Comprehensive Constitutional Genetic and Epigenetic Characterization of Lynch-Like Individuals
Estela Dámaso, Maribel González‐Acosta, Gardenia Vargas‐Parra, Matilde Navarro, Judith Balmañà, Teresa Ramón y Cajal, Noemí Tuset, Bryony A. Thompson, Fátima Marín, Anna Fernández, Carolina de la Torre, Àngela Velasco, Ares Solanes, Sílvia Iglesias, Gisela Urgel, Consol López, Jesús Del Valle, Olga Campos, Marı́a Santacana, Xavier Matías‐Guiu, Conxi Lázaro, Laura Valle, Joan Brunet, Marta Pineda, Gabriel Capellá
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.