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| Pàgina inicial > Articles > Articles publicats > Comprehensive constitutional genetic and epigenetic characterization of lynch-like individuals |
(Hospital Universitari de Bellvitge) (Hospital Universitari de Bellvitge) (Hospital Universitari de Bellvitge) (Vall d'Hebron Institut d'Oncologia) (Institut d'Investigació Biomèdica Sant Pau) (Hospital Universitari de Bellvitge) (Hospital Universitari de Bellvitge) (Hospital Universitari de Bellvitge) (Hospital Universitari de Bellvitge) (Hospital Universitari de Bellvitge) (Hospital Universitari de Bellvitge)| Data: | 2020 |
| Resum: | 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. |
| Ajuts: | 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 |
| Drets: | 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.  |
| Llengua: | Anglès |
| Document: | Article ; recerca ; Versió publicada |
| Matèria: | Cancer genes panel ; Epimutation ; Lynch syndrome ; Lynch-like syndrome ; Methylation ; Mismatch repair ; Next generation sequencing ; Variant of unknown significance |
| Publicat a: | Cancers, Vol. 12 Núm. 7 (july 2020) , p. 1-32, ISSN 2072-6694 |
