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More on Stool DNA Tests for Colorectal Cancer and Adenomas

Investigators present clinical results of new fecal DNA assays for detecting colorectal cancer.

Fecal DNA testing continues to emerge as a promising, noninvasive strategy for detecting colorectal neoplasia. These investigators present 2 reports on the clinical results of new stool DNA assays.

In one study, the investigators tested for adenomatous polyposis coli (APC) gene mutations in stool samples from 28 patients with nonmetastatic colorectal cancers, 18 patients with adenomas (1 cm), and 28 control patients without neoplastic disease. The authors developed methods to purify DNA templates that were large enough to allow them to perform PCR on a substantial region of the APC gene; they also developed a modified protein-truncation test (which they call digital-protein truncation) to overcome the large number of wild-type APC sequences in stool samples. This technology identified APC mutations in 57% of patients with neoplasms (95% CI, 41%-71%), including 61% of those with Dukes' stage B2 cancer and 50% of those with adenomas 1 cm. No control had a positive assay. In all 7 tested patients, mutations identified in their stool samples were identical with those identified in their tumors. The digital-protein-truncation assay correlated with DNA sequencing of APC gene mutations in stool samples from all 26 patients with positive tests. Among the 12 patients with cancer who had negative stool tests, APC mutations were identified in the tumors of 6.

In the second study, the authors evaluated detection of proximal cancers by identification of mutated BAT26 alleles (well known as the best single marker of microsatellite instability) in stool DNA from 46 patients with cancer between the cecum and hepatic flexure, 19 patients with adenomas in this location, and 69 patients with normal colonoscopies. Colorectal cancers with microsatellite instability are found almost entirely in the proximal colon. None of the patients had hereditary nonpolyposis colorectal cancer. BAT26 alterations were identified in 18 of the 46 patients with cancer, and identical mutations were identified in fecal DNA of 17 of the 18 patients with BAT26 mutations in the tumor (tumors from 57 patients were tested for BAT26 alterations). None of the 19 patients with adenomas, including 5 with adenomas 1 cm, had BAT26 mutations detected in fecal DNA. None of the 69 patients with negative colonoscopies exhibited BAT26 mutations.

Comment: The same university laboratory conducted both studies, and some investigators are employed by or involved with Exact Sciences, the company that will likely market the first multitarget stool DNA assay for sporadic colorectal cancers. Compared with the multitarget assay, the assays reported in these 2 new studies could be considered second-generation. Both assays had remarkable specificity (100%) -- specificity always has been an issue with fecal occult blood testing and with radiographic methods of colorectal cancer screening. The authors suggest that BAT26 testing could be a useful adjunct to sigmoidoscopy, but the large number of sporadic proximal colon cancers without BAT26 mutations and the lack of sensitivity for adenomas suggest that BAT26 is not, by itself, a sensitive screening test for sporadic proximal colorectal neoplasia. The real potential for stool DNA assays is in simultaneous testing for multiple mutations, combined with the potential for remarkable specificity. Soon, we will have performance data on the first-generation Exact assay in screening populations, and, then, we will be able to estimate its cost-effectiveness.

— Douglas K. Rex, MD

Published in Journal Watch Gastroenterology March 12, 2002

Citation(s):

Traverso G et al. Detection of APC mutations in fecal DNA from patients with colorectal tumors. N Engl J Med 2002 Jan 31; 346:311-20.

• Original article (Subscription may be required)
• Medline abstract (Free)

Traverso G et al. Detection of proximal colorectal cancers through analysis of faecal DNA. Lancet 2002 Feb 2; 359:403-4.

• Medline abstract (Free)