Analysis of somatic mutations across the kinome reveals loss-of-function mutations in multiple cancer types

Abstract In this study we use somatic cancer mutations to identify important functional residues within sets of related genes. We focus on protein kinases, a superfamily of phosphotransferases that share homologous sequences and structural motifs and have many connections to cancer. We develop sever...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Runjun D. Kumar, Ron Bose
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/2c968a60686444bfb6cc99fa031b2e91
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:2c968a60686444bfb6cc99fa031b2e91
record_format	dspace
spelling	oai:doaj.org-article:2c968a60686444bfb6cc99fa031b2e912021-12-02T11:52:58ZAnalysis of somatic mutations across the kinome reveals loss-of-function mutations in multiple cancer types10.1038/s41598-017-06366-x2045-2322https://doaj.org/article/2c968a60686444bfb6cc99fa031b2e912017-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-06366-xhttps://doaj.org/toc/2045-2322Abstract In this study we use somatic cancer mutations to identify important functional residues within sets of related genes. We focus on protein kinases, a superfamily of phosphotransferases that share homologous sequences and structural motifs and have many connections to cancer. We develop several statistical tests for identifying Significantly Mutated Positions (SMPs), which are positions in an alignment with mutations that show signs of selection. We apply our methods to 21,917 mutations that map to the alignment of human kinases and identify 23 SMPs. SMPs occur throughout the alignment, with many in the important A-loop region, and others spread between the N and C lobes of the kinase domain. Since mutations are pooled across the superfamily, these positions may be important to many protein kinases. We select eleven mutations from these positions for functional validation. All eleven mutations cause a reduction or loss of function in the affected kinase. The tested mutations are from four genes, including two tumor suppressors (TGFBR1 and CHEK2) and two oncogenes (KDR and ERBB2). They also represent multiple cancer types, and include both recurrent and non-recurrent events. Many of these mutations warrant further investigation as potential cancer drivers.Runjun D. KumarRon BoseNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-12 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Runjun D. Kumar Ron Bose Analysis of somatic mutations across the kinome reveals loss-of-function mutations in multiple cancer types
description	Abstract In this study we use somatic cancer mutations to identify important functional residues within sets of related genes. We focus on protein kinases, a superfamily of phosphotransferases that share homologous sequences and structural motifs and have many connections to cancer. We develop several statistical tests for identifying Significantly Mutated Positions (SMPs), which are positions in an alignment with mutations that show signs of selection. We apply our methods to 21,917 mutations that map to the alignment of human kinases and identify 23 SMPs. SMPs occur throughout the alignment, with many in the important A-loop region, and others spread between the N and C lobes of the kinase domain. Since mutations are pooled across the superfamily, these positions may be important to many protein kinases. We select eleven mutations from these positions for functional validation. All eleven mutations cause a reduction or loss of function in the affected kinase. The tested mutations are from four genes, including two tumor suppressors (TGFBR1 and CHEK2) and two oncogenes (KDR and ERBB2). They also represent multiple cancer types, and include both recurrent and non-recurrent events. Many of these mutations warrant further investigation as potential cancer drivers.
format	article
author	Runjun D. Kumar Ron Bose
author_facet	Runjun D. Kumar Ron Bose
author_sort	Runjun D. Kumar
title	Analysis of somatic mutations across the kinome reveals loss-of-function mutations in multiple cancer types
title_short	Analysis of somatic mutations across the kinome reveals loss-of-function mutations in multiple cancer types
title_full	Analysis of somatic mutations across the kinome reveals loss-of-function mutations in multiple cancer types
title_fullStr	Analysis of somatic mutations across the kinome reveals loss-of-function mutations in multiple cancer types
title_full_unstemmed	Analysis of somatic mutations across the kinome reveals loss-of-function mutations in multiple cancer types
title_sort	analysis of somatic mutations across the kinome reveals loss-of-function mutations in multiple cancer types
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/2c968a60686444bfb6cc99fa031b2e91
work_keys_str_mv	AT runjundkumar analysisofsomaticmutationsacrossthekinomerevealslossoffunctionmutationsinmultiplecancertypes AT ronbose analysisofsomaticmutationsacrossthekinomerevealslossoffunctionmutationsinmultiplecancertypes
_version_	1718394914525413376

Analysis of somatic mutations across the kinome reveals loss-of-function mutations in multiple cancer types

Ejemplares similares