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

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 familia...

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Autores: Belhadj, Sami, Moutinho, Cátia, Mur, Pilar, Llinàs-Arias, Pere, Pérez Salvia, Montserrat, Pons, Tirso, Pineda Riu, Marta, Brunet, Joan, Navarro, Matilde, Esteller, Manel, Valle Velasco, Laura
Tipo de recurso: artículo
Estado:Versión aceptada para publicación
Fecha de publicación:2019
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:2445/155943
Acceso en línea:https://hdl.handle.net/2445/155943
Access Level:acceso abierto
Palabra clave:Càncer colorectal
Genètica
Reparació de l'ADN
Metilació
Cèl·lules germinals
Colorectal cancer
Genetics
DNA repair
Methylation
Germ cells
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spelling Germline variation in O6-methylguanine-DNA methyltransferase (MGMT) as cause of hereditary colorectal cancerBelhadj, SamiMoutinho, CátiaMur, PilarLlinàs-Arias, PerePérez Salvia, MontserratPons, TirsoPineda Riu, MartaBrunet, JoanNavarro, MatildeEsteller, ManelValle Velasco, LauraCàncer colorectalGenèticaReparació de l'ADNMetilacióCèl·lules germinalsColorectal cancerGeneticsDNA repairMethylationGerm cellsSomatic 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.Elsevier B.V.2020202020192020info:eu-repo/semantics/articleinfo:eu-repo/semantics/acceptedVersion7 p.application/pdfhttps://hdl.handle.net/2445/155943Articles publicats en revistes (Ciències Fisiològiques)reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésVersió postprint del document publicat a: https://doi.org/10.1016/j.canlet.2019.01.019Cancer Letters, 2019, vol. 447, p. 86-92https://doi.org/10.1016/j.canlet.2019.01.019cc-by-nc-nd (c) Elsevier B.V., 2019http://creativecommons.org/licenses/by-nc-nd/3.0/esinfo:eu-repo/semantics/openAccessoai:recercat.cat:2445/1559432026-05-29T05:05:01Z
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
Càncer colorectal
Genètica
Reparació de l'ADN
Metilació
Cèl·lules germinals
Colorectal cancer
Genetics
DNA repair
Methylation
Germ cells
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, Cátia
Mur, Pilar
Llinàs-Arias, Pere
Pérez Salvia, Montserrat
Pons, Tirso
Pineda Riu, Marta
Brunet, Joan
Navarro, Matilde
Esteller, Manel
Valle Velasco, Laura
author Belhadj, Sami
author_facet Belhadj, Sami
Moutinho, Cátia
Mur, Pilar
Llinàs-Arias, Pere
Pérez Salvia, Montserrat
Pons, Tirso
Pineda Riu, Marta
Brunet, Joan
Navarro, Matilde
Esteller, Manel
Valle Velasco, Laura
author_role author
author2 Moutinho, Cátia
Mur, Pilar
Llinàs-Arias, Pere
Pérez Salvia, Montserrat
Pons, Tirso
Pineda Riu, Marta
Brunet, Joan
Navarro, Matilde
Esteller, Manel
Valle Velasco, Laura
author2_role author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Càncer colorectal
Genètica
Reparació de l'ADN
Metilació
Cèl·lules germinals
Colorectal cancer
Genetics
DNA repair
Methylation
Germ cells
topic Càncer colorectal
Genètica
Reparació de l'ADN
Metilació
Cèl·lules germinals
Colorectal cancer
Genetics
DNA repair
Methylation
Germ cells
description 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.
publishDate 2019
dc.date.none.fl_str_mv 2019
2020
2020
2020
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/acceptedVersion
format article
status_str acceptedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/155943
url https://hdl.handle.net/2445/155943
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Versió postprint del document publicat a: https://doi.org/10.1016/j.canlet.2019.01.019
Cancer Letters, 2019, vol. 447, p. 86-92
https://doi.org/10.1016/j.canlet.2019.01.019
dc.rights.none.fl_str_mv cc-by-nc-nd (c) Elsevier B.V., 2019
http://creativecommons.org/licenses/by-nc-nd/3.0/es
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc-by-nc-nd (c) Elsevier B.V., 2019
http://creativecommons.org/licenses/by-nc-nd/3.0/es
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv 7 p.
application/pdf
dc.publisher.none.fl_str_mv Elsevier B.V.
publisher.none.fl_str_mv Elsevier B.V.
dc.source.none.fl_str_mv Articles publicats en revistes (Ciències Fisiològiques)
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
repository.mail.fl_str_mv
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score 15,198674

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