Chromosomal instability in untreated primary prostate cancer as an indicator of metastatic potential

Abstract

Background: 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. Methods: 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).

Harnessing transcriptionally driven chromosomal instability adaptation to target therapy-refractory lethal prostate cancer

“…This CIN increase was corroborated by examining the FGA, as recently described, 19 in a PCa publicly available patient dataset containing primary and metastatic tumors 2 ( Figure 1 B). Similar results were obtained when analyzing CIN gene signatures reported to correlate well with genome instability 4 , 53 , 5 and to predict lethality in PCa, 47 in publicly available transcriptomic PCa patient datasets 1 , 2 , 3 ( Figure S1 A and Table S1 ).

Figure 1 High CIN therapy-resistant PCa develops dependencies to specific chromosomal stability maintenance kinases (A) Representative images and quantification of anaphases with chromosome segregation errors in primary and metastatic PCa patient tissue samples.

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“…Genomic abnormalities induced by CIN are pervasive events in cancers that correlate with advanced disease stages and higher aggressiveness by driving tumor evolution, metastases, and drug resistance. 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 38 In PCa, in which genome aberrations increase as a function of disease progression, 1 , 2 , 6 , 14 , 15 , 16 , 83 CIN and derived chromosomal errors have been associated with lethal disease, 19 , 46 , 47 but the mechanistic causes and consequences of CIN remain to be investigated. In this framework, here we uncovered that CIN is highest in castration chemotherapy-resistant metastatic PCa.…”

“… 25 , 26 , 4 , 39 , 40 , 41 , 42 , 43 Thus, suggesting that CIN must be maintained under a tolerable threshold to preserve cancer cell homeostasis and may represent a vulnerability of aggressive tumors. 43 , 44 , 45 In PCa, clinical correlative studies indicate that aneuploidy and CIN associate to aggressive lethal disease 46 , 47 ; however, the underlying causes of CIN, the adaptation mechanisms, and the potential therapeutic implications have not been studied.…”

Chronic hypoxia favours adoption to a castration-resistant cell state in prostate cancer

“…A loss of HR in the cells leads to increased genomic instability [51]. Therefore, the longer cells are exposed to hypoxia the more likely they are to become genetically unstable, promoting tumour genetic heterogeneity, observed in hypoxic prostate cancer samples [20] and an attribute of metastatic CRPC [52]. Collectively, our work proposes a contribution of chronic hypoxia towards increased risk of progression by favouring androgen insensitivity in prostate cancer.…”

Identification of DNA Damage Repair-Associated Prognostic Biomarkers for Prostate Cancer Using Transcriptomic Data Analysis

“…Rearrangements involving TMPRSS2 , which is regulated by androgen, are shown to contribute to prostate carcinogenesis as well [ 36 ], and these structural rearrangements such as TMPRSS2-ERG translocation might result in AR-related DNA double-strand breaks [ 37 , 38 , 39 , 40 ]. Miller et al found that chromosomal instability is highly indicative of metastatic potential, antiandrogen resistance and PC all-cause mortality, and is associated with the signaling pathways involving regulation of centrosomes, chromosomal segregation and assembly of mitotic spindles [ 41 ]. The functional annotation in our study also implied interactions between DDR and other biological pathways like cell cycle check points, TP53 activity, and DNA glycosylase ( Supplementary Figure S1 ).…”