REDUCED BILE ACID-INDUCED APOPTOSIS IN NORMAL COLORECTAL MUCOSA - A POTENTIAL BIOLOGICAL MARKER FOR CANCER RISK

Dietary factors, including bile acids, are important in the causation of colorectal cancer (CRC). We have previously shown that in vitro exp osure of colorectal mucosal biopsies to low concentrations of bile aci ds produces apoptosis selectively in goblet cells. Apoptosis is an imp ortant mechanism for clearing DNA-damaged cells. Inhibition of apoptos is would result in increasing accumulation of DNA-damaged cells, resul ting in increased cancer risk. We compared the percentage of apoptosis induced by bile acids in mucosal biopsies from CRC patients with that of noncancer subjects. Mucosal biopsies from 15 to 20 cm from the ana l verge were incubated in 1 mM sodium deoxycholate, and the percentage of goblet cells undergoing apoptosis was quantitated. Seven patients with a history of CRC within the previous 5 years were compared with 1 8 noncancer subjects [4 neoplasia free and 14 with small (less than or equal to 9 mm) polyps only]. The CRC patients had a significantly low er percentage of apoptosis than noncancer subjects; the mean for CRC w as 10.7% (range, 0.9-26%) and for noncancer subjects was 55.9% (range, 20.3-71%; P less than or equal to 0.001). Two other noncancer patient s had very high-risk lesions, i.e., large villous adenomas and multipl e large polyps during several colonoscopies over the previous 6 years. Their percentage of apoptosis was in the cancer range, i.e., 6.2 and 10.7%. Reduced apoptotic ability may imply increased cancer risk. By a pplying a quantitative bile acid-induced apoptosis assay to colorectal mucosal biopsies, the percentage of apoptosis was found to be signifi cantly reduced in CRC patients. This assay may prove to be a useful in termediate biological marker for identifying subjects at increased ris k of cancer.