Faculty Collaboration Database

Substantial interindividual and limited intraindividual genomic diversity among tumors from men with metastatic prostate cancer. Nat Med 2016 Apr;22(4):369-78

Date

03/02/2016

Pubmed ID

26928463

Pubmed Central ID

PMC5045679

DOI

10.1038/nm.4053

Scopus ID

2-s2.0-84959255550 (requires institutional sign-in at Scopus site)   518 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.

Author List

Kumar A, Coleman I, Morrissey C, Zhang X, True LD, Gulati R, Etzioni R, Bolouri H, Montgomery B, White T, Lucas JM, Brown LG, Dumpit RF, DeSarkar N, Higano C, Yu EY, Coleman R, Schultz N, Fang M, Lange PH, Shendure J, Vessella RL, Nelson PS

Author

Navonil De Sarkar PhD Assistant Professor in the Pathology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adult
Aged
Ataxia Telangiectasia Mutated Proteins
Carboplatin
Cell Proliferation
Comparative Genomic Hybridization
DNA Copy Number Variations
E2F1 Transcription Factor
Gene Expression Regulation, Neoplastic
Genetic Variation
Genome, Human
Humans
Male
Middle Aged
Neoplasm Metastasis
Prostatic Neoplasms
Receptors, Androgen
Retinoblastoma Protein