Comprehensive Constitutional Genetic and Epigenetic Characterization of Lynch-Like Individuals

The causal mechanism for cancer predisposition in Lynch-like syndrome (LLS) remains unknown. Our aim was to elucidate the constitutional basis of mismatch repair (MMR) deficiency in LLS patients throughout a comprehensive (epi)genetic analysis. One hundred and fifteen LLS patients harboring MMR-defi...

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Autores: Damaso, E, Gonzalez-Acosta, M, Vargas-Parra, G, Navarro, M, Balmana, J, Cajal, TRY, Tuset, N, Thompson, BA, Marin, F, Fernandez, A, Gomez, C, Velasco, A, Solanes, A, Iglesias, S, Urgel, G, Lopez, C, del Valle, J, Campos, O, Santacana, M, Matias-Guiu, X, Lazaro, C, Valle, L, Brunet, J, Pineda, M, Capella, G
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2020
País:España
Institución:Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunitat Valenciana (FISABIO)
Repositorio:r-FISABIO. Repositorio Institucional de Producción Científica
OAI Identifier:oai:fisabio.fundanetsuite.com:p12846
Acceso en línea:https://fisabio.portalinvestigacion.com/publicaciones/12846
Access Level:acceso abierto
Palabra clave:Lynch syndrome
Lynch-like syndrome
variant of unknown significance
epimutation
mismatch repair
methylation
cancer genes panel
next generation sequencing
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spelling Comprehensive Constitutional Genetic and Epigenetic Characterization of Lynch-Like IndividualsDamaso, EGonzalez-Acosta, MVargas-Parra, GNavarro, MBalmana, JCajal, TRYTuset, NThompson, BAMarin, FFernandez, AGomez, CVelasco, ASolanes, AIglesias, SUrgel, GLopez, Cdel Valle, JCampos, OSantacana, MMatias-Guiu, XLazaro, CValle, LBrunet, JPineda, MCapella, GLynch syndromeLynch-like syndromevariant of unknown significanceepimutationmismatch repairmethylationcancer genes panelnext generation sequencingThe causal mechanism for cancer predisposition in Lynch-like syndrome (LLS) remains unknown. Our aim was to elucidate the constitutional basis of mismatch repair (MMR) deficiency in LLS patients throughout a comprehensive (epi)genetic analysis. One hundred and fifteen LLS patients harboring MMR-deficient tumors and no germline MMR mutations were included. Mutational analysis of 26 colorectal cancer (CRC)-associated genes was performed. Pathogenicity of MMR variants was assessed by splicing and multifactorial likelihood analyses. Genome-wide methylome analysis was performed by the Infinium Human Methylation 450K Bead Chip. The multigene panel analysis revealed the presence of two MMR gene truncating mutations not previously found. Of a total of 15 additional MMR variants identified, five -present in 6 unrelated individuals- were reclassified as pathogenic. In addition, 13 predicted deleterious variants in other CRC-predisposing genes were found in 12 probands. Methylome analysis detected one constitutionalMLH1epimutation, but no additional differentially methylated regions were identified in LLS compared to LS patients or cancer-free individuals. In conclusion, the use of an ad-hoc designed gene panel combined with pathogenicity assessment of variants allowed the identification of deleterious MMR mutations as well as new LLS candidate causal genes. Constitutional epimutations in non-LS-associated genes are not responsible for LLS.MDPI2020info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttps://fisabio.portalinvestigacion.com/publicaciones/12846CancersISSN: 20726694reponame:r-FISABIO. Repositorio Institucional de Producción Científicainstname:Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunitat Valenciana (FISABIO)Inglésinfo:eu-repo/semantics/openAccessoai:fisabio.fundanetsuite.com:p128462026-06-11T12:45:17Z
dc.title.none.fl_str_mv Comprehensive Constitutional Genetic and Epigenetic Characterization of Lynch-Like Individuals
title Comprehensive Constitutional Genetic and Epigenetic Characterization of Lynch-Like Individuals
spellingShingle Comprehensive Constitutional Genetic and Epigenetic Characterization of Lynch-Like Individuals
Damaso, E
Lynch syndrome
Lynch-like syndrome
variant of unknown significance
epimutation
mismatch repair
methylation
cancer genes panel
