期刊
JCI INSIGHT
卷 7, 期 17, 页码 -出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/jci.insight.161370
关键词
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资金
- NIH [K22-CA237746, P01-CA163227, R01-CA234715, R01-GM107427, R01-CA193910, R01-CA251555, R35-CA197568]
- Department of Defense Prostate Cancer Research Program (Physician Research Award) [W81XWH-17-1-0358, W81XWH-19-1-0565, W81XWH-21-1-0234, PC200262]
- PCF Young Investigator Awards
- PCF-Movember Challenge Award
- Brotman Baty Institute for Precision Medicine
- Fund for Innovation in Cancer Informatics Major Grant
- V Foundation Scholar Grant
- Wong Family Award in Translational Oncology and Dana-Farber Cancer Institute Medical Oncology grant
- Snyder Medical Research Foundation
- Cutler Family Fund for Prevention and Early Detection
- Pan-Mass Challenge team IMAGINE
- American Cancer Society Research Professor grant
- NIH/National Cancer Institute Cancer Center Support grant [P30-CA015704]
- Pacific Northwest Prostate Cancer SPORE [P50-CA097186]
- Scientific Computing Infrastructure (ORIP grant) [S10OD028685]
This study systematically investigates the impact of structural variation on the genomic landscape of prostate cancer in different disease states using whole genome sequencing. The results reveal distinct recurrent breakpoints in localized and metastatic castration-resistant prostate cancers, with different patterns of structural variation and associated genes in mCRPC and localized prostate cancer. By defining mCRPC subtypes based on structural variation, this study provides insights into the clinical outcomes and genetic features of different subgroups.
The complex genomic landscape of prostate cancer evolves across disease states under therapeutic pressure directed toward inhibiting androgen receptor (AR) signaling. While significantly altered genes in prostate cancer have been extensively defined, there have been fewer systematic analyses of how structural variation shapes the genomic landscape of this disease across disease states. We uniformly characterized structural alterations across 531 localized and 143 metastatic prostate cancers profiled by whole genome sequencing, 125 metastatic samples of which were also profiled via whole transcriptome sequencing. We observed distinct significantly recurrent breakpoints in localized and metastatic castration-resistant prostate cancers (mCRPC), with pervasive alterations in noncoding regions flanking the AR, MYC, FOXA1, and LSAMP genes enriched in mCRPC and TMPRSS2-ERG rearrangements enriched in localized prostate cancer. We defined 9 subclasses of mCRPC based on signatures of structural variation, each associated with distinct genetic features and clinical outcomes. Our results comprehensively define patterns of structural variation in prostate cancer and identify clinically actionable subgroups based on whole genome profiling.
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