (ATM) exhibited significantly longer treatment-response durations to carboplatin than did men without defects in genes encoding DNA-repair proteins. Collectively, these data indicate that although exceptions exist, evaluating a single metastasis provides a reasonable assessment of the major oncogenic driver alterations that are present in disseminated tumors within an individual, and thus may be useful for selecting treatments on the basis of predicted molecular vulnerabilities.

Original languageEnglish (US)
Pages (from-to)369-378
Number of pages10
JournalNature medicine
Volume22
Issue number4
DOIs
Publication statusPublished - Apr 1 2016
Externally publishedYes

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ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Kumar, A., Coleman, I., Morrissey, C., Zhang, X., True, L. D., Gulati, R., ... Nelson, P. S. (2016). Substantial interindividual and limited intraindividual genomic diversity among tumors from men with metastatic prostate cancer. Nature medicine, 22(4), 369-378. https://doi.org/10.1038/nm.4053