title: The mechanism of microsatellite instability is different in synchronous and metachronous colorectal cancer.
abstract: MLH1 promoter hypermethylation has been described as the primary mechanism for high-frequency microsatellite instability (MSI-H) in sporadic colorectal cancers (CRCs). The underlying molecular mechanism for microsatellite instability (MSI) in synchronous and metachronous CRCs is not well described. A total of 33 metachronous CRC patients and 77 synchronous CRC patients were identified from 2884 consecutive patients undergoing cancer surgery in an academic center. Evaluable tumors were tested for MSI, immunohistochemistry for MLH1 and MSH2 protein expression, and hypermethylation of the MLH1 promoter. MSI-H tumors were found in 12 (36%) metachronous CRC patients and 29 (38%) synchronous CRC patients. MSI-H metachronous CRC patients were younger at index cancer diagnosis (64 vs. 76 years, P=0.01) and more often were diagnosed before 50 years of age (4 of 12 vs. 0 of 29, P=0.005). Loss of MLH1 expression associated with promoter hypermethylation was common in all patients, although more common in MSI-H synchronous patients (50% metachronous vs. 83% synchronous, P=0.03). Overall, MLH1 promoter hypermethylation was seen in 7 of 17 (41%) metachronous and 44 of 54 (81%) synchronous MSI-H CRCs tested (P=0.004). Although MSI occurred with equal frequency among patients with synchronous and metachronous CRCs, the underlying mechanism for MSI was different. Observed differences in MLH1 promoter hypermethylation and patient characteristics suggest most MSI-H synchronous CRCs in our population were sporadic in origin. In contrast, more MSI-H metachronous CRCs were associated with patient and tumor characteristics suggestive of underlying hereditary nonpolyposis CRC.
authors.affiliation: Division of Gastroenterology and Colorectal Cancer Prevention Center, Department of Medicine, University of California San Francisco, California, USA.
authors.forename: Fernando S
authors.initials: FS
authors.lastname: Velayos
authors.forename: Suk-Hwan
authors.initials: SH
authors.lastname: Lee
authors.forename: Hongming
authors.initials: H
authors.lastname: Qiu
authors.forename: Sharon
authors.initials: S
authors.lastname: Dykes
authors.forename: Raymond
authors.initials: R
authors.lastname: Yiu
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: Terdiman
authors.forename: Julio
authors.initials: J
authors.lastname: Garcia-Aguilar
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001483:Base Sequence; D002352:Carrier Proteins; D015331:Cohort Studies; D015179:Colorectal Neoplasms / Q000175:diagnosis / Q000235:genetics*; D019175:DNA Methylation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease; D042822:Genomic Instability; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D008969:Molecular Sequence Data; D000070957:MutL Protein Homolog 1; D009363:Neoplasm Proteins / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D016133:Polymerase Chain Reaction; D011336:Probability; D011401:Promoter Regions, Genetic; D018570:Risk Assessment; D012680:Sensitivity and Specificity
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C501486:MLH1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D000070957:MutL Protein Homolog 1