Integrative clinical genomics of advanced prostate cancer.
Toward development of a precision medicine framework for metastatic, castration-resistant prostate cancer (mCRPC), we established a multi-institutional clinical sequencing infrastructure to conduct prospective whole-exome and transcriptome sequencing of bone or soft tissue tumor biopsies from a cohort of 150 mCRPC affected individuals. Aberrations of AR, ETS genes, TP53, and PTEN were frequent (40%-60% of cases), with TP53 and AR alterations enriched in mCRPC compared to primary prostate cancer. We identified new genomic alterations in PIK3CA/B, R-spondin, BRAF/RAF1, APC, β-catenin, and ZBTB16/PLZF. Moreover, aberrations of BRCA2, BRCA1, and ATM were observed at substantially higher frequencies (19.3% overall) compared to those in primary prostate cancers. 89% of affected individuals harbored a clinically actionable aberration, including 62.7% with aberrations in AR, 65% in other cancer-related genes, and 8% with actionable pathogenic germline alterations. This cohort study provides clinically actionable information that could impact treatment decisions for these affected individuals.
Robinson, D; Van Allen, EM; Wu, Y-M; Schultz, N; Lonigro, RJ; Mosquera, J-M; Montgomery, B; Taplin, M-E; Pritchard, CC; Attard, G; Beltran, H; Abida, W; Bradley, RK; Vinson, J; Cao, X; Vats, P; Kunju, LP; Hussain, M; Feng, FY; Tomlins, SA; Cooney, KA; Smith, DC; Brennan, C; Siddiqui, J; Mehra, R; Chen, Y; Rathkopf, DE; Morris, MJ; Solomon, SB; Durack, JC; Reuter, VE; Gopalan, A; Gao, J; Loda, M; Lis, RT; Bowden, M; Balk, SP; Gaviola, G; Sougnez, C; Gupta, M; Yu, EY; Mostaghel, EA; Cheng, HH; Mulcahy, H; True, LD; Plymate, SR; Dvinge, H; Ferraldeschi, R; Flohr, P; Miranda, S; Zafeiriou, Z; Tunariu, N; Mateo, J; Perez-Lopez, R; Demichelis, F; Robinson, BD; Schiffman, M; Nanus, DM; Tagawa, ST; Sigaras, A; Eng, KW; Elemento, O; Sboner, A; Heath, EI; Scher, HI; Pienta, KJ; Kantoff, P; de Bono, JS; Rubin, MA; Nelson, PS; Garraway, LA; Sawyers, CL; Chinnaiyan, AM
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