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

• Published in: Nature medicine Vol. 22; no. 4; pp. 369 - 378
• Main Authors: Kumar, Akash, Coleman, Ilsa, Morrissey, Colm, Zhang, Xiaotun, True, Lawrence D, Gulati, Roman, Etzioni, Ruth, Bolouri, Hamid, Montgomery, Bruce, White, Thomas, Lucas, Jared M, Brown, Lisha G, Dumpit, Ruth F, DeSarkar, Navonil, Higano, Celestia, Yu, Evan Y, Coleman, Roger, Schultz, Nikolaus, Fang, Min, Lange, Paul H, Shendure, Jay, Vessella, Robert L, Nelson, Peter S
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.04.2016; Nature Publishing Group
• Subjects: 38/23; 45/61; 631/208/737/211; 692/699/67/589/466; 692/699/67/69; Adult; Aged; Ataxia Telangiectasia Mutated Proteins - genetics; Biomedicine; Cancer Research; Carboplatin - administration & dosage; Care and treatment; Cell Proliferation - drug effects; Comparative Genomic Hybridization; Deoxyribonucleic acid; DNA; DNA Copy Number Variations - genetics; E2F1 Transcription Factor - biosynthesis; E2F1 Transcription Factor - genetics; Gene Expression Regulation, Neoplastic - drug effects; Genetic aspects; Genetic Variation; Genome, Human; Genomics; Heterogeneity; Humans; Hybridization; Infectious Diseases; Male; Metabolic Diseases; Metastasis; Middle Aged; Molecular Medicine; Mutation; Neoplasm Metastasis; Neurosciences; Prostate cancer; Prostatic Neoplasms - drug therapy; Prostatic Neoplasms - genetics; Prostatic Neoplasms - pathology; Receptors, Androgen - biosynthesis; Receptors, Androgen - genetics; Retinoblastoma Protein - genetics; RNA sequencing; Tumors
• ISSN: 1078-8956; 1546-170X
• DOI: 10.1038/nm.4053

Genomic analysis of a single metastasis informs about the oncogenic—and potentially druggable—genomic alterations present in other tumors within the same man with metastatic prostate cancer. 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.