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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.

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Figure 1: Integrated landscape of somatic aberrations and AR activity in mCRPC.
Figure 2: Relationships between AR activity and the expression of AR and other nuclear hormone receptor genes.
Figure 3: Molecular aberrations are shared between metastases within individuals with mCRPC.
Figure 4: Tumor cell cycle activity within and between individuals.
Figure 5: CCP activity and E2F1 expression are inversely associated with AR activity.
Figure 6: Expression levels of FA-complex genes are associated with CCP and E2F1 expression.

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Acknowledgements

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.

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Authors and Affiliations

Authors

Contributions

A.K., T.W. and I.C. coordinated overall sequencing and bioinformatics analysis. I.C. and N.S. coordinated data deposition, assembly, figures and tables. R.G., R.E., I.C. and H.B. performed statistical analyses. A.K., I.C., R.C., R.F.D., T.W., N.D. and J.S. performed sequencing and analyses. L.D.T., M.F. and X.Z. coordinated central pathology review, FISH and immunohistochemistry studies. J.M.L. conducted gene-manipulation studies and growth assays. R.L.V., L.G.B. and C.M. coordinated clinical enrollment and tissue procurement. P.H.L., C.H., E.Y.Y., P.S.N. and B.M. enrolled patients and provided clinical insights. P.S.N., I.C., J.S. and A.K. wrote the manuscript, which all authors reviewed.

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Correspondence to Peter S Nelson.

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Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–6 (PDF 4395 kb)

Supplementary Table 1

CRPC Patient Clinical Data (XLSX 12 kb)

Supplementary Table 2

Patients, Tumor Sites, and Molecular Profiling Assays (XLSX 26 kb)

Supplementary Table 3

TMPRSS2-ERG Fusion by CGH or FISH (XLSX 10 kb)

Supplementary Table 4

MAF of mutations determined by WES (XLSX 2722 kb)

Supplementary Table 5

Target sequences for siRNAs (XLSX 8 kb)

Supplementary Table 6

Primer sequences for QRT-PCR (XLSX 8 kb)

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Kumar, A., Coleman, I., Morrissey, C. et al. Substantial interindividual and limited intraindividual genomic diversity among tumors from men with metastatic prostate cancer. Nat Med 22, 369–378 (2016). https://doi.org/10.1038/nm.4053

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