Integrative clinical genomics of advanced prostate cancer.

Cell
Authors
Keywords
Abstract

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.

Year of Publication
2015
Journal
Cell
Volume
161
Issue
5
Pages
1215-28
Date Published
2015 May 21
ISSN
1097-4172
DOI
10.1016/j.cell.2015.05.001
PubMed ID
26000489
PubMed Central ID
PMC4484602
Links
Grant list
UM1 HG006508 / HG / NHGRI NIH HHS / United States
UO1CA111275 / CA / NCI NIH HHS / United States
P50 CA090381 / CA / NCI NIH HHS / United States
L30 CA111031 / CA / NCI NIH HHS / United States
CEO13_2-002 / Prostate Cancer UK / United Kingdom
R01 CA129435 / CA / NCI NIH HHS / United States
R01 CA085912 / CA / NCI NIH HHS / United States
R01 CA193837 / CA / NCI NIH HHS / United States
P50 CA097186 / CA / NCI NIH HHS / United States
K08 CA188615 / CA / NCI NIH HHS / United States
Department of Health / United Kingdom
P50 CA092629 / CA / NCI NIH HHS / United States
R21 CA128352 / CA / NCI NIH HHS / United States
L30 CA103810 / CA / NCI NIH HHS / United States
R01 GM107427 / GM / NIGMS NIH HHS / United States
P30 CA008748 / CA / NCI NIH HHS / United States
R01 CA193910 / CA / NCI NIH HHS / United States
R01 CA155169 / CA / NCI NIH HHS / United States
Cancer Research UK / United Kingdom
DP2 OD002750 / OD / NIH HHS / United States
Howard Hughes Medical Institute / United States
K08 CA115927 / CA / NCI NIH HHS / United States
1K08CA188615 / CA / NCI NIH HHS / United States
PG12-49 / Prostate Cancer UK / United Kingdom
R01 CA116337 / CA / NCI NIH HHS / United States
P50 CA186786 / CA / NCI NIH HHS / United States
MR/M003272/1 / Medical Research Council / United Kingdom
T32 GM007266 / GM / NIGMS NIH HHS / United States
R01 CA136578 / CA / NCI NIH HHS / United States
P50 CA069568 / CA / NCI NIH HHS / United States
P30 CA006516 / CA / NCI NIH HHS / United States
P01 CA163227 / CA / NCI NIH HHS / United States
U01 CA111275 / CA / NCI NIH HHS / United States
UM1HG006508 / HG / NHGRI NIH HHS / United States
P50 CA90381 / CA / NCI NIH HHS / United States
R01CA092629 / CA / NCI NIH HHS / United States