Lenhard K et al. (2005) Analysis of promoter methylation in stool: a novel method for the detection of colorectal cancer. Clin Gastroenterol Hepatol 3: 142–149

Numerous diagnostic markers have been evaluated in ongoing efforts to reduce the considerable morbidity and mortality associated with colorectal cancer. Studies of genetic markers have so far centered on mutations in oncogenes, tumor-suppressor genes and microsatellite markers. Lenhard and co-workers have extended the search to include epigenetic factors; their recent paper describes the use of promoter methylation as a stool-based DNA marker.

The promoter of the HIC1 (hypermethylated in cancer 1) gene, a tumor-suppressor gene located on chromosome 17p13.3, is frequently methylated in colorectal cancer but not in normal tissue. Using methylation-specific polymerase chain reaction, Lenhard et al. studied HIC1 promoter methylation status in DNA from stool samples provided by patients with colorectal cancer (n = 26) or adenomatous polyps of ≥1 cm (n = 13). Samples from healthy individuals (n = 32), patients with hyperplastic polyps (n = 9) or chronic inflammatory bowel disease (n = 9) were used as controls. All the stool samples were also analyzed using the established screening method of fecal occult blood testing.

Sufficient DNA of adequate quality for methylation-specific polymerase chain reaction analysis was isolated from the majority (97%) of stool samples. Eleven patients (42%) with colorectal cancer tested positive for methylated HIC1 DNA (95% CI 23%–63%). In addition, samples from 31% of patients with adenomas gave a positive result. None of the samples from healthy controls revealed the presence of methylated HIC1 DNA, and, except in the case of one patient with ulcerative colitis, samples from patients with non-neoplastic disease all generated negative results. The HIC1 assay, therefore, was highly specific (98%, 95% CI 92%–100%). Compared with fecal occult blood testing, the new assay was both more sensitive and more specific for the detection of colorectal cancer in this study, although these differences were not statistically significant. Combining the two methods generated a detection rate of 65% (95% CI 44%–83%).

Lenhard et al. propose that analysis of HIC1 methylation, along with a small number of similarly sensitive and specific markers, might provide an accurate stool-based method for use in colorectal cancer screening.