The landscape and driver potential of site-specific hotspots across cancer genomes

Abstract Large sets of whole cancer genomes make it possible to study mutation hotspots genome-wide. Here we detect, categorize, and characterize site-specific hotspots using 2279 whole cancer genomes from the Pan-Cancer Analysis of Whole Genomes project and provide a resource of annotated hotspots...

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Autores principales:	Randi Istrup Juul, Morten Muhlig Nielsen, Malene Juul, Lars Feuerbach, Jakob Skou Pedersen
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Genetics QH426-470
Acceso en línea:	https://doaj.org/article/d01e75884cdc498f9e404ea996710e9f
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spelling	oai:doaj.org-article:d01e75884cdc498f9e404ea996710e9f2021-12-02T16:50:32ZThe landscape and driver potential of site-specific hotspots across cancer genomes10.1038/s41525-021-00197-62056-7944https://doaj.org/article/d01e75884cdc498f9e404ea996710e9f2021-05-01T00:00:00Zhttps://doi.org/10.1038/s41525-021-00197-6https://doaj.org/toc/2056-7944Abstract Large sets of whole cancer genomes make it possible to study mutation hotspots genome-wide. Here we detect, categorize, and characterize site-specific hotspots using 2279 whole cancer genomes from the Pan-Cancer Analysis of Whole Genomes project and provide a resource of annotated hotspots genome-wide. We investigate the excess of hotspots in both protein-coding and gene regulatory regions and develop measures of positive selection and functional impact for individual hotspots. Using cancer allele fractions, expression aberrations, mutational signatures, and a variety of genomic features, such as potential gain or loss of transcription factor binding sites, we annotate and prioritize all highly mutated hotspots. Genome-wide we find more high-frequency SNV and indel hotspots than expected given mutational background models. Protein-coding regions are generally enriched for SNV hotspots compared to other regions. Gene regulatory hotspots show enrichment of potential same-patient second-hit missense mutations, consistent with enrichment of hotspot driver mutations compared to singletons. For protein-coding regions, splice-sites, promoters, and enhancers, we see an excess of hotspots associated with cancer genes. Interestingly, missense hotspot mutations in tumor suppressors are associated with elevated expression, suggesting localized amino-acid changes with functional impact. For individual non-coding hotspots, only a small number show clear signs of positive selection, including known sites in the TERT promoter and the 5’ UTR of TP53. Most of the new candidates have few mutations and limited driver evidence. However, a hotspot in an enhancer of the oncogene POU2AF1, which may create a transcription factor binding site, presents multiple lines of driver-consistent evidence.Randi Istrup JuulMorten Muhlig NielsenMalene JuulLars FeuerbachJakob Skou PedersenNature PortfolioarticleMedicineRGeneticsQH426-470ENnpj Genomic Medicine, Vol 6, Iss 1, Pp 1-15 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Genetics QH426-470
spellingShingle	Medicine R Genetics QH426-470 Randi Istrup Juul Morten Muhlig Nielsen Malene Juul Lars Feuerbach Jakob Skou Pedersen The landscape and driver potential of site-specific hotspots across cancer genomes
description	Abstract Large sets of whole cancer genomes make it possible to study mutation hotspots genome-wide. Here we detect, categorize, and characterize site-specific hotspots using 2279 whole cancer genomes from the Pan-Cancer Analysis of Whole Genomes project and provide a resource of annotated hotspots genome-wide. We investigate the excess of hotspots in both protein-coding and gene regulatory regions and develop measures of positive selection and functional impact for individual hotspots. Using cancer allele fractions, expression aberrations, mutational signatures, and a variety of genomic features, such as potential gain or loss of transcription factor binding sites, we annotate and prioritize all highly mutated hotspots. Genome-wide we find more high-frequency SNV and indel hotspots than expected given mutational background models. Protein-coding regions are generally enriched for SNV hotspots compared to other regions. Gene regulatory hotspots show enrichment of potential same-patient second-hit missense mutations, consistent with enrichment of hotspot driver mutations compared to singletons. For protein-coding regions, splice-sites, promoters, and enhancers, we see an excess of hotspots associated with cancer genes. Interestingly, missense hotspot mutations in tumor suppressors are associated with elevated expression, suggesting localized amino-acid changes with functional impact. For individual non-coding hotspots, only a small number show clear signs of positive selection, including known sites in the TERT promoter and the 5’ UTR of TP53. Most of the new candidates have few mutations and limited driver evidence. However, a hotspot in an enhancer of the oncogene POU2AF1, which may create a transcription factor binding site, presents multiple lines of driver-consistent evidence.
format	article
author	Randi Istrup Juul Morten Muhlig Nielsen Malene Juul Lars Feuerbach Jakob Skou Pedersen
author_facet	Randi Istrup Juul Morten Muhlig Nielsen Malene Juul Lars Feuerbach Jakob Skou Pedersen
author_sort	Randi Istrup Juul
title	The landscape and driver potential of site-specific hotspots across cancer genomes
title_short	The landscape and driver potential of site-specific hotspots across cancer genomes
title_full	The landscape and driver potential of site-specific hotspots across cancer genomes
title_fullStr	The landscape and driver potential of site-specific hotspots across cancer genomes
title_full_unstemmed	The landscape and driver potential of site-specific hotspots across cancer genomes
title_sort	landscape and driver potential of site-specific hotspots across cancer genomes
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/d01e75884cdc498f9e404ea996710e9f
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The landscape and driver potential of site-specific hotspots across cancer genomes

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