Lynch Syndrome (LS) is an autosomal dominant disorder caused by germline mutations in any of the mismatch repair genes (MMR): MLH1, MSH2, MSH6 or PMS2. Although colorectal cancer is the most common tumour associated to the syndrome, the risk of endometrial cancer may be higher in some mutation carriers and be diagnosed at an earlier age. Therefore, identifying LS among endometrial cancer patients is crucial to identify LS and also help preventing colorectal cancer as a potential secondary malignancy.
Patients with endometrial cancer diagnosed less than 60 years of age were prospectively enrolled and their personal and family history was collected. All cases were evaluated for microsatellite instability (MSI), MMR protein expression by immunohistochemistry (IHC) and hypermethylation of the MLH1 promoter (if lack of expression of MLH1 was found). Patients with MSI and/or abnormal immunohistochemical staining were tested for germline mutations by DNA sequencing and large rearrangements analysis, once hypermethylation of the MLH1 promoter was ruled out.
76 endometrial cancer patients were included, median age was 53 years (range 33-60 years). 27 patients (35%) had molecular findings suggestive of Lynch syndrome and were referred for germline genetic testing. 14 patients (18%) with LS due to a germline mutation in the MMR genes were detected: two patients with a MLH1 mutation, six patients with a MSH2 mutation and six patients with a MSH6 mutation. Despite mutation carriers met classical clinical criteria more frequently than no carriers (p = 0.001), 29% of mutation carriers did not fulfil them. IHC combined with MLH1 promoter hypermethylation analysis was the most efficient method to select patients for genetic testing with sensitivity of 100%, specificity of 81% and positive predictive value of 54%.
Almost one out five patients with endometrial cancer less than 60 years is carrier of a germline mutation in LS. This justifies referring these patients for genetic counselling and testing. The best screening method to select patients is the combination of IHC with MLH1 promoter hypermethylation for those cases with lack of expression of MLH1.
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All authors have declared no conflicts of interest.