Home > Articles > Published articles > Comprehensive constitutional genetic and epigenetic characterization of lynch-like individuals |
Date: | 2020 |
Abstract: | 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 constitutional MLH1 epimutation, 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. |
Grants: | Ministerio de Economía y Competitividad SAF2012-33636 Ministerio de Economía y Competitividad SAF2015-68016-R Ministerio de Economía y Competitividad RD12/0036/0031 Ministerio de Economía y Competitividad RD12/0036/0008 |
Rights: | Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original. |
Language: | Anglès |
Document: | Article ; recerca ; Versió publicada |
Subject: | Cancer genes panel ; Epimutation ; Lynch syndrome ; Lynch-like syndrome ; Methylation ; Mismatch repair ; Next generation sequencing ; Variant of unknown significance |
Published in: | Cancers, Vol. 12 Núm. 7 (july 2020) , p. 1-32, ISSN 2072-6694 |
25 p, 1.8 MB |