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Endometrial tumour BRAF mutations and MLH1 promoter methylation as predictors of germline mismatch repair gene mutation status: a literature review.
Fam Cancer. 2014 Mar; 13(1):1-12.FC

Abstract

Colorectal cancer (CRC) that displays high microsatellite instability (MSI-H) can be caused by either germline mutations in mismatch repair (MMR) genes, or non-inherited transcriptional silencing of the MLH1 promoter. A correlation between MLH1 promoter methylation, specifically the 'C' region, and BRAF V600E status has been reported in CRC studies. Germline MMR mutations also greatly increase risk of endometrial cancer (EC), but no systematic review has been undertaken to determine if these tumour markers may be useful predictors of MMR mutation status in EC patients. Endometrial cancer cohorts meeting review inclusion criteria encompassed 2675 tumours from 20 studies for BRAF V600E, and 447 tumours from 11 studies for MLH1 methylation testing. BRAF V600E mutations were reported in 4/2675 (0.1%) endometrial tumours of unknown MMR mutation status, and there were 7/823 (0.9%) total sequence variants in exon 11 and 27/1012 (2.7%) in exon 15. Promoter MLH1 methylation was not observed in tumours from 32 MLH1 mutation carriers, or for 13 MSH2 or MSH6 mutation carriers. MMR mutation-negative individuals with tumour MLH1 and PMS2 IHC loss displayed MLH1 methylation in 48/51 (94%) of tumours. We have also detailed specific examples that show the importance of MLH1 promoter region, assay design, and quantification of methylation. This review shows that BRAF mutations occurs so infrequently in endometrial tumours they can be discounted as a useful marker for predicting MMR-negative mutation status, and further studies of endometrial cohorts with known MMR mutation status are necessary to quantify the utility of tumour MLH1 promoter methylation as a marker of negative germline MMR mutation status in EC patients.

Authors+Show Affiliations

Department of Genetics and Computational Biology, Queensland Institute of Medical Research, Herston, QLD, 4006, Australia.No affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Review
Systematic Review

Language

eng

PubMed ID

23880961

Citation

Metcalf, Alexander M., and Amanda B. Spurdle. "Endometrial Tumour BRAF Mutations and MLH1 Promoter Methylation as Predictors of Germline Mismatch Repair Gene Mutation Status: a Literature Review." Familial Cancer, vol. 13, no. 1, 2014, pp. 1-12.
Metcalf AM, Spurdle AB. Endometrial tumour BRAF mutations and MLH1 promoter methylation as predictors of germline mismatch repair gene mutation status: a literature review. Fam Cancer. 2014;13(1):1-12.
Metcalf, A. M., & Spurdle, A. B. (2014). Endometrial tumour BRAF mutations and MLH1 promoter methylation as predictors of germline mismatch repair gene mutation status: a literature review. Familial Cancer, 13(1), 1-12. https://doi.org/10.1007/s10689-013-9671-6
Metcalf AM, Spurdle AB. Endometrial Tumour BRAF Mutations and MLH1 Promoter Methylation as Predictors of Germline Mismatch Repair Gene Mutation Status: a Literature Review. Fam Cancer. 2014;13(1):1-12. PubMed PMID: 23880961.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Endometrial tumour BRAF mutations and MLH1 promoter methylation as predictors of germline mismatch repair gene mutation status: a literature review. AU - Metcalf,Alexander M, AU - Spurdle,Amanda B, PY - 2013/7/25/entrez PY - 2013/7/25/pubmed PY - 2015/5/12/medline SP - 1 EP - 12 JF - Familial cancer JO - Fam Cancer VL - 13 IS - 1 N2 - Colorectal cancer (CRC) that displays high microsatellite instability (MSI-H) can be caused by either germline mutations in mismatch repair (MMR) genes, or non-inherited transcriptional silencing of the MLH1 promoter. A correlation between MLH1 promoter methylation, specifically the 'C' region, and BRAF V600E status has been reported in CRC studies. Germline MMR mutations also greatly increase risk of endometrial cancer (EC), but no systematic review has been undertaken to determine if these tumour markers may be useful predictors of MMR mutation status in EC patients. Endometrial cancer cohorts meeting review inclusion criteria encompassed 2675 tumours from 20 studies for BRAF V600E, and 447 tumours from 11 studies for MLH1 methylation testing. BRAF V600E mutations were reported in 4/2675 (0.1%) endometrial tumours of unknown MMR mutation status, and there were 7/823 (0.9%) total sequence variants in exon 11 and 27/1012 (2.7%) in exon 15. Promoter MLH1 methylation was not observed in tumours from 32 MLH1 mutation carriers, or for 13 MSH2 or MSH6 mutation carriers. MMR mutation-negative individuals with tumour MLH1 and PMS2 IHC loss displayed MLH1 methylation in 48/51 (94%) of tumours. We have also detailed specific examples that show the importance of MLH1 promoter region, assay design, and quantification of methylation. This review shows that BRAF mutations occurs so infrequently in endometrial tumours they can be discounted as a useful marker for predicting MMR-negative mutation status, and further studies of endometrial cohorts with known MMR mutation status are necessary to quantify the utility of tumour MLH1 promoter methylation as a marker of negative germline MMR mutation status in EC patients. SN - 1573-7292 UR - https://www.unboundmedicine.com/medline/citation/23880961/Endometrial_tumour_BRAF_mutations_and_MLH1_promoter_methylation_as_predictors_of_germline_mismatch_repair_gene_mutation_status:_a_literature_review_ L2 - https://doi.org/10.1007/s10689-013-9671-6 DB - PRIME DP - Unbound Medicine ER -