Mismatch repair protein "nonclassic expression loss" pattern in colorectal cancer: an important staining pattern that...

The expression of mismatch repair (MMR) proteins does not follow a simple "intact" or "loss" pattern. Rather, "nonclassic loss" patterns can be presented.

We retrospectively collected data on 569 patients with colorectal cancer. According to the MMR protein expression patterns of intact expression (pattern A), complete absence (pattern B), regional/patchy loss of 10% or more tumor cells (pattern C), and positive signals of 10% or more tumor cells weaker than control cells (pattern D), the patients were divided into 3 groups: MMR proficiency (all 3 MMR proteins were pattern A), classic MMR deficiency (proteins exhibiting pattern B), and nonclassic possible MMR deficiency (regardless of the presence or absence of pattern B, with at least 1 protein exhibiting pattern C or D).

Patients with both complete and nonclassic loss patterns had microsatellite instability high status (17/17 [100.00%]); 64.71% (11/17) had MLH1/PMS2 co-complete loss combined with MSH6 regional loss. Microdissection of the MSH6 loss region and next-generation sequencing detection were performed, and pathogenic mutations were found in 6 patients (6/7 [85.71%]), 83.33% of whom had somatic mutations in the MSH6 gene. Among the 26 patients with only a nonclassic loss pattern, 8 (30.77%) had microsatellite instability high status, of whom 7 (26.92%) had MMR gene mutations and 3.85% probably had pathogenic germline heterozygous mutations.

Microsatellite instability high status (30.77%) and Lynch syndrome (3.85%) can occur in patients with only nonclassic loss of MMR proteins (without the B pattern). It is necessary to deepen our understanding of nonclassical MMR expression patterns to avoid missing patients with microsatellite instability high status and Lynch syndrome.