Non-Coding Mutations in Urothelial Bladder Cancer: Biological and Clinical Relevance and Potential Utility as Biomarkers

Yang, Alexander; Cross, Christopher; Townsend, Jeffrey P.

doi:10.3233/blc-200278

Cited by 5 publications

(3 citation statements)

References 12 publications

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“…Overall, 60% of patients with bladder cancer had a mutation in the TERT promoter region. These results are in agreement with widely reported data showing that TERT is the most frequently mutated gene in bladder cancer 12,21,22) .…”

Section: Discussionsupporting

confidence: 93%

Evaluation of TERT promoter mutations in tumor biopsies and urine sediment of Moroccan bladder cancer patients

Alaoui

Ahanidi

Azzouzi

et al. 2022

Ann. Cancer Res. Therap.

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Background: Human telomerase reverse transcriptase (hTERT) promoter mutations are common genetic events in bladder cancer (BC) and have been recognized as potential biomarkers for BC diagnosis and prognosis. Detection of TERT promoter mutations as urine-based tests has previously been reported to detect primary and recurrent BC. This study was planned to evaluate hTERT promoter mutations in both biopsies and urines from BC patients to assess the interest and the usefulness of introducing these biomarkers for better management of BC in Morocco. Methods: In a cohort study involving a series of BC 70 patients with different stages and grades, hTERT promoter mutations were identified in both fresh biopsies and urine sediments by PCR amplification and DNA sequencing. Results: Overall, hTERT promoter mutations were reported in 60% of cancer biopsies (42/70), the hotspot mutations C228T and C250T were respectively identified in 80.95% (34/42) and 16.67% (7/42) of positive cases. Other mutations: A161C and G149T were also reported and were obtained in 2.38% (1/42) and 2.38% (1/42), respectively. hTERT promoter mutations were identified in 30% of matched urine sediments (21/70) and showed an overall sensitivity of 50% and specificity of 100%. In patients with non-muscle invasive bladder cancer, no statistically significant association was detected between TERT promoter mutations and recurrence-free survival (HR: 1.224, 95% CI: 0.373-4.011, p = 0.739), and overall survival (HR: 0.363, 95% CI: 0.041-3.244, p = 0.364). Conclusion: hTERT promoter mutations are early events occurring with high frequencies and can be identified in the exfoliated cells, making them an interesting non-invasive biomarker for diagnosis and follow-up of bladder cancer.

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Section: Discussionsupporting

confidence: 93%

Evaluation of TERT promoter mutations in tumor biopsies and urine sediment of Moroccan bladder cancer patients

Alaoui

Ahanidi

Azzouzi

et al. 2022

Ann. Cancer Res. Therap.

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“…In the most recent study, Buisson et al [ 9 ] showed that a subset of hotspot mutations were passenger mutations, occurring through the preference of APOBEC3A for DNA hairpin loops. Though we and others have previously studied certain APOBEC-associated coding and non-coding hotspot mutations in BCa specifically [ 4 – 6 , 12 – 14 ], a systematic investigation of APOBEC-associated hotspot mutations and their oncogenic driver effects in BCa have not been reported thus far.…”

Section: Introductionmentioning

confidence: 99%

Identification of new driver and passenger mutations within APOBEC-induced hotspot mutations in bladder cancer

