@article{d36731e076544e0cab3d308ccb1012f5,
title = "Substantial interindividual and limited intraindividual genomic diversity among tumors from men with metastatic prostate cancer",
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 = "Akash Kumar and Ilsa Coleman and Colm Morrissey and Xiaotun Zhang and True, {Lawrence D.} and Roman Gulati and Ruth Etzioni and Hamid Bolouri and Bruce Montgomery and Thomas White and Lucas, {Jared M.} and Brown, {Lisha G.} and Dumpit, {Ruth F.} and Navonil DeSarkar and Celestia Higano and Yu, {Evan Y.} and Roger Coleman and Nikolaus Schultz and Min Fang and Lange, {Paul H.} and Jay Shendure and Vessella, {Robert L.} and Nelson, {Peter S.}",
note = "Funding Information: Acknowledgments We thank all of the men and their families who participated in this study. We thank A. McKenna and other members of the Nelson, Shendure and Vessella laboratories for helpful advice and assistance. We thank T. Taniguchi for helpful discussions. LNCaPAR cells were a kind gift from C. Sawyers (Memorial Sloan Kettering Cancer Center). We thank M. Roudier, J. Noteboom, J. Kho and all other members of the tissue-acquisition necropsy team for their hard work and dedication. This work was supported by a Stand Up To Cancer Prostate Cancer Foundation Prostate Dream Team Translational Cancer Research Grant. Stand Up To Cancer is a program of the Entertainment Industry Foundation administered by the American Association for Cancer Research (SU2C-AACR-DT0712) (B.M., N.S. and P.S.N.), and also by awards from the US National Institutes of Health: Pacific Northwest Prostate Cancer SPORE grant P50 CA097186 (P.S.N., B.M., L.D.T., R.L.V. and C.M.), P01 CA163227 (P.S.N., R.L.V. and C.M.), P01 CA85859 (R.L.V., C.M., M.F. and P.S.N.), US Department of Defense awards W81XWH-15-1-0562 and W81XWH-15-1-0430 (P.S.N., R.F.D., I.C., R.C. and N.S.) a Fred Hutchinson Cancer Research Center Solid Tumor Translational Research award (P.S.N., H.B. and B.M.) and the Prostate Cancer Foundation. J.S. and N.S. are supported by Prostate Cancer Foundation Young Investigator awards. Publisher Copyright: {\textcopyright} 2016 Nature America, Inc. All rights reserved.",
year = "2016",
month = apr,
day = "1",
doi = "10.1038/nm.4053",
language = "English (US)",
volume = "22",
pages = "369--378",
journal = "Nature Medicine",
issn = "1078-8956",
publisher = "Nature Publishing Group",
number = "4",
}