Chromosomal instability in untreated primary prostate cancer as an indicator of metastatic potential
Open Access
- 7 May 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in BMC Cancer
- Vol. 20 (1), 1-15
- https://doi.org/10.1186/s12885-020-06817-1
Abstract
Metastatic prostate cancer (PC) is highly lethal. The ability to identify primary tumors capable of dissemination is an unmet need in the quest to understand lethal biology and improve patient outcomes. Previous studies have linked chromosomal instability (CIN), which generates aneuploidy following chromosomal missegregation during mitosis, to PC progression. Evidence of CIN includes broad copy number alterations (CNAs) spanning > 300 base pairs of DNA, which may also be measured via RNA expression signatures associated with CNA frequency. Signatures of CIN in metastatic PC, however, have not been interrogated or well defined. We examined a published 70-gene CIN signature (CIN70) in untreated and castration-resistant prostate cancer (CRPC) cohorts from The Cancer Genome Atlas (TCGA) and previously published reports. We also performed transcriptome and CNA analysis in a unique cohort of untreated primary tumors collected from diagnostic prostate needle biopsies (PNBX) of localized (M0) and metastatic (M1) cases to determine if CIN was linked to clinical stage and outcome. PNBX were collected from 99 patients treated in the VA Greater Los Angeles (GLA-VA) Healthcare System between 2000 and 2016. Total RNA was extracted from high-grade cancer areas in PNBX cores, followed by RNA sequencing and/or copy number analysis using OncoScan. Multivariate logistic regression analyses permitted calculation of odds ratios for CIN status (high versus low) in an expanded GLA-VA PNBX cohort (n = 121). The CIN70 signature was significantly enriched in primary tumors and CRPC metastases from M1 PC cases. An intersection of gene signatures comprised of differentially expressed genes (DEGs) generated through comparison of M1 versus M0 PNBX and primary CRPC tumors versus metastases revealed a 157-gene “metastasis” signature that was further distilled to 7-genes (PC-CIN) regulating centrosomes, chromosomal segregation, and mitotic spindle assembly. High PC-CIN scores correlated with CRPC, PC-death and all-cause mortality in the expanded GLA-VA PNBX cohort. Interestingly, approximately 1/3 of M1 PNBX cases exhibited low CIN, illuminating differential pathways of lethal PC progression. Measuring CIN in PNBX by transcriptome profiling is feasible, and the PC-CIN signature may identify patients with a high risk of lethal progression at the time of diagnosis.Keywords
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Funding Information
- Prostate Cancer Foundation (17CHAL04, Creativity Award)
- Jean Perkins Foundation (NA)
- Movember Foundation (GAP6 Unique TMAs)
- Stephen Spielberg Foundation (NA)
- U.S. Department of Defense (PC131996, PC130244)
- National Cancer Institute (P01 CA098912-09, U54 CA143931, R01CA131255, P50CA092131)
This publication has 70 references indexed in Scilit:
- A new assay for measuring chromosome instability (CIN) and identification of drugs that elevate CIN in cancer cellsBMC Cancer, 2013
- The Subread aligner: fast, accurate and scalable read mapping by seed-and-voteNucleic Acids Research, 2013
- The mutational landscape of lethal castration-resistant prostate cancerNature, 2012
- Cancer chromosomal instability: therapeutic and diagnostic challengesEMBO Reports, 2012
- Molecular signatures database (MSigDB) 3.0Bioinformatics, 2011
- Hallmarks of Cancer: The Next GenerationCell, 2011
- Copy number and targeted mutational analysis reveals novel somatic events in metastatic prostate tumorsGenome Research, 2010
- Integrative Genomic Profiling of Human Prostate CancerCancer Cell, 2010
- Systematic and integrative analysis of large gene lists using DAVID bioinformatics resourcesNature Protocols, 2008
- A signature of chromosomal instability inferred from gene expression profiles predicts clinical outcome in multiple human cancersNature Genetics, 2006