Correspondence

Fecal DNA Tests for Colorectal Cancer

N Engl J Med 2002; 346:1912-1913June 13, 2002

Article

To the Editor:

Although the development of the digital-protein-truncation test described by Traverso et al. (Jan. 31 issue)1 is a “tour de force,”2 the 0 percent false positive rate for the detection of mutations in the adenomatous polyposis coli (APC) gene — considered an “important component” of the study1 and noted in the news3 — will probably increase substantially when the spectrum of subjects4 is broadened to include the more than 30 percent of Americans with adenomas smaller than 1.0 cm, for two reasons. First, mutant APC is thought to occur very early in the development of an adenoma.5 Second, more than 50 percent (6 of 11) of the adenomas listed as exactly 1.0 cm in diameter in Table 1 of the report had mutant APC, a rate similar to that among larger adenomas and colorectal cancers. If, as many people believe, it is not important clinically to identify adenomas smaller than 1.0 cm, then these results should be counted as falsely positive when detected by testing for mutant APC. If they are important (and thus are truly positive results), then an assay for mutant APC is not a sensitive method of identifying them.

The potential of the digital-protein-truncation test to discriminate between small adenomas and large adenomas and colorectal cancers ultimately depends on the amounts of mutant APC made by each type of lesion and on whether the test can accurately quantitate those amounts. In any case, mutant APC needs to be studied in a broader spectrum of subjects before conclusions can be drawn about the assay's false positive rate.

David F. Ransohoff, M.D.
University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7080
ransohof@med.unc.edu

5 References

1. 1

   Traverso G, Shuber A, Levin B, et al. Detection of APC mutations in fecal DNA from patients with colorectal tumors. N Engl J Med 2002;346:311-320
   Full Text | Web of Science | Medline

2. 2

   Schwartz RS. A needle in a haystack of genes. N Engl J Med 2002;346:302-304
   Full Text | Web of Science | Medline

3. 3

   Wade N. New gene test may provide early signs of colon cancer. New York Times. January 31, 2002:A22.
   

4. 4

   Ransohoff DF, Feinstein AR. Problems of spectrum and bias in evaluating the efficacy of diagnostic tests. N Engl J Med 1978;299:926-930
   Full Text | Web of Science | Medline

5. 5

   Vogelstein B, Fearon ER, Hamilton SE, et al. Genetic alterations during colorectal-tumor development. N Engl J Med 1988;319:525-532
   Full Text | Web of Science | Medline

Author/Editor Response

The authors reply:

To the Editor: The digital-protein-truncation assay described in our study did indeed have a false positive rate of 0 percent. False positive results were defined as positive tests for APC mutations in fecal DNA in patients without colorectal neoplasia. Dr. Ransohoff suggests that this definition should be revised to include the detection of neoplastic lesions smaller than 1.0 cm in diameter. If this criterion were generally applied, the false positive rates of endoscopic and barium-enema examinations would be extremely high. In fact, more than 90 percent of the neoplastic lesions detected by these conventional tests are adenomas that are smaller than 1.0 cm in diameter.1,2 Moreover, according to this line of reasoning, the use of endoscopy to remove these lesions would needlessly subject patients to such risks as perforation and death.3

Regardless, the digital-protein-truncation assay is unlikely to detect small adenomas. The shedding of mutant APC genes into the feces is probably directly related to the total mass of neoplastic cells containing such mutant genes. An adenoma that was 0.4 cm in diameter would contain only 0.8 percent of the mutant DNA present in the average neoplasm of 2.0 cm that we detected in our study, since the mass is proportional to the third power of the diameter. The expected contribution of these molecules to fecal DNA would be undetectable with use of the technique we described. Indeed, even somewhat larger adenomas would most likely not be detected. These predictions have been borne out by our preliminary studies of nine adenomas ranging from 0.4 to 0.8 cm in diameter; none gave rise to positive digital-protein-truncation tests. In addition, unlike endoscopic examination or barium enema, the assay does not detect hyperplastic polyps (which, unlike adenomatous polyps, do not contain APC mutations and pose little danger of progression to cancer).

We would expect that the digital-protein-truncation assay would identify some fraction of adenomas that are close to 1.0 cm in size. As we noted in our report, there are several hurdles to overcome before this test becomes a clinically useful tool. If the chief drawback of this method turned out to be the detection of an occasional adenoma that approached 1.0 cm in diameter, we would be very pleased indeed.

Giovanni Traverso, B.A.
Kenneth W. Kinzler, Ph.D.
Bert Vogelstein, M.D.
Johns Hopkins Medical Institutions, Baltimore, MD 21231
vogelbe@welch.jhu.edu

3 References

1. 1

   Lieberman DA, Weiss DG, Bond JH, Ahnen DJ, Garewal H, Chejfec G. Use of colonoscopy to screen asymptomatic adults for colorectal cancer. N Engl J Med 2000;343:162-168[Erratum, N Engl J Med 2000;343:1204.]
   Full Text | Web of Science | Medline

2. 2

   Winawer SJ, Stewart ET, Zauber AG, et al. A comparison of colonoscopy and double-contrast barium enema for surveillance after polypectomy. N Engl J Med 2000;342:1766-1772
   Full Text | Web of Science | Medline

3. 3

   Ransohoff DF, Sandler RS. Screening for colorectal cancer. N Engl J Med 2002;346:40-44
   Full Text | Web of Science | Medline

Citing Articles (1)

Citing Articles

1. 1

   Christian N. Arnold, Ajay Goel, Hubert E. Blum, C. Richard Boland. (2005) Molecular pathogenesis of colorectal cancer. Cancer 104:10, 2035-2047
   CrossRef