BACKGROUND: Although fecal occult-blood testing is the only available noninvasive screening method that reduces the risk of death from colorectal cancer, it has limited sensitivity. We compared an approach that identifies abnormal DNA in stool samples with the Hemoccult II fecal occult-blood test in average-risk, asymptomatic persons 50 years of age or older. METHODS: Eligible subjects submitted one stool specimen for DNA analysis, underwent standard Hemoccult II testing, and then underwent colonoscopy. Of 5486 subjects enrolled, 4404 completed all aspects of the study. A subgroup of 2507 subjects was analyzed, including all those with a diagnosis of invasive adenocarcinoma or advanced adenoma plus randomly chosen subjects with no polyps or minor polyps. The fecal DNA panel consisted of 21 mutations. RESULTS: The fecal DNA panel detected 16 of 31 invasive cancers, whereas Hemoccult II identified 4 of 31 (51.6 percent vs. 12.9 percent, P=0.003). The DNA panel detected 29 of 71 invasive cancers plus adenomas with high-grade dysplasia, whereas Hemoccult II identified 10 of 71 (40.8 percent vs. 14.1 percent, P<0.001). Among 418 subjects with advanced neoplasia (defined as a tubular adenoma at least 1 cm in diameter, a polyp with a villous histologic appearance, a polyp with high-grade dysplasia, or cancer), the DNA panel was positive in 76 (18.2 percent), whereas Hemoccult II was positive in 45 (10.8 percent). Specificity in subjects with negative findings on colonoscopy was 94.4 percent for the fecal DNA panel and 95.2 percent for Hemoccult II. CONCLUSIONS: Although the majority of neoplastic lesions identified by colonoscopy were not detected by either noninvasive test, the multitarget analysis of fecal DNA detected a greater proportion of important colorectal neoplasia than did Hemoccult II without compromising specificity. BACKGROUND: Although fecal occult-blood testing is the only available noninvasive screening method that reduces the risk of death from colorectal cancer, it has limited sensitivity. We compared an approach thatmers for DNA abuse testing with the Hemoccult II fecal occult-blood test in average-risk, asymptomatic persons 50 years of age or older. METHODS: Eligible subjects submitted one stool specimen for DNA analysis, underwent standard Hemoccult II testing, and then underwent colonoscopy. Of 5486 subjects enrolled, 4404 completed all aspects of the study. A femoral panel consisted of 21 mutations. RESULTS: The fecal DNA panel detected 16 of 31 invasive cancers, and Hemoccult II identified 4 of 31 (51.6 percent vs. 12.9 percent, P = 0.003). The DNA panel detected 29 of 71 invasive cancers plus adenomas with high-grade dysplasia, whereas Hemoccult II identified 10 of 71 (40.8 percent vs. 14.1 percent, P <0.001). All 418 subjects with advanced neoplasia (defined as a tubular adenoma at least 1 cm in diameter, a polyp with a villous histologic appearance, a polyp with high-grade dysplasia, or cancer), the DNA panel was positive in 76 (18.2 percent), while Hemoccult II was positive in 45 (10.8 percent). Specificity in subjects with negative findings on colonoscopy was 94.4 percent for the fecal DNA panel and 95.2 percent for Hemoccult II. CONCLUSIONS: Although the majority of neoplastic lesions identified by colonoscopy were not detected by either noninvasive test, the multitarget analysis of fecal DNA detected a greater proportion of important colorectal neoplasia than did Hemoccult II without compromising specificity.