Correspondence
Clinical Implications of the p53 Tumor-Suppressor Gene
N Engl J Med 1994; 330:864-865March 24, 1994
- Article
To the Editor:
Harris and Hollstein (Oct. 28 issue)1 reviewed the clinical implications of the p53 tumor-suppressor gene. Of particular interest to clinicians is the prognostic importance of p53 mutations. The authors mentioned that there is now more and more evidence of a correlation between the loss of p53 function and shortened survival. They argued that one might theoretically expect the loss of p53 function to be associated with more rapidly advancing disease. They also referred to some recent studies demonstrating that gene amplification is tremendously enhanced in cells lacking normal p53. However, they did not discuss recent results that suggest potential mechanisms through which the loss of p53 function may reduce the response of malignant tumors to treatment.
Gene amplification is a well-known mechanism conferring resistance to classic chemotherapy, as is the recently discovered up-regulation of the expression of the multidrug-resistance gene, MDR1, by certain mutants of p532. Loss of p53 function has also been associated with an increased intrinsic cellular resistance to radiotherapy, depending on the type of cell involved3,4. Furthermore, accelerated proliferation of tumor cells may itself contribute to resistance to radiotherapy5. Therefore, a more rapid proliferation of cells after the loss of p53 might also reduce the response to radiotherapy.
5 ReferencesH. Peter Rutz, M.D.
Rene O. Mirimanoff, M.D.
Centre Hospitalier Universitaire Vaudois, CH-1011 Lausanne, Switzerland1
Harris CC ,Hollstein M . Clinical implications of the p53 tumor-suppressor gene. N Engl J Med 1993;329:1318-1327
Full Text | Web of Science | Medline2
Chin K-V ,Ueda K ,Pastan I ,Gottesman MM . Modulation of activity of the promoter of the human MDR1 gene by Ras and p53. Science 1992;225:459-462
CrossRef | Web of Science3
Lee JM ,Bernstein A . p53 Mutations increase resistance to ionizing radiation. Proc Natl Acad Sci U S A 1993;90:5742-5746
CrossRef | Web of Science | Medline4
Slichenmyer WJ ,Nelson WG ,Slebos RJ ,Kastan MB . Loss of a p53-associated G1 checkpoint does not decrease cell survival following DNA damage. Cancer Res 1993;53:4164-4168
Web of Science | Medline5
Begg AC . Critical appraisal of in situ cell kinetic measurements as response predictors in human tumors. Semin Radiat Oncol 1993;3:144-151
CrossRef | Medline
To the Editor:
In their excellent review of the p53 tumor-suppressor gene, Drs. Harris and Hollstein mention the use of p53 immunohistochemical techniques as an easily available method of investigating p53 protein in tumor tissues. Mutations of the p53 gene may lead to the expression of a p53 protein with a prolonged half-life detectable by immunohistochemical techniques1. We would add superficial bladder cancer to the list of tumors in which a prognostic role of p53 mutations has been demonstrated (cancer of the breast, lung, and prostate)2-4 or is highly probable.
We investigated biopsy specimens obtained by transurethral resection from 41 patients with superficial bladder cancer (stage T1) for the detection of cytoplasmic levels of p53 with use of the monoclonal antibody pAb1801. Positivity for p53 was correlated with progression or relapse of bladder cancer.
In biopsy specimens from eight patients, more than 20 percent of cells were positive for p53. Biopsy specimens from 33 patients were negative for p53. After a median follow-up of 54 months, only 1 of the 33 patients (3 percent) who were negative for p53 had a relapse of bladder cancer, as compared with 7 of the 8 patients (87 percent) who were positive for p53 (P<0.01). Both groups of patients were comparable with respect to age, sex, type of treatment (instillation therapy), and the results of immunohistochemical staining for the proliferation markers Ki-67 and PCNA.
These results are in accordance with those of Sarkis et al.5 indicating the important role of p53 mutations as a prognostic marker in bladder cancer.
5 ReferencesCarsten Bokemeyer, M.D.
Markus A. Kuczyk, M.D.
Jurgen Sehrt, Ph.D.
