MLH1 promoter hypermethylation: are you absolutely sure about the absence of MLH1 germline mutation? About a new case

AbstractLynch syndrome accounts for 3 –5% of colorectal cancers and is due to a germline mutation in one of the mismatch repair genesMLH1,MSH2,MSH6, andPMS2. Somatic hypermethylation of theMLH1 promoter is commonly associated to sporadic cases. Strategies have been developed to identify patients with Lynch Syndrome based on clinical findings, tumoral phenotype, family history and immunohistochemistry analysis. However, there still are some pitfalls in this strategy, possibly responsible for an underdiagnosis of Lynch syndrome. Here we report the case of a 37 years-old man presenting with two concomitant tumors located in the rectosigmoid and in the ileocecal angle. Both tumors were microsatellites instability-high (MSI-H) and showed a loss ofMLH1 andPMS2 protein expression, but only one hadMLH1 promoter hypermethylation. Constitutional analysis of mismatch repair genes could not be performed from a blood sample, because of the early death of the patient. However, tumoral tissue analyses revealed in both tumors a pathogenic variant in theMLH1 gene. Further analysis of the surrounding tumor-free tissue also showed the presence of this alteration of theMHL1 gene. Finally, the same pathogenic variant was present constitutionally in one of the siblings of the patient, confirming its hereditary nature. This new case of concomitant presence ofMLH1 promoter hypermethylation andMLH1 germline mutation demonstrates that the presence ofMLH1 promoter hypermethylation should not rule out...
Source: Familial Cancer - Category: Cancer & Oncology Source Type: research