Affiliation of authors: Medizinische Klinik Innenstadt der Universität München, Germany.
Correspondence to: S. M. Lang, M.D., Medizinische Klinik Innenstadt der Universität München, Ziemssenstr.1, D-80336 München, Germany (e-mail: slang{at}medinn.med.uni-muenchen.de).
We have read the Brief Communication by Potter et al. (1) with great interest. We agree with the authors' contention that documenting multiple types of common mutations in colorectal cancer may enhance the likelihood of detecting early malignant lesions, and we agree that this approach holds promise as a screening tool for colorectal cancer. By use of colonic effluent samples, which contain fewer contaminants than stool and can be expected to harbor epithelial cells shed from all sections of the intestine, a convenient source of DNA is provided for molecular analysis, as shown by other investigators (2,3).
However, from a clinician's point of view, we do not share the pessimistic conclusions drawn, i.e., that even successful genetic analysis of four point-mutation sites has the potential to detect only 60% of colorectal cancers and that these results are no better than fecal occult blood testing. There is no doubt that the development of the Hemoccult® test has greatly facilitated the potential to detect occult fecal blood. Unfortunately, even when performed optimally, the Hemoccult test has major limitations as a screening technique. Between 35% and 50% of patients with documented colorectal cancer have a negative fecal Hemoccult test, consistent with the intermittent bleeding pattern of colorectal tumors. When random cohorts of asymptomatic individuals were tested, only 3%-6% had Hemoccult-positive stools; colorectal neoplasms were not found in the majority of those individuals who had occult blood in their stool (4).
Furthermore, in patients with inflammatory bowel disease, fecal occult blood testing cannot be used because diarrhea is often hemorrhagic. Essentially the same genetic lesions are found in tumors developing in patients with long-standing ulcerative colitis as are found in sporadic colon carcinomas (5). In a small series of patients with long-standing ulcerative colitis (i.e., individuals who are at increased risk for malignant transformation), we have recently shown (3) that colonoscopic lavage fluid collected during routine colonoscopy is suitable for the analysis of mutant p53 (also known as TP53) and Ki-ras genes. A larger study is now under way to confirm the clinical importance of these findings.
The noninvasive nature of molecular detection of colorectal carcinoma in stool or whole-gut lavage offers theoretically major advantages over current screening procedures (6). However, a note of caution is required because, at the present time, it is too early to demonstrate a reduction in mortality from molecular screening.
REFERENCES
1
Potter MA, Morris RG, Ferguson A, Wyllie AH. Detection of
mutations associated with colorectal cancer in DNA from whole-gut lavage fluid. J Natl
Cancer Inst 1998;90:623-6.
2 Tobi M, Luo FC, Ronai Z. Detection of K-ras mutation in colonic effluent samples from patients without evidence of colorectal carcinoma. J Natl Cancer Inst 1994;86:1007-10.[Abstract]
3 Lang SM, Heinzlmann M, Stratakis DF, Teschauer W, Loeschke K. Detection of Ki-ras mutations by PCR and differential hybridization and of p53 mutations by SSCP analysis in endoscopically obtained lavage solution from patients with long-standing ulcerative colitis. Am J Gastroenterol 1997;92:2166-70.[Medline]
4 Mayer RJ. Colorectal cancer. In: Fauci AS, et al., editors. Harrison's principles of internal medicine. 14th ed. New York (NY): McGraw-Hilil; 1998. p. 568-78.
5 Kern SE, Redston M, Seymour AB, Caldas C, Powell SM, Kornacki S, Kinzler KW. Molecular genetic profiles of colitis-associated neoplasms. Gastroenterology 1994;107:420-8.[Medline]
6 Villa E. Molecular screening: why haven't we started yet? [editorial]. Am J Gastroenterol. 1997;92:2144-6.[Medline]
Correspondence to: Mark Potter, F. R. C. S., Falkirk & District Royal Infirmary NHS Trust, Department of Surgery, Major's Loan, Falkirk FK1 5QE, Scotland, U.K. (e-mail: map{at}srv0. med.ed.ac.uk).
On behalf of my colleagues, I thank Drs. Lang, Stratakis, and Schiffl for their salient comments. As a clinician, I share their desire to find a suitable screening test for the early diagnosis of colorectal cancer.
I agree that the molecular detection of colorectal cancer theoretically offers a major advance over current screening procedures (1). Rather than being pessimistic, I exercise a note of caution toward over optimism. An effective screening test must be cheap, reliable, and easily repeatable. As a method by which to screen the general population, molecular analysis of colonic effluent is probably not cheap or easily repeatable, requiring dedicated laboratories and staff. One of the shortcomings of fecal occult blood testing is compliance, which falls with repeated testing (2). I fear that this may well be the case with molecular analysis of colonic effluent samples. Furthermore, in our series it was not possible to analyze 49% of the samples because of inhibition of the polymerase chain reaction (PCR). Lang and colleagues (3) also encountered substantial problems in obtaining high-quality DNA for PCR analysis, ultimately using commercial extraction kits to overcome the problem. We have certainly found lavage obtained at colonoscopy to be a better source of DNA for PCR than whole-gut lavage fluid (WGLF) (Potter MA, Morris RG, Ferguson A, Wyllie AH: unpublished data).
I agree, however, that for selected groups at high risk of colorectal cancer that are highly motivated from a screening point of view, molecular analysis of endoscopic effluent has great potential. One such group would be comprised of individuals with long-standing ulcerative colitis (3), in which molecular analysis of effluent samples "should be considered more as an improvement of the diagnostic capability of colonoscopy than as an independent screening tool" (1).
Ideally, a single site or focus of analysis would simplify molecular screening. Telomerase activity has been detected in almost 90% of colorectal cancers (4). Telomerase activity has also been detected in 60% of the colonic washings obtained from surgically resected cancer specimens (5), although the methodology in this study was rather artificial. Our initial attempts to identify telomerase activity in WGLF have been unsuccessful, but assaying for telomerase does offer a new horizon for the goal of a molecular screening test for colorectal cancer.
REFERENCES
1 Villa E. Molecular screening: why haven't we started yet? [editorial]. Am J Gastroenterol 1997;92:2144-6.[Medline]
2 Winawer SJ, Fletcher RH, Miller L, Godlee F, Stolar MH, Mulrow CD, et al. Colorectal cancer screening: clinical guidelines and rationale [published errata appear in Gastroenterology 1997;112:1060; 1998;114:625]. Gastroenterology 1997;112:594-642.[Medline]
3 Lang SM, Heinzlmann M, Stratakis DF, Teschauer W, Loeschke K. Detection of Ki-ras mutations by PCR and differential hybridization and of p53 mutations by SSCP analysis in endoscopically obtained lavage solution from patients with long-standing ulcerative colitis. Am J Gastroenterol 1997;92:2166-70.[Medline]
4 Shay JW, Bacchetti S. A survey of telomerase activity in human cancer. Eur J Cancer 1997;33:787-91.[Medline]
5 Yoshida K, Sugino T, Goodison S, Warren BF, Nolan D, Wadsworth S, et al. Detection of telomerase activity in exfoliated cancer cells in colonic luminal washings and its related clinical implications. Br J Cancer 1997;75:548-53.[Medline]
![]() |
||||
|
Oxford University Press Privacy Policy and Legal Statement |