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...
| Autores: | , , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Tipo de recurso: | artículo |
| Estado: | Versión publicada |
| Fecha de publicación: | 2020 |
| 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:2445/171747 |
| Acceso en línea: | https://hdl.handle.net/2445/171747 |
| Access Level: | acceso abierto |
| Palabra clave: | Càncer colorectal Genètica Colorectal cancer Genetics |
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Comprehensive Constitutional Genetic and Epigenetic Characterization of Lynch-Like IndividualsDámaso, EstelaGonzález Acosta, María IsabelVargas Parra, Gardenía MaríaNavarro, MatildeBalmaña, JudithRamon y Cajal, TeresaTuset, NoemíThompson, Bryony A.Marín, FátimaFernández, AnnaGomez, CarolinaVelasco, ÀngelaSolanes, AresIglesias Casals, SílviaUrgel, GiselaLópez, ConsolValle, Jesús delCampos, OlgaSantacana, MariaMatias-Guiu, Xavier, 1958-Lázaro García, ConxiValle, LauraBrunet, JoanPineda Riu, MartaCapellá, G. (Gabriel)Càncer colorectalGenèticaColorectal cancerGeneticsThe 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.MDPI2020202020202020info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersion25 p.application/pdfapplication/pdfhttps://hdl.handle.net/2445/171747Articles publicats en revistes (Ciències Clíniques)reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésReproducció del document publicat a: https://doi.org/10.3390/cancers12071799Cancers, 2020, vol. 12, num. 7https://doi.org/10.3390/cancers12071799cc by (c) Dámaso et al., 2020http://creativecommons.org/licenses/by/3.0/es/info:eu-repo/semantics/openAccessoai:recercat.cat:2445/1717472026-05-29T05:05:01Z |
| 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 Dámaso, Estela Càncer colorectal Genètica Colorectal cancer Genetics |
| 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 |
Dámaso, Estela González Acosta, María Isabel Vargas Parra, Gardenía María Navarro, Matilde Balmaña, Judith Ramon y Cajal, Teresa Tuset, Noemí Thompson, Bryony A. Marín, Fátima Fernández, Anna Gomez, Carolina Velasco, Àngela Solanes, Ares Iglesias Casals, Sílvia Urgel, Gisela López, Consol Valle, Jesús del Campos, Olga Santacana, Maria Matias-Guiu, Xavier, 1958- Lázaro García, Conxi Valle, Laura Brunet, Joan Pineda Riu, Marta Capellá, G. (Gabriel) |
| author |
Dámaso, Estela |
| author_facet |
Dámaso, Estela González Acosta, María Isabel Vargas Parra, Gardenía María Navarro, Matilde Balmaña, Judith Ramon y Cajal, Teresa Tuset, Noemí Thompson, Bryony A. Marín, Fátima Fernández, Anna Gomez, Carolina Velasco, Àngela Solanes, Ares Iglesias Casals, Sílvia Urgel, Gisela López, Consol Valle, Jesús del Campos, Olga Santacana, Maria Matias-Guiu, Xavier, 1958- Lázaro García, Conxi Valle, Laura Brunet, Joan Pineda Riu, Marta Capellá, G. (Gabriel) |
| author_role |
author |
| author2 |
González Acosta, María Isabel Vargas Parra, Gardenía María Navarro, Matilde Balmaña, Judith Ramon y Cajal, Teresa Tuset, Noemí Thompson, Bryony A. Marín, Fátima Fernández, Anna Gomez, Carolina Velasco, Àngela Solanes, Ares Iglesias Casals, Sílvia Urgel, Gisela López, Consol Valle, Jesús del Campos, Olga Santacana, Maria Matias-Guiu, Xavier, 1958- Lázaro García, Conxi Valle, Laura Brunet, Joan Pineda Riu, Marta Capellá, G. (Gabriel) |
| 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 |
Càncer colorectal Genètica Colorectal cancer Genetics |
| topic |
Càncer colorectal Genètica Colorectal cancer Genetics |
| 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 2020 2020 2020 |
| dc.type.none.fl_str_mv |
info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion |
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article |
| status_str |
publishedVersion |
| dc.identifier.none.fl_str_mv |
https://hdl.handle.net/2445/171747 |
| url |
https://hdl.handle.net/2445/171747 |
| dc.language.none.fl_str_mv |
Inglés |
| language_invalid_str_mv |
Inglés |
| dc.relation.none.fl_str_mv |
Reproducció del document publicat a: https://doi.org/10.3390/cancers12071799 Cancers, 2020, vol. 12, num. 7 https://doi.org/10.3390/cancers12071799 |
| dc.rights.none.fl_str_mv |
cc by (c) Dámaso et al., 2020 http://creativecommons.org/licenses/by/3.0/es/ info:eu-repo/semantics/openAccess |
| rights_invalid_str_mv |
cc by (c) Dámaso et al., 2020 http://creativecommons.org/licenses/by/3.0/es/ |
| eu_rights_str_mv |
openAccess |
| dc.format.none.fl_str_mv |
25 p. application/pdf application/pdf |
| dc.publisher.none.fl_str_mv |
MDPI |
| publisher.none.fl_str_mv |
MDPI |
| dc.source.none.fl_str_mv |
Articles publicats en revistes (Ciències Clíniques) reponame:Recercat. Dipósit de la Recerca de Catalunya instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya) |
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Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya) |
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Recercat. Dipósit de la Recerca de Catalunya |
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Recercat. Dipósit de la Recerca de Catalunya |
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