Microsatellite instability in aberrant crypt foci from patients without concurrent colon cancer

Abstract

Aberrant crypt foci (ACF) are microscopic surface abnormalities that are putative precursors to colorectal cancer (CRC). ACF exhibit similar histological and molecular abnormalities to adenomas and CRC and potentially represent useful biomarkers of cancer risk. Microsatellite instability (MSI) is one molecular abnormality identified in concurrent ACF from CRC patients that may indicate a risk for progression. To determine if MSI can be detected in ACF from cancer-free subjects, we examined 45 ACF from 20 subjects undergoing colonoscopies. The group included 12 patients at elevated risk for CRC based on family history of CRC or personal history of CRC or advanced adenoma and 8 patients with no known risk factors. ACF were identified using close-focus magnifying chromendoscopy and collected by biopsy in situ. Genomic DNA was prepared from ACF and adjacent normal colonic epithelium isolated by laser capture microdissection and analyzed for MSI. MSI was identified in at least one marker from 9 of 30 (30%) lesions from patients at elevated risk for CRC and in 2 of 15 (13%) lesions from average risk patients. Using methylation-specific PCR analysis, we also examined the ACF for promoter hypermethylation of the DNA repair genes hMLH1 and MGMT and found moderate changes (8/39 and 3/32, respectively). Although we found only a limited relationship between hMLH1 hypermethylation and MSI, all the lesions with MGMT hypermethylation displayed an MSI-low phenotype. These lesions may be precursors to MSI-low CRC, providing a potential early biomarker to assess the effects of cancer prevention strategies.