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Open Access 01-12-2018 | Research article

MLH1–93 G/a polymorphism is associated with MLH1 promoter methylation and protein loss in dysplastic sessile serrated adenomas with BRAF^V600E mutation

Authors: Lochlan J. Fennell, Saara Jamieson, Diane McKeone, Tracie Corish, Megan Rohdmann, Tori Furner, Mark Bettington, Cheng Liu, Futoshi Kawamata, Catherine Bond, Jolieke Van De Pols, Barbara Leggett, Vicki Whitehall

Published in: BMC Cancer | Issue 1/2018

Abstract

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.

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Title: MLH1–93 G/a polymorphism is associated with MLH1 promoter methylation and protein loss in dysplastic sessile serrated adenomas with BRAFV600E mutation
Authors: Lochlan J. Fennell
Saara Jamieson
Diane McKeone
Tracie Corish
Megan Rohdmann
Tori Furner
Mark Bettington
Cheng Liu
Futoshi Kawamata
Catherine Bond
Jolieke Van De Pols
Barbara Leggett
Vicki Whitehall
Publication date: 01-12-2018
Publisher: BioMed Central
Published in: BMC Cancer / Issue 1/2018
Electronic ISSN: 1471-2407
DOI: https://doi.org/10.1186/s12885-017-3946-5

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