Clinicopathological features of mismatch repair protein expression patterns in colorectal cancer

Microsatellite instability (MSI) is reflective of a deficient mismatch repair (dMMR) system, which is mostly associated with the methylation of mismatch repair (MMR) genes and BRAF mutations in sporadic colorectal cancers (CRCs). We performed a retrospective study to analyze the clinicopathological features of dMMR CRCs and their association with the BRAF V600E mutation. The incidence of dMMR CRCs in our cohort was 7.4 % (118/1603). Immunohistochemistry (IHC) revealed four common dMMR IHC patterns in 116 dMMR CRCs from 110 patients. dMMR type 1 (MLH1-/PMS2-) CRCs were the most frequent pattern, usually showing typical proximal location and MSI histology. The BRAF V600E mutation was almost exclusively observed in dMMR type 1 (32 of 72) and dMMR type 2 (PMSonly, 7 of 18) CRCs (p = 0.001). Patients with dMMR type 3 (MSH2-/MSH6-) CRCs were usually diagnosed at younger ages (p < 0.001) and had the strongest family history of Lynch syndrome-associated tumors (p = 0.002). dMMR type 3 CRCs frequently presented at advanced stages (p = 0.005) with perineural invasion (p = 0.021). We also found a significant positive association of dMMR type 1 and type 3 with advanced stages of CRC, whereas dMMR types 2 and 4 (MSH6- only) were usually diagnosed at early stages of CRC (p < 0.001). In conclusion, BRAF V600E mutations almost exclusively occurred in dMMR type 1 and 2 CRCs. Patterns of MMR protein expression display distinct associations with tumor staging and age at diagnosis.

Automated summary

Microsatellite instability (MSI) in colorectal cancers (CRCs) is associated with mismatch repair system deficiencies, particularly due to methylation of MMR genes and BRAF mutations. Different patterns of dMMR were found to be associated with specific clinicopathological features, with BRAF V600E mutations predominantly occurring in certain types. The expression patterns of MMR proteins also showed distinct associations with tumor staging and age at diagnosis.