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dc.contributor.authorDamaso, Estela
dc.contributor.authorGonzalez Acosta, Maribel
dc.contributor.authorVargas Parra, Gardenia
dc.contributor.authorNavarro, Matilde
dc.contributor.authorBalmana, Judith
dc.contributor.authorRamon y Cajal, Teresa
dc.contributor.authorTuset, Noemi
dc.contributor.authorThompson, Bryony A.
dc.contributor.authorMarín, Fàtima
dc.contributor.authorFernández, Anna
dc.contributor.authorGómez, Carolina
dc.contributor.authorVelasco, Àngela
dc.contributor.authorSolanes, Ares
dc.contributor.authorIglesias, Sílvia
dc.contributor.authorUrgel, Gisela
dc.contributor.authorLópez, Consol
dc.contributor.authordel Valle, Jesús
dc.contributor.authorCampos, Olga
dc.contributor.authorSantacana Espasa, Maria
dc.contributor.authorMatias-Guiu, Xavier
dc.contributor.authorLázaro, Conxi
dc.contributor.authorValle, Laura
dc.contributor.authorBrunet, Joan
dc.contributor.authorPineda, Marta
dc.contributor.authorCapellà, Gabriel
dc.description.abstractThe 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.ca_ES
dc.description.sponsorshipThis work was funded by the Spanish Ministry of Economy and Competitiveness and cofunded by FEDER funds -a way to build Europe-(grants SAF2012-33636, SAF2015-68016-R and SAF2016-80888-R), CIBERONC, RTICC Network (RD12/0036/0031 and RD12/0036/0008), the Spanish Association Against Cancer (AECC) (080253), the Government of Catalonia (grant 2014SGR338, 2017SGR1282 and PERIS SLT002/16/0037), Fundacion Mutua Madrilena (grant AP114252013). We thank CERCA Programme for institutional support. ED was supported by a grant from the Spanish Ministry of Economy and Competitiveness. The AECC fellowship to MG-A. AF was supported by a grant from the Catalonian Health Department (SLT002/16/00409). FM was supported by CIBERONC. The Mexican National Council for Science and Technology (CONACyT) fellowship to GV.ca_ES
dc.relation.isformatofReproducció del document publicat a
dc.relation.ispartofCancers, 2020, vol. 12, núm. 7, p.1-25ca_ES
dc.rightscc-by (c) Damaso et al., 2020ca_ES
dc.subject.otherGens del càncerca_ES
dc.titleComprehensive constitutional genetic and epigenetic characterization of lynch-like individualsca_ES

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