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Background  Sessile serrated adenomas with  BRAF  mutation progress rapidly to cancer following the development of dysplasia (SSAD). Approximately 75% of SSADs methylate the mismatch repair gene  MLH1 , develop mismatch repair deficiency and the resultant cancers have a good prognosis. The remaining SSADs and  BRAF  mutant traditional serrated adenomas (TSA) develop into microsatellite stable cancers with a poor prognosis. The reason for this dichotomy is unknown. In this study, we assessed the genotypic frequency of the  MLH1– 93 polymorphism rs1800734 in SSADs and TSAs to determine if the uncommon variant A allele predisposes to  MLH1  promoter hypermethylation.    Methods  We performed genotyping for the  MLH1– 93 polymorphism, quantitative methylation specific PCR, and MLH1 immunohistochemistry on 124 SSAD, 128 TSA, 203  BRAF  mutant CRCs and 147 control subjects with normal colonoscopy.    Results  The minor A allele was significantly associated with a dose dependent increase in methylation at the  MLH1  promoter in SSADs ( p  = 0.022). The AA genotype was only observed in SSADs with MLH1 loss. The A allele was also overrepresented in BRAF mutant cancers with MLH1 loss. Only one of the TSAs showed loss of MLH1 and the overall genotype distribution in TSAs did not differ from controls.    Conclusions  The  MLH1 –93 AA genotype is significantly associated with promoter hypermethylation and MLH1 loss in the context of SSADs.  BRAF  mutant microsatellite stable colorectal cancers with the AA genotype most likely arise in TSAs since the A allele does not predispose to methylation in this context.

MLH1–93 G/a polymorphism is associated with MLH1 promoter methylation and protein loss in dysplastic sessile serrated adenomas with BRAFV600E mutation