next generation sequencing
title_short Comprehensive Constitutional Genetic and Epigenetic Characterization of Lynch-Like Individuals
title_full Comprehensive Constitutional Genetic and Epigenetic Characterization of Lynch-Like Individuals
title_fullStr Comprehensive Constitutional Genetic and Epigenetic Characterization of Lynch-Like Individuals
title_full_unstemmed Comprehensive Constitutional Genetic and Epigenetic Characterization of Lynch-Like Individuals
title_sort Comprehensive Constitutional Genetic and Epigenetic Characterization of Lynch-Like Individuals
dc.creator.none.fl_str_mv Damaso, E
Gonzalez-Acosta, M
Vargas-Parra, G
Navarro, M
Balmana, J
Cajal, TRY
Tuset, N
Thompson, BA
Marin, F
Fernandez, A
Gomez, C
Velasco, A
Solanes, A
Iglesias, S
Urgel, G
Lopez, C
del Valle, J
Campos, O
Santacana, M
Matias-Guiu, X
Lazaro, C
Valle, L
Brunet, J
Pineda, M
Capella, G
author Damaso, E
author_facet Damaso, E
Gonzalez-Acosta, M
Vargas-Parra, G
Navarro, M
Balmana, J
Cajal, TRY
Tuset, N
Thompson, BA
Marin, F
Fernandez, A
Gomez, C
Velasco, A
Solanes, A
Iglesias, S
Urgel, G
Lopez, C
del Valle, J
Campos, O
Santacana, M
Matias-Guiu, X
Lazaro, C
Valle, L
Brunet, J
Pineda, M
Capella, G
author_role author
author2 Gonzalez-Acosta, M
Vargas-Parra, G
Navarro, M
Balmana, J
Cajal, TRY
Tuset, N
Thompson, BA
Marin, F
Fernandez, A
Gomez, C
Velasco, A
Solanes, A
Iglesias, S
Urgel, G
Lopez, C
del Valle, J
Campos, O
Santacana, M
Matias-Guiu, X
Lazaro, C
Valle, L
Brunet, J
Pineda, M
Capella, G
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Lynch syndrome
Lynch-like syndrome
variant of unknown significance
epimutation
mismatch repair
methylation
cancer genes panel
next generation sequencing
topic Lynch syndrome
Lynch-like syndrome
variant of unknown significance
epimutation
mismatch repair
methylation
cancer genes panel
next generation sequencing
description The causal mechanism for cancer predisposition in Lynch-like syndrome (LLS) remains unknown. Our aim was to elucidate the constitutional basis of mismatch repair (MMR) deficiency in LLS patients throughout a comprehensive (epi)genetic analysis. One hundred and fifteen LLS patients harboring MMR-deficient tumors and no germline MMR mutations were included. Mutational analysis of 26 colorectal cancer (CRC)-associated genes was performed. Pathogenicity of MMR variants was assessed by splicing and multifactorial likelihood analyses. Genome-wide methylome analysis was performed by the Infinium Human Methylation 450K Bead Chip. The multigene panel analysis revealed the presence of two MMR gene truncating mutations not previously found. Of a total of 15 additional MMR variants identified, five -present in 6 unrelated individuals- were reclassified as pathogenic. In addition, 13 predicted deleterious variants in other CRC-predisposing genes were found in 12 probands. Methylome analysis detected one constitutionalMLH1epimutation, but no additional differentially methylated regions were identified in LLS compared to LS patients or cancer-free individuals. In conclusion, the use of an ad-hoc designed gene panel combined with pathogenicity assessment of variants allowed the identification of deleterious MMR mutations as well as new LLS candidate causal genes. Constitutional epimutations in non-LS-associated genes are not responsible for LLS.
publishDate 2020
dc.date.none.fl_str_mv 2020
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 https://fisabio.portalinvestigacion.com/publicaciones/12846
url https://fisabio.portalinvestigacion.com/publicaciones/12846
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv MDPI
publisher.none.fl_str_mv MDPI
dc.source.none.fl_str_mv Cancers
ISSN: 20726694
reponame:r-FISABIO. Repositorio Institucional de Producción Científica
instname:Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunitat Valenciana (FISABIO)
instname_str Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunitat Valenciana (FISABIO)
reponame_str r-FISABIO. Repositorio Institucional de Producción Científica
collection r-FISABIO. Repositorio Institucional de Producción Científica
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15.811543

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