Genomic loss of MLH1/PMS2 loci defines a mismatch repair deficient subgroup in monomorphic epitheliotropic intestinal T-cell lymphoma.

Primary intestinal T-cell lymphomas (ITCLs), comprising enteropathy-associated T-cell lymphoma (EATL) and monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL), are rare aggressive tumors. The role of DNA mismatch repair (MMR) deficiency (dMMR) and microsatellite instability (MSI) in the development of ITCLs remains largely unexplored. Here, we investigated the incidence, molecular mechanisms and clinical relevance of dMMR/MSI in 86 ITCLs (30 EATLs, 56 MEITLs) using whole-exome sequencing, PCR-based MSI testing, DNA methylation profiling, and immunohistochemistry for MLH1, MSH2, MSH6 and PMS2. MMR deficiency was detected in 3 of 53 MEITLs (6%) but in none of the EATLs. dMMR MEITLs showed the highest tumor mutational burden (8.3-17.1 mutations/Mb), compared to median TMBs of 1.9 in MEITL and 2.4 in EATL. The complete loss of MLH1/PMS2 expression in two MSI-high tumors and isolated PMS2 loss in the third case were all associated with biallelic deletions of the affected loci. Notably, MLH1 deletions significantly co‑occurred with SETD2 deletions (p = 0.001), the latter representing a major driver of MEITL tumorigenesis. dMMR MEITLs lacked distinctive clinicopathologic features. These findings indicate that dMMR/MSI occurs in a subset of MEITLs probably during tumor progression, rather than being an initiating driver event, and provide a biological rationale to explore the efficacy of immune checkpoint inhibitors in some of this unfavorable subtype of ITCL.