Hannover University Medical School, 30625 Hannover, Germany1
Gannon JV ,Greaves R ,Iggo R ,Lane DP . Activating mutations in p53 produce a common conformational effect: a monoclonal antibody specific for the mutant form. EMBO J 1990;9:1595-1602
Web of Science | Medline2
Thor AD ,Moor DH II ,Edgerton SM , et al. Accumulation of p53 tumor suppressor gene protein: an independent marker of prognosis in breast cancers. J Natl Cancer Inst 1992;84:845-855
CrossRef | Web of Science | Medline3
Quinlan DC ,Davidson AG ,Summers CL ,Warden HE ,Doshi HM . Accumulation of p53 protein correlates with a poor prognosis in human lung cancer. Cancer Res 1992;52:4828-4831
Web of Science | Medline4
Visakorpi T ,Kallioniemi OP ,Heikkinen A ,Koivula T ,Isola J . Small subgroup of aggressive, highly proliferative prostatic carcinomas defined by p53 accumulation. J Natl Cancer Inst 1992;84:883-887
CrossRef | Web of Science | Medline5
Sarkis AS ,Dalbagni G ,Cordon-Cardo C , et al. Nuclear overexpression of p53 protein in transitional cell bladder carcinoma: a marker for disease progression. J Natl Cancer Inst 1993;85:53-59
CrossRef | Web of Science | Medline
To the Editor:
In their review of the clinical implications of the p53 tumor-suppressor gene, Harris and Hollstein discussed the phenomenon of a humoral immune response against p53 in patients with cancer. Anti-p53 antibodies (anti-p53) have been demonstrated in up to 25 percent of patients with various malignant conditions, including lymphomas and colorectal, mammary, lung, and liver tumors1,2. We have performed a serologic analysis of anti-p53 in more than 500 patients with different tumors using immunoblotting with recombinant p53. In addition, to facilitate large-scale analysis we have developed an anti-p53 enzyme-linked immunosorbent assay (ELISA).
Serum samples from 532 patients with cancer of the liver (n = 80), esophagus (n = 47), stomach (n = 128), colon (n = 182), rectum (n = 35), pancreas (n = 17), breast (n = 24), or urogenital tract (n = 19) were tested by immunoblotting and, in some cases, by ELISA. A total of 379 patients without tumors served as controls. Overall, anti-p53 was found in 116 of the 532 patients with malignant disease (22 percent; range, 6 to 33 percent) but in none of the controls. Individual serum samples had high anti-p53 titers; a sample from one patient with metastatic breast cancer was reactive at a dilution of up to 1:130,000. In general, anti-p53 seroconversion could be shown for 40 percent of the patients with progressive disease (10 of 25) during a follow-up of one to two years. In contrast, in some patients a postoperative decline in anti-p53 reactivity was observed.
2 ReferencesMartina Muller, M.D.
Martin Volkmann, M.D.
University of Heidelberg, 69115 Heidelberg, GermanyHanswalter Zentgraf, Ph.D.
German Cancer Research Center, 69120 Heidelberg, GermanyPeter R. Galle, M.D.
University of Heidelberg, 69115 Heidelberg, Germany1
Harris CC ,Hollstein M . Clinical implications of the p53 tumor-suppressor gene. N Engl J Med 1993;329:1318-1327
Full Text | Web of Science | Medline2
Volkmann M ,Muller M ,Hofmann WJ , et al. The humoral immune response to p53 in patients with hepatocellular carcinoma is specific for malignancy and independent of the alpha-fetoprotein status. Hepatology 1993;18:559-565
CrossRef | Web of Science | Medline
- Citing Articles (2)
Citing Articles
1
H. P. Rutz, M. Mariotta, M. Knebel Doeberitz, R. O. Mirimanoff. (1998) Dexamethasone-induced radioresistance occurring independent of human papilloma virus gene expression in cervical carcinoma cells. Strahlentherapie und Onkologie 174:2, 71-74
CrossRef2
Rutz, H. Peter, . (1994) Cancer Therapy Meets p53. New England Journal of Medicine 331:19, 1314-1315
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