Germline variation in O6-methylguanine-DNA methyltransferase (MGMT) as cause of hereditary colorectal cancer

© 2019 The Authors.

Detalles Bibliográficos
Autores: Belhadj, Sami, Moutinho, Catia, Mur, Pilar, Setien, Fernando, Llinàs‑Arias, Pere, Pérez-Salvia, Montserrat, Pons, Tirso, Pineda, Marta, Brunet, Joan, Navarro, Matilde, Capellá, Gabriel, Esteller, Manel, Valle, Laura
Tipo de recurso: artículo
Fecha de publicación:2019
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/240516
Acceso en línea:http://hdl.handle.net/10261/240516
Access Level:acceso abierto
Palabra clave:MGMT
Hereditary cancer
Cancer genetics
Epimutation
Promoter hypermethylation
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spelling Germline variation in O6-methylguanine-DNA methyltransferase (MGMT) as cause of hereditary colorectal cancerBelhadj, SamiMoutinho, CatiaMur, PilarSetien, FernandoLlinàs‑Arias, PerePérez-Salvia, MontserratPons, TirsoPineda, MartaBrunet, JoanNavarro, MatildeCapellá, GabrielEsteller, ManelValle, LauraMGMTHereditary cancerCancer geneticsEpimutationPromoter hypermethylation© 2019 The Authors.Somatic epigenetic inactivation of the DNA repair protein O6-methylguanine DNA methyltransferase (MGMT) is frequent in colorectal cancer (CRC); however, its involvement in CRC predisposition remains unexplored. We assessed the role and relevance of MGMT germline mutations and epimutations in familial and early-onset CRC. Mutation and promoter methylation screenings were performed in 473 familial and/or early-onset mismatch repair-proficient nonpolyposis CRC cases. No constitutional MGMT inactivation by promoter methylation was observed. Of six rare heterozygous germline variants identified, c.346C > T (p.H116Y) and c.476G > A (p.R159Q), detected in three and one families respectively, affected highly conserved residues and showed segregation with cancer in available family members. In vitro, neither p.H116Y nor p.R159Q caused statistically significant reduction of MGMT repair activity. No evidence of somatic second hits was found in the studied tumors. Case-control data showed over-representation of c.346C > T (p.H116Y) in familial CRC compared to controls, but no overall association of MGMT mutations with CRC predisposition. In conclusion, germline mutations and constitutional epimutations in MGMT are not major players in hereditary CRC. Nevertheless, the over-representation of c.346C > T (p.H116Y) in our familial CRC cohort warrants further research.This work was funded by the Spanish Ministry of Science, Innovation and Universities, co-funded by FEDER funds -a way to build Europe- [SAF2016-80888-R (LV), SAF2014-55000-R (ME), SAF2015-68016-R (GC/MP), Juan de la Cierva and Sara Borrell postdoctoral contracts (PM)]; Instituto de Salud Carlos III [DTS16/00153 (ME) and CIBERONC CB16/12/00234]; the Government of Catalonia [Pla Estratègic de Recerca i Innovació en Salut SLT002/16/0037, 2017SGR1282, 2017SGR1080, 2014SGR633 and 2009SGR1315]; and Fundación Olga Torres. We thank the CERCA/Generalitat de Catalunya Program for institutional support. This study has been enabled by COST Action CA17118.ElsevierMinisterio de Economía y Competitividad (España)Instituto de Salud Carlos IIIGeneralitat de CatalunyaFundación Olga TorresEuropean Cooperation in Science and TechnologyConsejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]2021202120192021info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501http://hdl.handle.net/10261/240516reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE#info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SAF2016-80888-Rinfo:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SAF2014-55000-Rinfo:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SAF2015-68016-Rhttp://dx.doi.org/10.1016/j.canlet.2019.01.019Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/2405162026-05-22T06:33:51Z
dc.title.none.fl_str_mv Germline variation in O6-methylguanine-DNA methyltransferase (MGMT) as cause of hereditary colorectal cancer
title Germline variation in O6-methylguanine-DNA methyltransferase (MGMT) as cause of hereditary colorectal cancer
spellingShingle Germline variation in O6-methylguanine-DNA methyltransferase (MGMT) as cause of hereditary colorectal cancer
Belhadj, Sami
MGMT
Hereditary cancer
Cancer genetics
Epimutation
Promoter hypermethylation
title_short Germline variation in O6-methylguanine-DNA methyltransferase (MGMT) as cause of hereditary colorectal cancer
title_full Germline variation in O6-methylguanine-DNA methyltransferase (MGMT) as cause of hereditary colorectal cancer
title_fullStr Germline variation in O6-methylguanine-DNA methyltransferase (MGMT) as cause of hereditary colorectal cancer
title_full_unstemmed Germline variation in O6-methylguanine-DNA methyltransferase (MGMT) as cause of hereditary colorectal cancer
title_sort Germline variation in O6-methylguanine-DNA methyltransferase (MGMT) as cause of hereditary colorectal cancer
dc.creator.none.fl_str_mv Belhadj, Sami
Moutinho, Catia
Mur, Pilar
Setien, Fernando
Llinàs‑Arias, Pere
Pérez-Salvia, Montserrat
Pons, Tirso
Pineda, Marta
Brunet, Joan
Navarro, Matilde
Capellá, Gabriel
Esteller, Manel
Valle, Laura
author Belhadj, Sami
author_facet Belhadj, Sami
Moutinho, Catia
Mur, Pilar
Setien, Fernando
Llinàs‑Arias, Pere
Pérez-Salvia, Montserrat
Pons, Tirso
Pineda, Marta
Brunet, Joan
Navarro, Matilde
Capellá, Gabriel
Esteller, Manel
Valle, Laura
author_role author
author2 Moutinho, Catia
Mur, Pilar
Setien, Fernando
Llinàs‑Arias, Pere
Pérez-Salvia, Montserrat
Pons, Tirso
Pineda, Marta
Brunet, Joan
Navarro, Matilde
Capellá, Gabriel
Esteller, Manel
Valle, Laura
author2_role author
author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Ministerio de Economía y Competitividad (España)
Instituto de Salud Carlos III
Generalitat de Catalunya
Fundación Olga Torres
European Cooperation in Science and Technology
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv MGMT
Hereditary cancer
Cancer genetics
Epimutation
Promoter hypermethylation
topic MGMT
Hereditary cancer
Cancer genetics
Epimutation
Promoter hypermethylation
description © 2019 The Authors.
publishDate 2019
dc.date.none.fl_str_mv 2019
2021
2021
2021
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
format article
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/240516
url http://hdl.handle.net/10261/240516
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv #PLACEHOLDER_PARENT_METADATA_VALUE#
#PLACEHOLDER_PARENT_METADATA_VALUE#
#PLACEHOLDER_PARENT_METADATA_VALUE#
info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SAF2016-80888-R
info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SAF2014-55000-R
info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SAF2015-68016-R
http://dx.doi.org/10.1016/j.canlet.2019.01.019
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Elsevier
publisher.none.fl_str_mv Elsevier
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
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