Is it all Lynch Syndrome? An assessment of family history in individuals with mismatch repair deficient tumors

BACKGROUND & AIMS: Mismatch repair deficient (MMRD) colorectal (CRC) and endometrial (EC) cancers may be suggestive of Lynch syndrome (LS). LS can only be confirmed by positive germline testing. It is unclear if individuals with MMRD tumors but no identifiable cause (MMRD+/germline−) have LS. As LS is hereditary, individuals with LS are expected to have family histories of LS-related tumors. Our study compared the family histories of MMRD+/germline− CRC and/or EC patients to LS CRC and/or EC patients. METHODS: 253 individuals with an MMRD CRC or EC from one institution were included in analysis in 1 of 4 groups: LS, MMRD+/germline−, MMRD+/VUS, sporadic MSI-H (MMRD tumor with MLH1 promoter hypermethylation or BRAF mutation). Family histories were analyzed utilizing MMRpro and PREMM(1,2,6). Kruskal-Wallis tests were used to compare family history scores. RESULTS: MMRD+/germline− individuals had significantly lower median family history scores (MMRpro=8.1, PREMM(1,2,6)=7.3) than LS individuals (MMRpro=89.8, PREMM(1,2,6)=26.1, p<0.0001). CONCLUSION: MMRD+/germline− individuals have less suggestive family histories of LS than individuals with LS. These results imply that MMRD+/germline− individuals may not all have LS. This finding highlights the need to determine other causes of MMRD tumors so that these patients and their families can be accurately counseled regarding screening and management.