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

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• dc.contributor.author Esteban-Jurado, Clara
• dc.contributor.author Abulí, Anna
• dc.contributor.author Bessa Caserras, Xavier
• dc.contributor.author Andreu García, Montserrat
• dc.contributor.author Castellví Bel, Sergi
• dc.date.accessioned 2023-12-18T06:50:54Z
• dc.date.available 2023-12-18T06:50:54Z
• dc.date.issued 2015
• dc.description.abstract 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.
• dc.description.sponsorship 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).
• dc.format.mimetype application/pdf
• dc.identifier.citation Esteban-Jurado C, Vila-Casadesús M, Garre P, Lozano JJ, Pristoupilova A, Beltran S, et al. Whole-exome sequencing identifies rare pathogenic variants in new predisposition genes for familial colorectal cancer. Genetics in Medicine. 2015 Feb;17(2):131-42. DOI: 10.1038/gim.2014.89
• dc.identifier.doi http://dx.doi.org/10.1038/gim.2014.89
• dc.identifier.issn 1098-3600
• dc.identifier.uri http://hdl.handle.net/10230/58542
• dc.language.iso eng
• dc.publisher Elsevier
• dc.relation.ispartof Genetics in Medicine. 2015 Feb;17(2):131-42
• dc.relation.projectID info:eu-repo/grantAgreement/ES/3PN/SAF2010-19273
• dc.rights This 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/
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by-nc-nd/3.0/
• dc.subject.keyword Colorectal neoplasm
• dc.subject.keyword Genetic variant
• dc.subject.keyword Genetic predisposition to disease
• dc.subject.keyword Hereditary disease
• dc.subject.keyword Next-generation sequencing
• dc.title Whole-exome sequencing identifies rare pathogenic variants in new predisposition genes for familial colorectal cancer
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion