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

Lochlan 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

doi:10.1186/s12885-017-3946-5

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

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

Lochlan Fennell, Saara Jamieson, Diane McKeone, Tracie Corish, Megan Rohdmann, Tori Furner, Mark Bettington, Cheng Liu, Futoshi Kawamata, Catherine Bond, …

BMC Cancer, Vol.18(1), pp.1-7

2018

DOI: https://doi.org/10.1186/s12885-017-3946-5

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Abstract

BRAF

colorectal cancer

mismatch repair

sessile serrated adenoma

CpG Island Methylator phenotype

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 Fennell (Author) - University of the Sunshine Coast - Faculty of Science, Health, Education and Engineering
Saara Jamieson (Author) - Queensland Medical Institute of Research Berghofer
Diane McKeone (Author) - Queensland Medical Institute of Research Berghofer
Tracie Corish (Author) - Queensland Medical Institute of Research Berghofer
Megan Rohdmann (Author) - Queensland Medical Institute of Research Berghofer
Tori Furner (Author) - Queensland Medical Institute of Research Berghofer
Mark Bettington (Author) - Envoi Specialist Pathology
Cheng Liu (Author) - Queensland Medical Institute of Research Berghofer
Futoshi Kawamata (Author) - Queensland Medical Institute of Research Berghofer
Catherine Bond (Author) - Queensland Medical Institute of Research Berghofer
Jolieke Van De Pols (Author) - Queensland University of Technology
Barbara Leggett (Author) - Queensland Medical Institute of Research Berghofer
Vicki Whitehall (Author) - Queensland Medical Institute of Research Berghofer
Publication details: BMC Cancer, Vol.18(1), pp.1-7
Publisher: BioMed Central Ltd.
Date published: 2018
DOI: 10.1186/s12885-017-3946-5
ISSN: 1471-2407
Copyright note: Copyright © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Organisation Unit: School of Health - Biomedicine; School of Health and Sport Sciences - Legacy; School of Health and Behavioural Sciences - Legacy
Language: English
Record Identifier: 99450536802621
Output Type: Journal article

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