Annals of Oncology Advance Access originally published online on November 15, 2005
Annals of Oncology 2006 17(6):1026; doi:10.1093/annonc/mdj081
© 2005 European Society for Medical Oncology
letter to the editor |
Molecular stool testing for the early detection of colorectal cancer: swan song for p53?
In the Editorial accompanying the manuscript by Russo et al. [1
], Hoff [2] asserts that this study does not support routine testing for p53 mutations in colorectal cancer. Patients with p53 mutations showed a non-significant trend toward worse survival, but the prognostic value was modest and the presence of p53 mutations failed to predict which patients would benefit from fluorouracil-based adjuvant chemotherapy. Moreover, the authors of the Russo et al. study [1] affirm that ‘additional trials on the prognostic value of p53 mutation are probably not warranted in view of the relatively weak associations observed’.
Colorectal screening should aim to detect cancer in the premalignant phase to avoid surgery-associated morbidity. Molecular screening should focus on the ability of genetic markers in stool to identify cancers and adenomas with high malignant potential with reasonable sensitivity and specificity, detecting mutations in the genes involved in the adenoma-to-carcinoma sequence. Providing a true negative result is crucial in screening and is possible only if DNA can be extracted from all stool samples. By contrast, in the study by Dong et al. [3] p53 alone detected 30 of the 51 cases of colorectal cancer, even though these authors were able to show that all patients with p53 mutations in their tumors at specific hotspots had identical mutations in their stool samples. Owing to less efficient degradation by apoptosis of cells shed by tumors, the quantity and quality of the DNA extracted from stools is superior in the presence of colorectal neoplasia [4]. Only one study [5] has reported successful DNA extraction from 100% of stool samples from people with endoscopically normal colons. Previous data have shown that p53 has no role in the detection of adenomas (except perhaps in those with severe dysplasia) [5].
There are many technical difficulties in detecting abnormal DNA from tumor cells shed into the colon, including collection and storage of samples, extraction of DNA from stool, removal of PCR inhibitors (food digestion products and bacterial contaminants) and the not always successful amplification of mutant DNA to a detectable amount. Furthermore, p53 functional inactivation does not seem to occur early in colorectal cancer development [6], since mutations in p53 are found in 4–26% of adenomas and up to 75% of colon cancers [7, 8]. Finally, considered the modest prognostic value of p53 mutations in colorectal cancer according to the above-mentioned manuscripts [1, 2], the question immediately arises as to whether p53 could be still considered a suitable marker for future studies on molecular screening for colorectal cancer in stool.
Department of Medical Oncology, Regina Elena Cancer Institute, Via Elio Chianesi 53, 00144 Rome, Italy
* E-mail: gia.fer{at}flashnet.it
References
1. Russo R, Bazan V, Iacopetta B et al. The TP53 Colorectal Cancer International Collaborative Study on the Prognostic and Predictive Significance of p53 Mutation: Influence of Tumor Site, Type of Mutation, and Adjuvant Treatment. J Clin Oncol 2005; 20: 7518–7528.
2. Hoff PM. Is there a role for routine p53 testing in colorectal cancer? J Clin Oncol 2005; 20: 7395–7396.[CrossRef]
3. Dong SM, Traverso G, Johnson C et al. Detecting colorectal cancer in stool with the use of multiple genetic targets. J Natl Cancer Inst 2001; 93: 858–865.
4. Villa E, Dugani A, Rebecchi AM et al. Identification of subjects at risk for colorectal carcinoma through a test based on K-ras determination in the stool. Gastroenterology 1996; 110: 1346–1353.[CrossRef][Web of Science][Medline]
5. Ahlquist DA, Skoletsky JE, Boynton KA et al. Colorectal cancer screening by detection of altered human DNA in stool: feasibility of a multitarget assay panel. Gastroenterology 2000; 119: 1219–1227.[CrossRef][Web of Science][Medline]
6. Mak T, Lalloo F, Evans DG, Hill J. Molecular stool screening for colorectal cancer. Br J Surg 2004; 91: 790–800.[Medline]
7. Vogelstein B, Fearon ER, Kern SE et al. Allelotype of colorectal carcinomas. Science 1989; 244: 207–221.
8. Vogelstein B, Fearon ER, Hamilton SR et al. Genetic alterations during colorectal-tumor development. N Engl J Med 1988; 319: 525–532.[Abstract]
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