TY - JOUR AU - Golubicki, Mariano AU - Bonjoch, Laia AU - Acuña-Ochoa, José G. AU - Díaz-Gay, Marcos AU - Muñoz, Jenifer AU - Cuatrecasas, Miriam AU - Ocaña, Teresa AU - Iseas, Soledad AU - Mendez, Guillermo AU - Cisterna, Daniel AU - Schubert, Stephanie A. AU - Nielsen, Maartje AU - van Wezel, Tom AU - Goldberg, Yael AU - Pikarsky, Eli AU - Robbio, Juan AU - Roca, Enrique AU - Castells, Antoni AU - Balaguer, Francesc AU - Antelo, Marina AU - Castellví-Bel, Sergi T1 - Germline biallelic Mcm8 variants are associated with early-onset Lynch-like syndrome PY - 2020/09/17/ AB - Lynch syndrome is the most common cause of hereditary colorectal cancer (CRC), and it is characterized by DNA mismatch repair (MMR) deficiency. The term Lynch-like syndrome (LLS) is used for patients with MMR-deficient tumors and neither germline mutation in MLH1, MSH2, MSH6, PMS2, or EPCAM nor MLH1 somatic methylation. 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 male patient with LLS with fertility 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 cancer 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 MMR genes. We suggest MCM8 as a gene involved in CRC germline predisposition with a recessive pattern of inheritance. JF - JCI Insight JA - JCI Insight SN - 2379-3708 DO - 10.1172/jci.insight.140698 VL - 5 IS - 18 UR - https://doi.org/10.1172/jci.insight.140698 PB - The American Society for Clinical Investigation ER -