Molecular Profiling of Germline Variants in the DNA Mismatch Repair Genes in Chinese Colorectal Cancer Patients

A multicenter study on the DNA mismatch repair (MMR) genes enabled us to study the profiling of germline variants in MMR genes of colorectal cancer (CRC) patients with MMR deficiency (dMMR). The clinicopathological differences between Lynch syndrome (LS) patients and sporadic dMMR CRC patients were compared by Student's t-test and χ² test. The molecular profiling of germline variants in MMR genes in Chinese CRC patients with dMMR is clarified.

A total of 326 CRC patients with dMMR were enrolled. Next-generation sequencing (NGS) and Sanger sequencing were performed using tumor-adjacent tissues of enrolled patients. Four MMR genes (MLH1, MSH2, MSH6, and PMS2) are included in the NGS panel.

A total of 113 germline variants were detected, including 81 pathogenic and likely pathogenic variants. The clinicopathologic differences between CRC patients with/without LS were observed in age, family history, lesion location, and dMMR patterns. The CRC cohort with IHC-MSH6 negative alone shows the highest prevalence rate of LS. MLH1 was detected with the most germline variants. The mutational hotspot region of MLH1 is Exon 8, Exon 4 for MSH6, Exon 11 for PMS2, and Exon 7 for MSH2. Several germline hotspots were labeled on each MMR gene sequence by fixed-size bin analysis. In addition, some variants were novel discovered based on the presence or absence of the RS number and allele frequency record.

Our study classified the clinicopathological features between sporadic CRC patients and LS patients. More importantly, the molecular profiling of the MMR gene germline variant was experimentally elucidated, which deepens the knowledge of MMR genes and provides a new perspective for the subsequent studies on the landscape of germline variants of Chinese LS patients.