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Cited by 541Prostate Cancer Treatment and ResearchCancer Genomics and DiagnosticsChromatin Remodeling and Cancer

Prospective Genomic Profiling of Prostate Cancer Across Disease States Reveals Germline and Somatic Alterations That May Affect Clinical Decision Making

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Abida, Wassim, Armenia, Joshua, Gopalan, Anuradha, Brennan, Ryan, Walsh, Michael, Barron, David, Danila, Daniel, Rathkopf, Dana +33 more·2017·JCO Precision Oncology
DOI 10.1200/po.17.00029PMC PMC5558263
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Abstract

Purpose: A long natural history and a predominant osseous pattern of metastatic spread are impediments to the adoption of precision medicine in patients with prostate cancer. To establish the feasibility of clinical genomic profiling in this disease, we performed targeted deep sequencing of tumor and normal DNA from patients with locoregional, metastatic noncastrate, and metastatic castration-resistant prostate cancer. Patients and Methods: Patients consented to genomic analysis of their tumor and germline DNA. A hybridization capture-based clinical assay was used to identify single-nucleotide variations, small insertions and deletions, copy number alterations, and structural rearrangements in more than 300 cancer-related genes in tumors and matched normal blood. Results: We successfully sequenced 504 tumors from 451 patients with prostate cancer. Potentially actionable alterations were identified in DNA damage repair, phosphatidylinositol 3-kinase, and mitogen-activated protein kinase pathways. Twenty-seven percent of patients harbored a germline or a somatic alteration in a DNA damage repair gene that may predict for response to poly (ADP-ribose) polymerase inhibition. Profiling of matched tumors from individual patients revealed that somatic TP53 and BRCA2 alterations arose early in tumors from patients who eventually developed metastatic disease. In contrast, comparative analysis across disease states revealed that APC alterations were enriched in metastatic tumors, whereas ATM alterations were specifically enriched in castration-resistant prostate cancer. Conclusion: Through genomic profiling of prostate tumors that represent the disease clinical spectrum, we identified a high frequency of potentially actionable alterations and possible drivers of disease initiation, metastasis, and castration resistance. Our findings support the routine use of tumor and germline DNA profiling for patients with advanced prostate cancer for the purpose of guiding enrollment in targeted clinical trials and counseling families at increased risk of malignancy.

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  • In one study, approximately 50% of somatic mutations in homologous recombination repair (HRR) genes were also identified on germline testing.

    “In one study, ~50% of somatic mutations in homologous recombination repair (HRR) genes were also identified on germline testing [53].”

    From Navigating therapeutic sequencing in the metastatic castration-resistant prostate cancer patient journey (2025) · cites this paper as [53]

    The Results section (page unavailable) says germline testing alone identified approximately half of patients who had either germline or somatic alterations in BRCA2, BRCA1, ATM, or CHEK2. That is a proportion of patients with alterations found by either method, not a finding that approximately half of somatic HRR mutations were also found on germline testing. (LLM, conf=0.86)

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Authors
Abida, W., Armenia, J., Gopalan, A., Brennan, R., Walsh, M., Barron, D., Danila, D., Rathkopf, D., Morris, M., Slovin, S., McLaughlin, B., Curtis, K., Hyman, D. M., Durack, J. C., Solomon, S. B., Arcila, M. E., Zehir, A., Syed, A., Gao, J., Chakravarty, D., Vargas, H. A., Robson, M. E., Vijai, J., Offit, K., Donoghue, M. T. A., Abeshouse, A. A., Kundra, R., Heins, Z. J., Penson, A. V., Harris, C., Taylor, B. S., Ladanyi, M., Mandelker, D., Zhang, L., Reuter, V. E., Kantoff, P. W., Solit, D. B., Berger, M. F., Sawyers, C. L., Schultz, N., & Scher, H. I.
Affiliations
Memorial Sloan Kettering Cancer Center (US)
ORCID
Venue
JCO Precision Oncology
Publisher
American Society of Clinical Oncology (ASCO)
Published
2017-11
Volume
2017
Issue
1
Pages
1-16
ISSN
2473-4284 (ISSN-L)
DOI
10.1200/po.17.00029
PMC
PMC5558263
OpenAlex
W2620706965
Cited by
541
References
7
Citations by year
2026: 25 · 2025: 56 · 2024: 79 · 2023: 82 · 2022: 96 · 2021: 80 · 2020: 54 · 2019: 35 · 2018: 29 · 2017: 5
FWCI
27.83
Type
journal article
Language
en
Open access
Locations
  • JCO Precision Oncology (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Stand Up To Cancer
  • National Cancer Institute (P30CA008748, P50CA092629, R01CA193837)
Topics
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Prostate Cancer Treatment and Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
Keywords
prostate cancer, genomic profiling, germline alterations, somatic alterations, metastatic castration-resistant prostate cancer, DNA repair genes, poly(ADP-ribose) polymerase inhibition, TP53, BRCA2, APC, ATM, phosphatidylinositol 3-kinase pathway, MAPK signaling, copy number alterations, structural rearrangement, precision medicine, targeted therapy

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