Chromosomal instability in tumor suppressor genes–altered prostate cancer.

Abstract

226 Background: Metastatic prostate cancer (PC) accumulates significant genomic alterations as the disease progresses, exhibiting the highest levels of chromosomal instability (CIN) among all metastatic tumors (Bakhoum, Nature 2018). Furthermore, tumor suppressor genes (TSG; RB1 , PTEN and TP53 ) are frequently altered in metastatic PC and are associated with adverse outcomes. Here, we aim to investigate CIN in metastatic hormone-sensitive PC (mHSPC) harbouring alterations in TSG. Methods: TSG and whole transcriptome gene expression was assessed by nCounter platform (N=354) and RNA-seq (N=60) in mHPSC samples, respectively. TSG low was considered when ≥2 out of 3 TSG presented low expression of a previously stablished cut-off, and TSG wt in the remaining cases. Differential gene expression analysis between TSG low vs TSG wt tumors of our RNA-seq cohort (N=60) and TCGA cohort (N=333) was performed. Differential expressed genes (DEGs) were considered if FDR <0.05 and log2FoldChange (LFC)>0.5. DEGs were correlated with castration-resistance PC-free survival (CRPC-FS) and overall survival (OS) by Cox analysis. CIN gene signatures were obtained from literature and the rest of Hallmark signatures from MSigDB. Results: In our cohort of mHSPC patients treated with androgen deprivation therapy + docetaxel, TSG low tumors (16.7%) displayed higher levels of CIN compared with TSG wt (CIN25 normalized enrichment score [NES] 2.13, p<0.001 and CIN70 NES 2.54, p<0001). Cell cycle and DNA-repair signatures were also overexpressed in TSG low tumors, contrasting with a low expression of androgen receptor pathway. Results were validated in the TCGA cohort, where TSG low presented also overexpression of CIN signatures. In our RNA-seq cohort, we found 22 DEGs associated with CIN (29.3% of the total DEGs) in TSG low tumors compared with TSG wt . 51 genes were significantly correlated with CRPC-FS in a multivariate analysis and 16 of them (31,3%) were CIN-associated genes. Among these genes, 5 encode proteins that are targetable for metastatic PC, with specific inhibitors already developed: BUB1 (LFC 1.06, FDR 0.034), CDC7 (LFC 12.4 FDR 0.003), KIFC1 , (LFC 11,7, FDR 0.01), PLK1 (LFC 1.08, FDR <0.001) and WEE1 (LFC 0.79, FDR 0.011). Conclusions: TSG-altered mHSPC tumors harbor high levels of CIN, and differentially expressed CIN-associated genes could potentially be targets in mHSPC.