title: 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.
  
  
  CONCLUSIONS
  MLH1 DNA methylation status should be taken into account in etiologic studies.
authors.affiliation: Stanford Cancer Institute, Stanford University, Palo Alto, California. ajoanlev@stanford.edu.
authors.forename: A Joan
authors.initials: AJ
authors.lastname: Levine
authors.affiliation: Epidemiology Department, University of Washington, Seattle, Washington. Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Amanda I
authors.initials: AI
authors.lastname: Phipps
authors.affiliation: Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
authors.forename: John A
authors.initials: JA
authors.lastname: Baron
authors.affiliation: Colorectal Oncogenomics Group, Genetic Epidemiology Laboratory, Centre for Epidemiology and Biostatistics and Department of Pathology, The University of Melbourne, Victoria, Australia.
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Buchanan
authors.affiliation: University of Colorado School of Medicine, Denver, Colorado.
authors.forename: Dennis J
authors.initials: DJ
authors.lastname: Ahnen
authors.affiliation: Division of Oncology, University of Washington, Seattle, Washington. Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Stacey A
authors.initials: SA
authors.lastname: Cohen
authors.affiliation: Clinical and Molecular Genetics, Department of Health Science Research, Mayo Clinic Arizona, Scottsdale, Arizona.
authors.forename: Noralane M
authors.initials: NM
authors.lastname: Lindor
authors.affiliation: Epidemiology Department, University of Washington, Seattle, Washington. Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Polly A
authors.initials: PA
authors.lastname: Newcomb
authors.affiliation: Envoi Pathology, Brisbane, QLD, The University of Melbourne, Melbourne, Australia. Department of Pathology, The University of Melbourne, Melbourne, Australia.
authors.forename: Christophe
authors.initials: C
authors.lastname: Rosty
authors.affiliation: Stanford Cancer Institute, Stanford University, Palo Alto, California.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Haile
authors.affiliation: Center for Epigenomics, Van Andel Research Institute, Grand Rapids, Michigan.
authors.forename: Peter W
authors.initials: PW
authors.lastname: Laird
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, California.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Weisenberger
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000368:Aged; D014408:Biomarkers, Tumor; D016022:Case-Control Studies; D015179:Colorectal Neoplasms / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology*; D018899:CpG Islands / Q000235:genetics*; D019175:DNA Methylation; D005260:Female; D005500:Follow-Up Studies; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D009154:Mutation / Q000235:genetics; D009367:Neoplasm Staging; D009687:Nuclear Proteins / Q000235:genetics*; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics*; D012307:Risk Factors; D015996:Survival Rate
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D014408:Biomarkers, Tumor; C501486:MLH1 protein, human; D009687:Nuclear Proteins; D000070957:MutL Protein Homolog 1