GERMLINE BIALLELIC VARIANTS IN MCM8 ARE ASSOCIATED WITH EARLY-ONSET LYNCH-LIKE SYNDROME

GOLUBICKI, MARIANO; BONJOCH, LAIA; JOSÉ G. ACUÑA-OCHOA, JOSE; DÍAZ-GAY, MARCOS; MUÑOZ, JENIFER; CUATRECASAS, MIRIAM; OCAÑA, TERESA; ISEAS, SOLEDAD; CISTERNA, DANIEL; SCHUBERT, STEPHANIE A; NIELSEN, MAARTJE ; VAN WEZEL, TOM; GOLDBERG, YAEL; PIKARSKY, ELI; ROBBIO, JUAN; ROCA, ENRIQUE; CASTELLS, ANTONI; BALAGUER, FRANCESC; ANTELO, MARINA; CASTELLVI-BELL, SERGI

The Journal of Clinical Investigation insight

American Society for Clinical Investigation

Lugar: Ann Arbor; Año: 2020

Lynch syndrome is the most common colorectal cancer (CRC) hereditary form and it is characterized by DNA mismatch repair (MMR) deficiency. The term Lynch-like syndrome (LLS) is used for patients with MMR-deficient tumors but no germline mutation in MLH1,MSH2, MSH6, PMS2, or EPCAM. Biallelic somatic inactivation or cryptic germline MMR variants undetected during genetic testing have been proposed to be involved. Sixteen patients with early-onset LLS CRC were selected for germline and tumor whole-exome sequencing. Two potentially pathogenic germline MCM8 variants were detected in a LLS male patient with infertility problems. A knockout cellular model for MCM8 was generated by CRISPR-Cas9 and detected genetic variants were produced by mutagenesis. DNA damage, microsatellite instability and mutational signatures were monitored. DNA damage was evident for MCM8KO cells and the analyzed genetic variants. Microsatellite instability and mutational signatures in MCM8KO cells were compatible with the involvement of MCM8 in MMR. Replication in an independent familial CRC cohort detected additional carriers. Unexplained MMR-deficient CRC cases, even showing somatic biallelic MMR inactivation, may be caused by underlying germline defects in genes different than the MMR genes. We suggest MCM8 as a new gene involved in CRC germline predisposition with a recessive pattern of inheritance