Whole-exome sequencing identifies rare pathogenic variants in new predisposition genes for familial colorectal cancer

Purpose. Colorectal cancer is an important cause of mortality in the developed world. Hereditary forms are due to germ-line mutations in APC, MUTYH, and the mismatch repair genes, but many cases present familial aggregation but an unknown inherited cause. The hypothesis of rare high-penetrance mutat...

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Autores: Esteban-Jurado, Clara, Abulí, Anna, Bessa i Caserras, Xavier, Andreu García, Montserrat, Castellví Bel, Sergi
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2015
País:España
Institución:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositorio:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:10230/58542
Acceso en línea:http://hdl.handle.net/10230/58542
http://dx.doi.org/10.1038/gim.2014.89
Access Level:acceso abierto
Palabra clave:Colorectal neoplasm
Genetic variant
Genetic predisposition to disease
Hereditary disease
Next-generation sequencing
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spelling Whole-exome sequencing identifies rare pathogenic variants in new predisposition genes for familial colorectal cancerEsteban-Jurado, ClaraAbulí, AnnaBessa i Caserras, XavierAndreu García, MontserratCastellví Bel, SergiColorectal neoplasmGenetic variantGenetic predisposition to diseaseHereditary diseaseNext-generation sequencingPurpose. Colorectal cancer is an important cause of mortality in the developed world. Hereditary forms are due to germ-line mutations in APC, MUTYH, and the mismatch repair genes, but many cases present familial aggregation but an unknown inherited cause. The hypothesis of rare high-penetrance mutations in new genes is a likely explanation for the underlying predisposition in some of these familial cases. Methods. Exome sequencing was performed in 43 patients with colorectal cancer from 29 families with strong disease aggregation without mutations in known hereditary colorectal cancer genes. Data analysis selected only very rare variants (0–0.1%), producing a putative loss of function and located in genes with a role compatible with cancer. Variants in genes previously involved in hereditary colorectal cancer or nearby previous colorectal cancer genome-wide association study hits were also chosen. Results. Twenty-eight final candidate variants were selected and validated by Sanger sequencing. Correct family segregation and somatic studies were used to categorize the most interesting variants in CDKN1B, XRCC4, EPHX1, NFKBIZ, SMARCA4, and BARD1. Conclusion. We identified new potential colorectal cancer predisposition variants in genes that have a role in cancer predisposition and are involved in DNA repair and the cell cycle, which supports their putative involvement in germ-line predisposition to this neoplasm.We are sincerely grateful to the Centre Nacional d'Anàlisi Genòmica and the Biobank of Hospital Clínic–IDIBAPS, Barcelona, for technical help, and the International Cancer Genome Consortium for access to exome data set. The work was carried out (in part) at the Esther Koplowitz Centre, Barcelona. CEJ and JM are supported by a contract from CIBERehd. MVC is supported by Ministerio de Educación, Cultura y Deporte (FPU12/05138). PG and SCB are supported by a contract from the Fondo de Investigación Sanitaria (JR13/00013 and CP 03-0070, respectively). CIBERehd and CIBERER are funded by the Instituto de Salud Carlos III. This work was supported by grants from the Fondo de Investigación Sanitaria/FEDER (10/00641, 11/00219, 11/00681, RD12/0036/006, 13/02588), the Ministerio de Economía y Competitividad (SAF2010-19273), Fundación Científica de la Asociación Española contra el Cáncer (GCB13131592CAST), COST Action BM1206 (SCB and CRP), Beca Grupo de Trabajo “Oncología” AEG (Asociación Española de Gastroenterología), and Agència de Gestió d'Ajuts Universitaris i de Recerca (Generalitat de Catalunya, 2014SGR255).Elsevier202320232015info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfapplication/pdfhttp://hdl.handle.net/10230/58542http://dx.doi.org/10.1038/gim.2014.89reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésGenetics in Medicine. 2015 Feb;17(2):131-42info:eu-repo/grantAgreement/ES/3PN/SAF2010-19273This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/3.0/http://creativecommons.org/licenses/by-nc-nd/3.0/info:eu-repo/semantics/openAccessoai:recercat.cat:10230/585422026-05-29T05:05:01Z
