TY - JOUR
T1 - Comprehensive constitutional genetic and epigenetic characterization of lynch-like individuals
AU - Dámaso, Estela
AU - González-Acosta, Maribel
AU - Vargas-Parra, Gardenia
AU - Navarro, Matilde
AU - Balmaña Gelpí, Judith
AU - Ramon y Cajal, Teresa
AU - Tuset, Noemí
AU - Thompson, Bryony A.
AU - Marín, Fátima
AU - Fernández Torné, Ana
AU - Gómez, Carolina
AU - Velasco, Àngela
AU - Solanes, Ares
AU - Iglesias, Sílvia
AU - Urgel, Gisela
AU - López, Consol
AU - Del Valle, Jesús
AU - Campos, Olga
AU - Santacana, Maria
AU - Matías-Guiu, Xavier
AU - Lazaro Garcia, Conxi
AU - Valle, Laura
AU - Brunet, Joan
AU - Pineda, Marta
AU - Capella, Gabriel
PY - 2020
Y1 - 2020
N2 - 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.
AB - 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.
KW - Cancer genes panel
KW - Epimutation
KW - Lynch syndrome
KW - Lynch-like syndrome
KW - Methylation
KW - Mismatch repair
KW - Next generation sequencing
KW - Variant of unknown significance
U2 - 10.3390/cancers12071799
DO - 10.3390/cancers12071799
M3 - Article
C2 - 32635641
SN - 2072-6694
VL - 12
SP - 1
EP - 32
JO - Cancers
JF - Cancers
IS - 7
ER -
