Dataset Information

Genomic Instability Signature of Palindromic Non-Coding Somatic Mutations in Bladder Cancer.

ABSTRACT: Numerous pan-genomic studies identified alterations in protein-coding genes and signaling pathways involved in bladder carcinogenesis, while non-coding somatic alterations remain weakly explored. The goal of this study was to identify clinical biomarkers in non-coding regions for bladder cancer patients. We have previously identified in bladder tumors two non-coding mutational hotspots occurring at high frequencies (?30%). These mutations are located close to the GPR126 and PLEKHS1 genes, at the guanine or the cytosine of a TGAACA core motif flanked, on both sides, by a stretch of palindromic sequences. Here, we hypothesize that such a pattern of recurrent non-coding mutations could be a signature of somatic genomic instability specifically involved in bladder cancer. We analyzed 26 additional mutable non-coding sites with the same core motif in a cohort of 103 bladder cancers composed of 44 NMIBC cases and 59 MIBC cases using high-resolution melting (HRM) and Sanger sequencing. Five bladder cancers were additionally analyzed for protein-coding gene mutations using a targeted NGS panel composed of 571 genes. Expression levels of three members of the APOBEC3 family genes were assessed using real-time quantitative RT-PCR. Non-coding somatic mutations were observed for at least one TGAACA core motif locus in 62.1% (64/103) of bladder tumor samples. These non-coding mutations co-occurred in the bladder tumors but were absent in prostate tumor, HPV-positive Head and Neck Squamous Cell Carcinoma, and high microsatellite instability (MSI-H) colorectal tumor series. This signature of palindromic non-coding somatic mutations, specific to bladder tumors, was not associated with patients' outcome and was more frequent in females. Interestingly, this signature was associated with high tumor mutational burden (TMB) and high expression levels of APOBEC3B and interferon inducible genes. We identified a new type of somatic genomic instability targeting the TGAACA core motif loci flanked by palindromic sequences in bladder cancer. This mutational signature is a promising candidate clinical biomarker for the early detection of relapse and a major low-cost alternative to the TMB to monitor the response to immunotherapy for bladder cancer patients.

SUBMITTER: Vacher S

PROVIDER: S-EPMC7650671 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Genomic Instability Signature of Palindromic Non-Coding Somatic Mutations in Bladder Cancer.

Vacher Sophie S Suybeng Voreak V Girard Elodie E Masliah Planchon Julien J Thomson Grégory G Le Goux Constance C Garinet Simon S Schnitzler Anne A Chemlali Walid W Firlej Virginie V Damotte Diane D Allory Yves Y Kamal Maud M Pignot Géraldine G Bieche Ivan I

Cancers 20201008 10

Numerous pan-genomic studies identified alterations in protein-coding genes and signaling pathways involved in bladder carcinogenesis, while non-coding somatic alterations remain weakly explored. The goal of this study was to identify clinical biomarkers in non-coding regions for bladder cancer patients. We have previously identified in bladder tumors two non-coding mutational hotspots occurring at high frequencies (≥30%). These mutations are located close to the <i>GPR126</i> and <i>PLEKHS1</i> ...[more]

PMID: 33049910

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Project description:Background: Genomic instability is considered as one of the hallmarks of hepatocellular carcinoma (HCC) and poses a significant challenge to the clinical treatment. The emerging evidence has revealed the roles of long non-coding RNAs (lncRNAs) in the maintenance of genomic instability. This study is aimed to develop a genomic instability-related lncRNA signature for determining HCC prognosis and the suitability of patients for immunotherapy. Methods: In this study, data related to transcriptome profiling, clinical features, and the somatic mutations of patients with HCC were downloaded from The Cancer Genomic Atlas (TCGA). Bioinformatics analysis was performed to identify and construct a somatic mutation-derived genomic instability-associated lncRNA signature (GILncSig). Single-sample gene set enrichment analysis (ssGSEA) was applied to estimate the levels of immune cell infiltration. A nomogram was constructed, and calibration was performed to assess the effectiveness of the model. Results: In the study, seven genomic instability-related lncRNAs were identified and used to define a prognostic signature. Patients with HCC were stratified into high- and low-risk groups with significant differences in the survival (median survival time = 1.489, 1.748 year; p = 0.006) based on the optimal cutoff value (risk score = 1.010) of the risk score in the training group. In addition, GILncSig was demonstrated to be an independent risk factor for the patients with HCC when compared to the clinical parameters (p < 0.001). According to the receiver operating characteristic (ROC) curve, nomogram, and calibration plot, the signature could predict the survival rate for the patients with HCC in the 1st, 3rd, and 5th years. Furthermore, ssGSEA revealed the potential of the signature in guiding decisions for administering clinical treatment. Conclusions: In this study, we developed a novel prognostic model based on the somatic mutation-derived lncRNAs and validated it using an internal dataset. The independence of the GILncSig was estimated using univariate and follow-up multivariate analyses. Immunologic analysis was used to evaluate the complex factors involved in the HCC progression.

Project description:Ultraconserved regions (UCRs) have been shown to originate non-coding RNA transcripts (T-UCRs) that have different expression profiles and play functional roles in the pathophysiology of multiple cancers. The relevance of these functions to the pathogenesis of bladder cancer (BlCa) is speculative. To elucidate this relevance, we first used genome-wide profiling to evaluate the expression of T-UCRs in BlCa tissues. Analysis of two datasets comprising normal bladder tissues and BlCa specimens with a custom T-UCR microarray identified ultraconserved RNA (uc.) 8+ as the most upregulated T-UCR in BlCa tissues, although its expression was lower than in pericancerous bladder tissues. These results were confirmed on BlCa tissues by real-time PCR and by in situ hybridization. Although uc.8+ is located within intron 1 of CASZ1, a zinc-finger transcription factor, the transcribed non-coding RNA encoding uc.8+ is expressed independently of CASZ1. In vitro experiments evaluating the effects of uc.8+ silencing, showed significantly decreased capacities for cancer cell invasion, migration, and proliferation. From this, we proposed and validated a model of interaction in which uc.8+ shuttles from the nucleus to the cytoplasm of BlCa cells, interacts with microRNA (miR)-596, and cooperates in the promotion and development of BlCa. Using computational analysis, we investigated the miR-binding domain accessibility, as determined by base-pairing interactions within the uc.8+ predicted secondary structure, RNA binding affinity, and RNA species abundance in bladder tissues and showed that uc.8+ is a natural decoy for miR-596. Thus uc.8+ upregulation results in increased expression of MMP9, increasing the invasive potential of BlCa cells. These interactions between evolutionarily conserved regions of DNA suggest that natural selection has preserved this potentially regulatory layer that uses RNA to modulate miR levels, opening up the possibility for development of useful markers for early diagnosis and prognosis as well as for development of new RNA-based cancer therapies.

Dataset Information

Genomic Instability Signature of Palindromic Non-Coding Somatic Mutations in Bladder Cancer.

Publications

Genomic Instability Signature of Palindromic Non-Coding Somatic Mutations in Bladder Cancer.

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