Biology subjects

Vermes, I.

Publications and source records attributed to Vermes, I..

3 recordsLinked to original sources

bioRxiv2024

Activation of Wnt/β-catenin signalling by mutually exclusive FBXW11 and CTNNB1 hotspot mutations drives salivary gland basal cell adenoma

Wnt signalling must be just right to promote tumour growth. Basal cell adenoma (BCA) and basal cell adenocarcinoma (BCAC) of the salivary gland are rare tumours that can be difficult to distinguish from each other and other salivary gland tumour subtypes. Due to their rarity, the genetic profiles of BCA and BCAC have not been extensively explored. Using whole-exome and transcriptome sequencing of BCA and BCAC cohorts, we identify a novel recurrent FBXW11 missense mutation (p.F517S) in BCA, that was mutually exclusive with the previously reported CTNNB1 p.I35T gain-of-function (GoF) mutation. These driver events collectively accounted for 94% of BCAs. In vitro, mutant FBXW11 had a dominant negative affect, characterised by defective binding to {beta}-catenin and the accumulation of {beta}-catenin in cells. This was consistent with the nuclear expression of {beta}-catenin observed in BCA cases harbouring the FBXW11 p.F517S mutation and activation of the Wnt/{beta}-catenin pathway. The genomic profiles of BCAC were distinct from BCA, with hotspot DICER1 and HRAS mutations and putative driver mutations affecting PI3K/AKT and NF-{kappa}B signalling pathway genes. A single BCAC, which may represent a malignant transformation of BCA, harboured the recurrent FBXW11 mutation. These findings have important implications for the diagnosis and treatment of BCA and BCAC, which, despite histopathologic overlap, may be unrelated entities.

cancer biology↗

bioRxiv2023

Assigning mutational signatures to individual samples and individual somatic mutations with SigProfilerAssignment

Analysis of mutational signatures is a powerful approach for understanding the mutagenic processes that have shaped the evolution of a cancer genome. Here we present SigProfilerAssignment, a desktop and an online computational framework for assigning all types of mutational signatures to individual samples. SigProfilerAssignment is the first tool that allows both analysis of copy-number signatures and probabilistic assignment of signatures to individual somatic mutations. As its computational engine, the tool uses a custom implementation of the forward stagewise algorithm for sparse regression and nonnegative least squares for numerical optimization. Analysis of 2,700 synthetic cancer genomes with and without noise demonstrates that SigProfilerAssignment outperforms four commonly used approaches for assigning mutational signatures. SigProfilerAssignment is freely available at https://github.com/AlexandrovLab/SigProfilerAssignment with a web implementation at https://cancer.sanger.ac.uk/signatures/assignment/.

bioinformatics↗

bioRxiv2022

Topography of mutational signatures in human cancer

The somatic mutations found in a cancer genome are imprinted by different mutational processes. Each process exhibits a characteristic mutational signature, which can be affected by the genome architecture. However, the interplay between mutational signatures and topographical genomic features has not been extensively explored. Here, we integrate mutations from 5,120 whole-genome sequenced tumours from 40 cancer types with 516 topographical features from ENCODE to evaluate the effect of nucleosome occupancy, histone modifications, CTCF binding, replication timing, and transcription/replication strand asymmetries on the cancer-specific accumulation of mutations from distinct mutagenic processes. Most mutational signatures are affected by topographical features with signatures of related aetiologies being similarly affected. Certain signatures exhibit periodic behaviours or cancer-type specific enrichments/depletions near topographical features, revealing further information about the processes that imprinted them. Our findings, disseminated via COSMIC, provide a comprehensive online resource for exploring the interactions between mutational signatures and topographical features across human cancer. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=175 SRC="FIGDIR/small/493921v2_figu1.gif" ALT="Figure 1"> View larger version (50K): org.highwire.dtl.DTLVardef@abf065org.highwire.dtl.DTLVardef@33ad99org.highwire.dtl.DTLVardef@ca37b6org.highwire.dtl.DTLVardef@fa7c6_HPS_FORMAT_FIGEXP M_FIG C_FIG HIGHLIGHTSO_LIComprehensive topography analysis of mutational signatures encompassing 82,890,857 somatic mutations in 5,120 whole-genome sequenced tumours integrated with 516 tissue-matched topographical features from the ENCODE project. C_LIO_LIThe accumulation of somatic mutations from most mutational signatures is affected by nucleosome occupancy, histone modifications, CTCF binding sites, transcribed regions, or replication strand/timing. C_LIO_LIMutational signatures with related aetiologies are consistently characterized by similar genome topographies across tissue types. C_LIO_LITopography analysis allows both separating signatures from different aetiologies and understanding the genomic specificity of clustered somatic mutations. C_LIO_LIA comprehensive online resource, disseminate through the COSMIC signatures database, that allows researchers to explore the interactions between somatic mutational processes and genome architecture within and across cancer types. C_LI

cancer biology↗