dc.title.none.fl_str_mv Whole-exome sequencing identifies rare pathogenic variants in new predisposition genes for familial colorectal cancer
title Whole-exome sequencing identifies rare pathogenic variants in new predisposition genes for familial colorectal cancer
spellingShingle Whole-exome sequencing identifies rare pathogenic variants in new predisposition genes for familial colorectal cancer
Esteban-Jurado, Clara
Colorectal neoplasm
Genetic variant
Genetic predisposition to disease
Hereditary disease
Next-generation sequencing
title_short Whole-exome sequencing identifies rare pathogenic variants in new predisposition genes for familial colorectal cancer
title_full Whole-exome sequencing identifies rare pathogenic variants in new predisposition genes for familial colorectal cancer
title_fullStr Whole-exome sequencing identifies rare pathogenic variants in new predisposition genes for familial colorectal cancer
title_full_unstemmed Whole-exome sequencing identifies rare pathogenic variants in new predisposition genes for familial colorectal cancer
title_sort Whole-exome sequencing identifies rare pathogenic variants in new predisposition genes for familial colorectal cancer
dc.creator.none.fl_str_mv Esteban-Jurado, Clara
Abulí, Anna
Bessa i Caserras, Xavier
Andreu García, Montserrat
Castellví Bel, Sergi
author Esteban-Jurado, Clara
author_facet Esteban-Jurado, Clara
Abulí, Anna
Bessa i Caserras, Xavier
Andreu García, Montserrat
Castellví Bel, Sergi
author_role author
author2 Abulí, Anna
Bessa i Caserras, Xavier
Andreu García, Montserrat
Castellví Bel, Sergi
author2_role author
author
author
author
dc.subject.none.fl_str_mv Colorectal neoplasm
Genetic variant
Genetic predisposition to disease
Hereditary disease
Next-generation sequencing
topic Colorectal neoplasm
Genetic variant
Genetic predisposition to disease
Hereditary disease
Next-generation sequencing
description Purpose. Colorectal cancer is an important cause of mortality in the developed world. Hereditary forms are due to germ-line mutations in APC, MUTYH, and the mismatch repair genes, but many cases present familial aggregation but an unknown inherited cause. The hypothesis of rare high-penetrance mutations in new genes is a likely explanation for the underlying predisposition in some of these familial cases. Methods. Exome sequencing was performed in 43 patients with colorectal cancer from 29 families with strong disease aggregation without mutations in known hereditary colorectal cancer genes. Data analysis selected only very rare variants (0–0.1%), producing a putative loss of function and located in genes with a role compatible with cancer. Variants in genes previously involved in hereditary colorectal cancer or nearby previous colorectal cancer genome-wide association study hits were also chosen. Results. Twenty-eight final candidate variants were selected and validated by Sanger sequencing. Correct family segregation and somatic studies were used to categorize the most interesting variants in CDKN1B, XRCC4, EPHX1, NFKBIZ, SMARCA4, and BARD1. Conclusion. We identified new potential colorectal cancer predisposition variants in genes that have a role in cancer predisposition and are involved in DNA repair and the cell cycle, which supports their putative involvement in germ-line predisposition to this neoplasm.
publishDate 2015
dc.date.none.fl_str_mv 2015
2023
2023
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10230/58542
http://dx.doi.org/10.1038/gim.2014.89
url http://hdl.handle.net/10230/58542
http://dx.doi.org/10.1038/gim.2014.89
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Genetics in Medicine. 2015 Feb;17(2):131-42
info:eu-repo/grantAgreement/ES/3PN/SAF2010-19273
dc.rights.none.fl_str_mv http://creativecommons.org/licenses/by-nc-nd/3.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv http://creativecommons.org/licenses/by-nc-nd/3.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Elsevier
publisher.none.fl_str_mv Elsevier
dc.source.none.fl_str_mv reponame:Recercat. Dipósit de la Recerca de Catalunya
instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
instname_str Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
reponame_str Recercat. Dipósit de la Recerca de Catalunya
collection Recercat. Dipósit de la Recerca de Catalunya
repository.name.fl_str_mv
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