Causes of DNA mismatch repair deficiency in sebaceous skin lesions demonstrating loss of MLH1 protein expression: constitutional over somatic MLH1 promoter methylation.

Approximately 30% of sebaceous skin lesions (or sebaceous neoplasia) demonstrate DNA mismatch repair (MMR)-deficiency. MMR-deficiency can be caused by Lynch syndrome, resulting from germline pathogenic variants in the DNA MMR genes MLH1, MSH2, MSH6 and PMS2, but other causes include somatic MLH1 gene promoter hypermethylation, constitutional MLH1 gene promoter hypermethylation (MLH1 epimutation), or biallelic somatic MMR gene mutations. In colorectal (CRCs) and endometrial cancers (ECs), tumour MMR-deficiency showing loss of MLH1 and PMS2 protein expression (MLH1/PMS2-deficiency) is predominantly caused by somatic MLH1 hypermethylation, however, it is not clear if somatic MLH1 hypermethylation is a cause of MLH1/PMS2-deficiency in sebaceous neoplasia. This study investigated the causes of MLH1/PMS2-deficiency in 28 cases with sebaceous neoplasia. Germline pathogenic variants in MLH1 were identified in 11 of 28 cases. Of the remaining 17 non-Lynch syndrome cases, two (11.8%) were positive for MLH1 hypermethylation in blood-derived DNA (constitutional MLH1 epimutations). The corresponding sebaceous tissue of these two cases also showed MLH1 hypermethylation. None of the other eight cases with sufficient sebaceous tissue-derived DNA for testing showed somatic MLH1 hypermethylation. Multi-gene panel testing of sebaceous tissue and matched blood-derived DNA identified four cases with biallelic somatic MLH1 mutations as the cause of MLH1/PMS2-deficiency. No cause of MLH1/PMS2-deficiency could be identified in one case. This study demonstrates that biallelic somatic MLH1 mutations and constitutional MLH1 epimutations underlie MLH1/PMS2-deficiency in sebaceous neoplasms after excluding Lynch syndrome. Unlike CRCs and ECs, somatic MLH1 hypermethylation was not identified suggesting it is not a common cause of MLH1/PMS2-deficiency in sebaceous neoplasia.