Clinicopathologic Risk Factor Distributions for MLH1 Promoter Region Methylation in CIMP-Positive Tumors.

Abstract

BACKGROUND:

The CpG island methylator phenotype (CIMP) is a major molecular pathway in colorectal cancer. Approximately 25% to 60% of CIMP tumors are microsatellite unstable (MSI-H) due to DNA hypermethylation of the MLH1 gene promoter. Our aim was to determine if the distributions of clinicopathologic factors in CIMP-positive tumors with MLH1 DNA methylation differed from those in CIMP-positive tumors without DNA methylation of MLH1.

METHODS:

We assessed the associations between age, sex, tumor-site, MSI status BRAF and KRAS mutations, and family colorectal cancer history with MLH1 methylation status in a large population-based sample of CIMP-positive colorectal cancers defined by a 5-marker panel using unconditional logistic regression to assess the odds of MLH1 methylation by study variables.

RESULTS:

Subjects with CIMP-positive tumors without MLH1 methylation were significantly younger, more likely to be male, and more likely to have distal colon or rectal primaries and the MSI-L phenotype. CIMP-positive MLH1-unmethylated tumors were significantly less likely than CIMP-positive MLH1-methylated tumors to harbor a BRAF V600E mutation and significantly more likely to harbor a KRAS mutation. MLH1 methylation was associated with significantly better overall survival (HR, 0.50; 95% confidence interval, 0.31-0.82).

CONCLUSIONS:

These data suggest that MLH1 methylation in CIMP-positive tumors is not a completely random event and implies that there are environmental or genetic determinants that modify the probability that MLH1 will become methylated during CIMP pathogenesis.

IMPACT:

MLH1 DNA methylation status should be taken into account in etiologic studies.

• Authors: A Joan Levine, Amanda I Phipps, John A Baron, Daniel D Buchanan, Dennis J Ahnen, Stacey A Cohen, Noralane M Lindor, Polly A Newcomb, Christophe Rosty, Robert W Haile, Peter W Laird, Daniel J Weisenberger
• Journal: Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology (Cancer Epidemiol Biomarkers Prev) Vol. 25 Issue 1 Pg. 68-75 (Jan 2016) ISSN: 1538-7755 [Electronic] United States
• PMID: 26512054 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural)
• Copyright: ©2015 American Association for Cancer Research.

Chemical References

• Adaptor Proteins, Signal Transducing
• Biomarkers, Tumor
• MLH1 protein, human
• Nuclear Proteins
• MutL Protein Homolog 1

Topics

• Adaptor Proteins, Signal Transducing (genetics)
• Aged
• Biomarkers, Tumor
• Case-Control Studies
• Colorectal Neoplasms (epidemiology, genetics, pathology)
• CpG Islands (genetics)
• DNA Methylation
• Female
• Follow-Up Studies
• Gene Expression Regulation, Neoplastic
• Humans
• Male
• Microsatellite Instability
• Middle Aged
• MutL Protein Homolog 1
• Mutation (genetics)
• Neoplasm Staging
• Nuclear Proteins (genetics)
• Prognosis
• Promoter Regions, Genetic (genetics)
• Risk Factors
• Survival Rate