Effect of co-inheritance of KMT2C germline mutations on the phenotype of MSI-L/MSS Lynch syndrome patients.

Abstract

e15085 Background: Germline mutations in MSH6 account for approximately 10–20% of all Lynch syndrome (LS) cases. MSH6 mutation carriers typically exhibit a distinct phenotype characterized by later-onset cancers and often an MSI-L/MSS phenotype which complicates clinical diagnosis and treatment. We present data of a family with a MSH6 in-frame exon skipping variant and MSI-L/MSS phenotype with extremely severe clinical presentation reminiscent of Amsterdam I - Lynch Syndrome with co-inheritance of a germline variant in the KMT2C gene. Methods: A family with 8 affected members over 3 generations with early onset invasive colorectal and endometrial cancer was referred for Lynch syndrome testing. dMMR/MSI and promotor methylation analyses were performed on tumor DNA from 3 members using standard methodology. WES of peripheral blood and/or tumor DNA was performed for detailed germline and molecular profiling including TMB and MSI analysis. Results: A germline c.457+1G > T splice site variant in the MSH6 gene and a likely pathogenic c.2573G > T p. Trp858Leu missense variant in the KMT2C gene were co-segregating in all affected members of the family. The MSH6 variant resulted in the production of a truncated transcript lacking exon 2 which was detected in all mutation carriers. The tumors displayed MSI-L/MSS (3.84% to 4.56% of unstable loci) and partial loss (heterogeneous) of the MSH6 protein expression, suggesting a potentially intact MMR activity. The TMB values ranged from 10.89 to 23.06 (6.33 to 14.6 non-synonymous TMB), being higher in samples with additional somatic pathogenic mutation in the MSH6 and/or KMT2C genes. Although the MSH6 variant affects the PWWP domain (critical for spatial and functional coordination of mismatch repair) the absence of a MSI-H phenotype linked to a high TMB in affected members indicates that this feature of the protein is not indispensable for the MMR function of this protein, and hence for the severe clinical presentation of the disease in this family. Somatic KMT2C variants are frequently detected in various tumors associated with higher MSI and TMB scores. KMT2C plays a critical role in chromatin remodeling, gene transcription regulation, and maintenance of genomic stability, and its inactivation was associated with tumor development. Although the variant we detected does not affect any of the domains with the known function of the protein, its absence from most databases and the co-segregation with the disease, suggest that it is a functional/pathogenic variant that can contribute to the cancer predisposition in this family. Conclusions: Our results suggest that germline mutations in the KMT2C gene may co-occur with MMR gene mutations in LS patients, especially with unusual phenotypes. In addition, the severity of the disease in this family suggests that the KMT2C mutations could be considered as additive or modifying factor, leading to a more aggressive cancer phenotype.