Dataset Information

HotSpotAnnotations-a database for hotspot mutations and annotations in cancer.

ABSTRACT: Hotspots, recurrently mutated DNA positions in cancer, are thought to be oncogenic drivers because random chance is unlikely and the knowledge of clear examples of oncogenic hotspots in genes like BRAF, IDH1, KRAS and NRAS among many other genes. Hotspots are attractive because provide opportunities for biomedical research and novel treatments. Nevertheless, recent evidence, such as DNA hairpins for APOBEC3A, suggests that a considerable fraction of hotspots seem to be passengers rather than drivers. To document hotspots, the database HotSpotsAnnotations is proposed. For this, a statistical model was implemented to detect putative hotspots, which was applied to TCGA cancer datasets covering 33 cancer types, 10?182 patients and 3?175?929 mutations. Then, genes and hotspots were annotated by two published methods (APOBEC3A hairpins and dN/dS ratio) that may inform and warn researchers about possible false functional hotspots. Moreover, manual annotation from users can be added and shared. From the 23?198 detected as possible hotspots, 4435 were selected after false discovery rate correction and minimum mutation count. From these, 305 were annotated as likely for APOBEC3A whereas 442 were annotated as unlikely. To date, this is the first database dedicated to annotating hotspots for possible false functional hotspots.

SUBMITTER: Trevino V

PROVIDER: S-EPMC7211031 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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HotSpotAnnotations-a database for hotspot mutations and annotations in cancer.

Trevino Victor V

Database : the journal of biological databases and curation 20200101

Hotspots, recurrently mutated DNA positions in cancer, are thought to be oncogenic drivers because random chance is unlikely and the knowledge of clear examples of oncogenic hotspots in genes like BRAF, IDH1, KRAS and NRAS among many other genes. Hotspots are attractive because provide opportunities for biomedical research and novel treatments. Nevertheless, recent evidence, such as DNA hairpins for APOBEC3A, suggests that a considerable fraction of hotspots seem to be passengers rather than dri ...[more]

PMID: 32386297

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Project description:BackgroundAPOBEC-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.MethodsWe 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.ResultsWe 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.ConclusionsOur 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.

Dataset Information

HotSpotAnnotations-a database for hotspot mutations and annotations in cancer.

Publications

HotSpotAnnotations-a database for hotspot mutations and annotations in cancer.

Similar Datasets

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