Aberrant crypt foci: detection, gene abnormalities, and clinical usefulness

Area of Science:

• Gastroenterology
• Oncology
• Molecular Biology

Background:

• Aberrant crypt foci (ACF) are identified as precursor lesions in human colorectal carcinogenesis.
• Magnifying endoscopy enables analysis of ACF number, size, and dysplastic features.

Purpose of the Study:

• To investigate the role of ACF as precursor lesions in the human adenoma-carcinoma sequence.
• To analyze molecular alterations (K-ras, APC mutations) in sporadic and familial adenomatous polyposis (FAP) ACF.
• To explore ACF apoptosis resistance and its association with glutathione S-transferase P1-1 (GSTP1-1).
• To evaluate ACF as a target for chemoprevention strategies.

Main Methods:

• Identification and analysis of ACF in human colonic mucosa using magnifying endoscopy.
• Mutation analysis of K-ras and APC genes in ACF.
• Assessment of apoptosis resistance and GSTP1-1 expression in ACF.
• Clinical trial of sulindac for ACF reduction.

Main Results:

• Dysplastic ACF are strongly suggested as precursors in the human adenoma-carcinoma sequence.
• Sporadic ACF typically harbor K-ras mutations (APC negative), while FAP ACF show APC mutations (K-ras negative).
• ACF exhibit resistance to bile salt-induced apoptosis, linked to GSTP1-1 expression.
• Sulindac treatment significantly reduced ACF numbers in an open-label trial.

Conclusions:

• ACF, particularly dysplastic ACF, are significant precursors to human colorectal cancer.
• Distinct molecular profiles of sporadic and FAP ACF suggest divergent carcinogenesis mechanisms.
• ACF apoptosis resistance and GSTP1-1 expression are key factors in their development.
• ACF serve as a viable target for chemopreventive interventions, as demonstrated by sulindac efficacy.