Combined exome and transcriptome sequencing of non-muscle-invasive bladder cancer: associations between genomic changes, expression subtypes, and clinical outcomes

Abstract

Background Three-quarters of bladder cancer patients present with early-stage disease (non-muscle-invasive bladder cancer, NMIBC, UICC TNM stages Ta, T1 and Tis); however, most next-generation sequencing studies to date have concentrated on later-stage disease (muscle-invasive BC, stages T2+). We used exome and transcriptome sequencing to comprehensively characterise NMIBCs of all grades and stages to identify prognostic genes and pathways that could facilitate treatment decisions. Tumour grading is based upon microscopy and cellular appearances (grade 1 BCs are less aggressive, and grade 3 BCs are most aggressive), and we chose to also focus on the most clinically complex NMIBC subgroup, those patients with grade 3 pathological stage T1 (G3 pT1) disease. Methods Whole-exome and RNA sequencing were performed in total on 96 primary NMIBCs including 22 G1 pTa, 14 G3 pTa and 53 G3 pT1s, with both exome and RNA sequencing data generated from 75 of these individual samples. Associations between genomic alterations, expression profiles and progression-free survival (PFS) were investigated. Results NMIBCs clustered into 3 expression subtypes with different somatic alteration characteristics. Amplifications of ARNT and ERBB2 were significant indicators of worse PFS across all NMIBCs. High APOBEC mutagenesis and high tumour mutation burden were both potential indicators of better PFS in G3pT1 NMIBCs. The expression of individual genes was not prognostic in BCG-treated G3pT1 NMIBCs; however, downregulated interferon-alpha and gamma response pathways were significantly associated with worse PFS (adjusted p-value < 0.005). Conclusions Multi-omic data may facilitate better prognostication and selection of therapeutic interventions in patients with G3pT1 NMIBC. These findings demonstrate the potential for improving the management of high-risk NMIBC patients and warrant further prospective validation.

Patterns of mutations in nine cancer-related genes and PAF development among smoking male patients diagnosed with bladder cancer

“…As histopathological tissues were stained with H&E, it was demonstrated that there were no considerable differences between Groups 2 and 3. With a close tie to cigarette smoking, inflammatory channels of spread are essential preconditions of BC development, with elevated PAF release potentially contributing to cancer cell development, spread, and tumor tissue production, confirmed and described by several past studies [11,12,24,32,36,[38][39][40].…”

“…Moreover, cancer-associated genes (comprising oncogenes and tumor suppressor genes) are mutated, causing cells to grow rapidly, thus leading to cancer. Among many cancer-associated genes, nine BCassociated genes were selected as the most common in this study [24,35,36,38], relying on NGS technology, which identified thirteen observable mutations in 7 of 9 cancer-associated genes of DNA samples among non-smoking and smoking participants with BC. These mutations were confirmed by structural signature variation (SSV), detecting a similar number of mutation patterns in the studied genes.…”

Drug repurposing analysis with co-expressed genes identifies novel drugs and small molecules for bladder cancer

“…There are few studies focused on bladder cancer, and NMIBC-related research is more limited. Goel et al used exome and transcriptome sequencing to characterise all grades of NMIBCs to determine prognostic genes and indicated that multi-omic data may help to better identify treatment in high-risk patients [11].…”