title: Molecular characterization of MSI-H colorectal cancer by MLHI promoter methylation, immunohistochemistry, and mismatch repair germline mutation screening.
abstract: Microsatellite instability (MSI) occurs in 10% to 20% of colorectal cancers (CRC) and has been attributed to both MLH1 promoter hypermethylation and germline mutation in the mismatch repair (MMR) genes. We present results from a large population- and clinic-based study of MLH1 methylation, immunohistochemistry, and MMR germline mutations that enabled us to (a) estimate the prevalence of MMR germline mutations and MLH1 methylation among MSI-H cases and help us understand if all MSI-H CRC is explained by these mechanisms and (b) estimate the associations between MLH1 methylation and sex, age, and tumor location within the colon. MLH1 methylation was measured in 1,061 population-based and 172 clinic-based cases of CRC. Overall, we observed MLH1 methylation in 60% of population-based MSI-H cases and in 13% of clinic-based MSI-H cases. Within the population-based cases with MMR mutation screening and conclusive immunohistochemistry results, we identified a molecular event in MMR in 91% of MSI-H cases: 54% had MLH1 methylation, 14% had a germline mutation in a MMR gene, and 23% had immunohistochemistry evidence for loss of a MMR protein. We observed a striking age difference, with the prevalence of a MMR germline mutation more than 4-fold lower and the prevalence of MLH1 methylation more than 4-fold higher in cases diagnosed after the age of 50 years than in cases diagnosed before that age. We also determined that female sex is an independent predictor of MLH1 methylation within the MSI-H subgroup. These results reinforce the importance of distinguishing between the underlying causes of MSI in studies of etiology and prognosis.
authors.affiliation: Department of Preventive Medicine, University of Southern California, Los Angeles, CA 90033-9176, USA.
authors.forename: Jenny N
authors.initials: JN
authors.lastname: Poynter
authors.forename: Kimberly D
authors.initials: KD
authors.lastname: Siegmund
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Weisenberger
authors.forename: Tiffany I
authors.initials: TI
authors.lastname: Long
authors.forename: Stephen N
authors.initials: SN
authors.lastname: Thibodeau
authors.forename: Noralane
authors.initials: N
authors.lastname: Lindor
authors.forename: Joanne
authors.initials: J
authors.lastname: Young
authors.forename: Mark A
authors.initials: MA
authors.lastname: Jenkins
authors.forename: John L
authors.initials: JL
authors.lastname: Hopper
authors.forename: John A
authors.initials: JA
authors.lastname: Baron
authors.forename: Dan
authors.initials: D
authors.lastname: Buchanan
authors.forename: Graham
authors.initials: G
authors.lastname: Casey
authors.forename: A Joan
authors.initials: AJ
authors.lastname: Levine
authors.forename: Loïc
authors.initials: L
authors.lastname: Le Marchand
authors.forename: Steven
authors.initials: S
authors.lastname: Gallinger
authors.forename: Bharati
authors.initials: B
authors.lastname: Bapat
authors.forename: John D
authors.initials: JD
authors.lastname: Potter
authors.forename: Polly A
authors.initials: PA
authors.lastname: Newcomb
authors.forename: Robert W
authors.initials: RW
authors.lastname: Haile
authors.forename: Peter W
authors.initials: PW
authors.lastname: Laird
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000368:Aged; D016009:Chi-Square Distribution; D015179:Colorectal Neoplasms / Q000235:genetics*; D019175:DNA Methylation; D053843:DNA Mismatch Repair; D005260:Female; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006801:Humans; D007150:Immunohistochemistry; D016015:Logistic Models; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D009687:Nuclear Proteins / Q000235:genetics*; D015995:Prevalence; D012042:Registries
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C501486:MLH1 protein, human; D009687:Nuclear Proteins; D000070957:MutL Protein Homolog 1