Synapse - Prospective genomic profiling of prostate cancer across disease states reveals germline and somatic alterations that may affect clinical decision making

Prospective genomic profiling of prostate cancer across disease states reveals germline and somatic alterations that may affect clinical decision making Journal Article

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.
Article Title:	Prospective genomic profiling of prostate cancer across disease states reveals germline and somatic alterations that may affect clinical decision making
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.Toestablish 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 germlineDNA. 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 germlineDNAprofiling for patients with advanced prostate cancer for the purpose of guiding enrollment in targeted clinical trials and counseling families at increased risk of malignancy. © 2018 American Society of Clinical Oncology.
Keywords:	mitogen activated protein kinase; adult; controlled study; human tissue; aged; major clinical study; sequence analysis; single nucleotide polymorphism; somatic mutation; gene deletion; prospective study; genetic analysis; medical decision making; dna damage; gene; dna repair; metastasis; gene expression profiling; phosphatidylinositol 3 kinase; protein p53; prediction; gleason score; cancer genetics; tumor suppressor gene; gene rearrangement; gene identification; nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase inhibitor; androgen receptor; dna sequence; cancer tissue; gene insertion; pik3ca gene; castration resistant prostate cancer; copy number variation; atm gene; germline mutation; apc gene; tp53 gene; ar gene; human; male; priority journal; article; dna damage repair gene
Journal Title:	JCO Precision Oncology
Volume:	1
ISSN:	2473-4284
Publisher:	American Society of Clinical Oncology
Date Published:	2017-05-31
Language:	English
DOI:	10.1200/po.17.00029
PROVIDER:	scopus
PMCID:	PMC5558263
PUBMED:	28825054
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85028926936&doi=10.1200%2fPO.17.00029&partnerID=40&md5=cdf780ddc75ba478f9f134d6d99151a8
Notes:	Article -- Export Date: 23 March 2020 -- Source: Scopus