Frequency and Molecular Characteristics of Mismatch Repair-deficient Status among Multiple Synchronous Colorectal...

Mismatch repair (MMR)-deficient (dMMR) colorectal cancer (CRC) have been largely categorized into three subtypes: MLH1-methylated, Lynch syndrome (LS)-associated, and Lynch-like syndrome (LLS)-associated. No studies have examined the prevalence and subtypes of synchronously diagnosed dMMR CRCs in detail. Therefore, this study aimed to examine the frequency and molecular characteristics of the dMMR status among multiple synchronous CRCs to clarify the clinical significance of identifying patients with such tumors.

Immunohistochemistry (IHC) of MMR proteins (MLH1, MSH2, MSH6, and PMS2) was performed for surgically and endoscopically resected (in conjunction with surgical resection) lesions from consecutive patients with initially diagnosed multiple synchronous CRCs between July 2014 and June 2020. When necessary, MLH1-methylation analysis and testing of germline and somatic MMR genes were performed.

In total, 133 patients (33 females) had 309 lesions. The combinations of synchronous tumor sites were the left-sided colon/rectum only (n=67, 50.4%), both the right-sided colon and left-sided colon/rectum (n=42, 31.6%), and the right-sided colon only (n=24, 18.0%). IHC showed a loss of expression of at least one MMR protein in 10 (7.5%) of 133 patients and 17 (5.5%) of 309 lesions. Molecular analysis revealed that these 10 patients were categorized as having MLH1-methylated (n=5, 3.8% of all patients), LS-associated (n=4, 3.0%), or LLS-associated (n=1, 0.8%) CRC.

Our data will be useful for genetic counseling in patients with synchronous CRCs suspected of having LS. Screening for LS using IHC for MMR proteins in individuals with multiple synchronous CRCs is an effective approach.