MLH1–93 G/a polymorphism is associated with MLH1 promoter methylation and protein loss in dysplastic sessile serrated adenomas with BRAFV600E mutation
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 remai...
Main Authors: | , , , , , , , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
BMC
2018-01-01
|
Series: | BMC Cancer |
Subjects: | |
Online Access: | http://link.springer.com/article/10.1186/s12885-017-3946-5 |
id |
doaj-bb82f40e1840403ba62324331328b137 |
---|---|
record_format |
Article |
spelling |
doaj-bb82f40e1840403ba62324331328b1372020-11-25T00:30:25ZengBMCBMC Cancer1471-24072018-01-011811710.1186/s12885-017-3946-5MLH1–93 G/a polymorphism is associated with MLH1 promoter methylation and protein loss in dysplastic sessile serrated adenomas with BRAFV600E mutationLochlan J. Fennell0Saara Jamieson1Diane McKeone2Tracie Corish3Megan Rohdmann4Tori Furner5Mark Bettington6Cheng Liu7Futoshi Kawamata8Catherine Bond9Jolieke Van De Pols10Barbara Leggett11Vicki Whitehall12Conjoint Gastroenterology Laboratory, QIMR Berghofer Medical Research InstituteConjoint Gastroenterology Laboratory, QIMR Berghofer Medical Research InstituteConjoint Gastroenterology Laboratory, QIMR Berghofer Medical Research InstituteConjoint Gastroenterology Laboratory, QIMR Berghofer Medical Research InstituteConjoint Gastroenterology Laboratory, QIMR Berghofer Medical Research InstituteConjoint Gastroenterology Laboratory, QIMR Berghofer Medical Research InstituteEnvoi Specialist PathologyConjoint Gastroenterology Laboratory, QIMR Berghofer Medical Research InstituteConjoint Gastroenterology Laboratory, QIMR Berghofer Medical Research InstituteConjoint Gastroenterology Laboratory, QIMR Berghofer Medical Research InstituteQueensland University of Technology, Faculty of HealthConjoint Gastroenterology Laboratory, QIMR Berghofer Medical Research InstituteConjoint Gastroenterology Laboratory, QIMR Berghofer Medical Research InstituteAbstract 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.http://link.springer.com/article/10.1186/s12885-017-3946-5Colorectal cancerBRAFMismatch repairSessile serrated adenoma, CpG Island Methylator phenotype |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
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 |
spellingShingle |
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 MLH1–93 G/a polymorphism is associated with MLH1 promoter methylation and protein loss in dysplastic sessile serrated adenomas with BRAFV600E mutation BMC Cancer Colorectal cancer BRAF Mismatch repair Sessile serrated adenoma, CpG Island Methylator phenotype |
author_facet |
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 |
author_sort |
Lochlan J. Fennell |
title |
MLH1–93 G/a polymorphism is associated with MLH1 promoter methylation and protein loss in dysplastic sessile serrated adenomas with BRAFV600E mutation |
title_short |
MLH1–93 G/a polymorphism is associated with MLH1 promoter methylation and protein loss in dysplastic sessile serrated adenomas with BRAFV600E mutation |
title_full |
MLH1–93 G/a polymorphism is associated with MLH1 promoter methylation and protein loss in dysplastic sessile serrated adenomas with BRAFV600E mutation |
title_fullStr |
MLH1–93 G/a polymorphism is associated with MLH1 promoter methylation and protein loss in dysplastic sessile serrated adenomas with BRAFV600E mutation |
title_full_unstemmed |
MLH1–93 G/a polymorphism is associated with MLH1 promoter methylation and protein loss in dysplastic sessile serrated adenomas with BRAFV600E mutation |
title_sort |
mlh1–93 g/a polymorphism is associated with mlh1 promoter methylation and protein loss in dysplastic sessile serrated adenomas with brafv600e mutation |
publisher |
BMC |
series |
BMC Cancer |
issn |
1471-2407 |
publishDate |
2018-01-01 |
description |
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. |
topic |
Colorectal cancer BRAF Mismatch repair Sessile serrated adenoma, CpG Island Methylator phenotype |
url |
http://link.springer.com/article/10.1186/s12885-017-3946-5 |
work_keys_str_mv |
AT lochlanjfennell mlh193gapolymorphismisassociatedwithmlh1promotermethylationandproteinlossindysplasticsessileserratedadenomaswithbrafv600emutation AT saarajamieson mlh193gapolymorphismisassociatedwithmlh1promotermethylationandproteinlossindysplasticsessileserratedadenomaswithbrafv600emutation AT dianemckeone mlh193gapolymorphismisassociatedwithmlh1promotermethylationandproteinlossindysplasticsessileserratedadenomaswithbrafv600emutation AT traciecorish mlh193gapolymorphismisassociatedwithmlh1promotermethylationandproteinlossindysplasticsessileserratedadenomaswithbrafv600emutation AT meganrohdmann mlh193gapolymorphismisassociatedwithmlh1promotermethylationandproteinlossindysplasticsessileserratedadenomaswithbrafv600emutation AT torifurner mlh193gapolymorphismisassociatedwithmlh1promotermethylationandproteinlossindysplasticsessileserratedadenomaswithbrafv600emutation AT markbettington mlh193gapolymorphismisassociatedwithmlh1promotermethylationandproteinlossindysplasticsessileserratedadenomaswithbrafv600emutation AT chengliu mlh193gapolymorphismisassociatedwithmlh1promotermethylationandproteinlossindysplasticsessileserratedadenomaswithbrafv600emutation AT futoshikawamata mlh193gapolymorphismisassociatedwithmlh1promotermethylationandproteinlossindysplasticsessileserratedadenomaswithbrafv600emutation AT catherinebond mlh193gapolymorphismisassociatedwithmlh1promotermethylationandproteinlossindysplasticsessileserratedadenomaswithbrafv600emutation AT joliekevandepols mlh193gapolymorphismisassociatedwithmlh1promotermethylationandproteinlossindysplasticsessileserratedadenomaswithbrafv600emutation AT barbaraleggett mlh193gapolymorphismisassociatedwithmlh1promotermethylationandproteinlossindysplasticsessileserratedadenomaswithbrafv600emutation AT vickiwhitehall mlh193gapolymorphismisassociatedwithmlh1promotermethylationandproteinlossindysplasticsessileserratedadenomaswithbrafv600emutation |
_version_ |
1725326750600134656 |