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.
Highlights
Lynch syndrome (LS) is a hereditary cancer predisposition syndrome that increases the risk for colorectal and endometrial cancer as well as other tumors [1]
mismatch repair (MMR) variants were found in two cases fulfilling the Amsterdam criteria
MMR VUS were identified in probands (Table 2): seven in MSH6, five in
Summary
Lynch syndrome (LS) is a hereditary cancer predisposition syndrome that increases the risk for colorectal and endometrial cancer as well as other tumors [1]. It is mainly caused by pathogenic germline (epi)genetic alterations in the mismatch repair (MMR) genes MLH1, MSH2, MSH6 and PMS2 [1]. In MMR-deficient sporadic tumors, MLH1 loss of expression is mainly due to somatic MLH1 promoter methylation [2]. Even in the absence of somatic MLH1 promoter methylation, no MMR germline pathogenic variants are identified as a causal mechanism in approximately 55% of patients showing MMR-deficiency in tumors; constituting the so called Lynch-like syndrome (LLS) [3]. The identification of causal mechanisms is crucial for guiding individualized surveillance strategies for LLS patients and their relatives
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