et al. 2020

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Background APOBEC-driven mutagenesis and functional positive selection of mutated genes may synergistically drive the higher frequency of some hotspot driver mutations compared to other mutations within the same gene, as we reported for FGFR3 S249C. Only a few APOBEC-associated driver hotspot mutations have been identified in bladder cancer (BCa). Here, we systematically looked for and characterised APOBEC-associated hotspots in BCa. Methods We analysed 602 published exome-sequenced BCas, for part of which gene expression data were also available. APOBEC-associated hotspots were identified by motif-mapping, mutation signature fitting and APOBEC-mediated mutagenesis comparison. Joint analysis of DNA hairpin stability and gene expression was performed to predict driver or passenger hotspots. Aryl hydrocarbon receptor (AhR) activity was calculated based on its target genes expression. Effects of AhR knockout/inhibition on BCa cell viability were analysed. Results We established a panel of 44 APOBEC-associated hotspot mutations in BCa, which accounted for about half of the hotspot mutations. Fourteen of them overlapped with the hotspots found in other cancer types with high APOBEC activity. They mostly occurred in the DNA lagging-strand templates and the loop of DNA hairpins. APOBEC-associated hotspots presented systematically a higher prevalence than the other mutations within each APOBEC-target gene, independently of their functional impact. A combined analysis of DNA loop stability and gene expression allowed to distinguish known passenger from known driver hotspot mutations in BCa, including loss-of-function mutations affecting tumour suppressor genes, and to predict new candidate drivers, such as AHR Q383H. We further characterised AHR Q383H as an activating driver mutation associated with high AhR activity in luminal tumours. High AhR activity was also found in tumours presenting amplifications of AHR and its co-receptor ARNT. We finally showed that BCa cells presenting those different genetic alterations were sensitive to AhR inhibition. Conclusions Our study identified novel potential drivers within APOBEC-associated hotspot mutations in BCa reinforcing the importance of APOBEC mutagenesis in BCa. It could allow a better understanding of BCa biology and aetiology and have clinical implications such as AhR as a potential therapeutic target. Our results also challenge the dogma that all hotspot mutations are drivers and mostly gain-of-function mutations affecting oncogenes.

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“…We subsequently confirmed these findings and reported the frequencies of the mutations in 302 incident BCs, finding mutations in at least one hotspot in 74% of tumours 6 . The mutation hotspots are all within palindromic sequences that are prone to APOBEC mutagenesis and it is likely that they are passenger mutations resulting from APOBEC activity rather than BC-driver mutations 7-9 , perhaps with the exception of the chr10: 96162368 C/T mutation in TBC1D12 3,7,10 . As such, the mutations cannot be considered as useful urinary biomarkers for BC until the distribution of the mutations in the urine of patients with and without BC have been defined.…”

mentioning

confidence: 99%

Properties of non-coding mutation hotspots as urinary biomarkers for bladder cancer detection

Baxter

Gordon²,

Ott³

et al. 2023

Sci Rep

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Mutations at specific hotspots in non-coding regions of ADGRG6, PLEKHS1, WDR74, TBC1D12 and LEPROTL1 frequently occur in bladder cancer (BC). These mutations could function as biomarkers for the non-invasive detection of BC but this remains largely unexplored. Massively-parallel sequencing of non-coding hotspots was applied to 884 urine cell pellet DNAs: 591 from haematuria clinic patients (165 BCs, 426 non-BCs) and 293 from non-muscle invasive BC surveillance patients (29 with recurrence). Urine samples from 142 non-BC haematuria clinic patients were used to optimise variant calling. Non-coding mutations are readily detectable in the urine of BC patients and undetectable, or present at much lower frequencies, in the absence of BC. The mutations can be used to detect incident BC with 66% sensitivity (95% CI 58–75) at 92% specificity (95% CI 88–95) and recurrent disease with 55% sensitivity (95% CI 36–74) at 85% specificity (95% CI 80–89%) using a 2% variant allele frequency threshold. In the NMIBC surveillance setting, the detection of non-coding mutations in urine in the absence of clinically detectable disease was associated with an increased relative risk of future recurrence (RR = 4.62 (95% CI 3.75–5.48)). As urinary biomarkers, non-coding hotspot mutations behave similarly to driver mutations in BC-associated genes and could be included in biomarker panels for BC detection.

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Non-Coding Mutations in Urothelial Bladder Cancer: Biological and Clinical Relevance and Potential Utility as Biomarkers

Cited by 5 publications

References 12 publications

Evaluation of TERT promoter mutations in tumor biopsies and urine sediment of Moroccan bladder cancer patients

Evaluation of TERT promoter mutations in tumor biopsies and urine sediment of Moroccan bladder cancer patients

Identification of new driver and passenger mutations within APOBEC-induced hotspot mutations in bladder cancer

Properties of non-coding mutation hotspots as urinary biomarkers for bladder cancer detection

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