Comprehensive constitutional genetic and epigenetic characterization of lynch-like individuals

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2020
Author
Damaso, Estela
Gonzalez Acosta, Maribel
Vargas Parra, Gardenia
Navarro, Matilde
Balmana, Judith
Ramon y Cajal, Teresa
Tuset, Noemi
Thompson, Bryony A.
Marín, Fàtima
Fernández, Anna
Gómez, Carolina
Velasco, Àngela
Solanes, Ares
Iglesias, Sílvia
Urgel, Gisela
López, Consol
del Valle, Jesús
Campos, Olga
Santacana, Maria
Matias-Guiu, Xavier
Lázaro, Conxi
Valle, Laura
Brunet, Joan
Pineda, Marta
Capella, Gabriel
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Damaso, Estela; Gonzalez Acosta, Maribel; Vargas Parra, Gardenia; Navarro, Matilde; Balmana, Judith; Ramon y Cajal, Teresa; ... Capella, Gabriel. (2020) . Comprehensive constitutional genetic and epigenetic characterization of lynch-like individuals. Cancers, 2020, vol. 12, núm. 7, p.1-25. https://doi.org/10.3390/cancers12071799.
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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 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.
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http://hdl.handle.net/10459.1/70046
DOI
https://doi.org/10.3390/cancers12071799
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Cancers, 2020, vol. 12, núm. 7, p.1-25
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cc-by (c) Damaso et al., 2020
Except where otherwise noted, this item's license is described as cc-by (c) Damaso et al., 2020