Accumulation of Nuclear p53 and Tumor Progression in Bladder Cancer
David Esrig, Donald Elmajian, Susan Groshen, John A. Freeman, John P. Stein, Su-Chiu Chen, Peter W. Nichols, Donald G. Skinner, Peter A. Jones, and Richard J. Cote
Background We have previously demonstrated a strong associationbetween nuclear accumulation of p53 protein, as determined byimmunohistochemical analysis, and mutations in the p53 gene.The purpose of this study was to determine the relation betweennuclear accumulation of p53 and tumor progression in transitional-cellcarcinoma of the bladder.
Methods Histologic specimens of transitional-cell carcinomaof the bladder (stages Pa, noninvasive disease, to P4, diseasewith direct extension into adjacent organs or structures) from243 patients who were treated by radical cystectomy were examinedfor the immunohistochemical detection of p53 protein. Nuclearp53 reactivity was then analyzed in relation to time to recurrenceand overall survival.
Results The detection of nuclear p53 was significantly associatedwith an increased risk of recurrence of bladder cancer (P<0.001)and with decreased overall survival (P<0.001). In patientswith cancer confined to the bladder, the rates of recurrencefor stage P1, P2, and P3a tumors that had no detectable nuclearp53 reactivity at five years were 7, 12, and 11 percent, respectively,as compared with 62, 56, and 80 percent, respectively, for tumorsthat had p53 immunoreactivity. Similar results were obtainedwhen the presence or absence of p53 in the nuclei of the tumorcells was studied in relation to overall survival. In a multivariableanalysis stratified according to grade, pathological stage,and lymph-node status, nuclear p53 status was an independentpredictor (and in cancer confined to the bladder, the only independentpredictor) of recurrence and overall survival (P<0.001).
Conclusions In patients with transitional-cell carcinoma confinedto the bladder, an accumulation of p53 in the tumor-cell nucleidetected by immunohistochemical methods predicts a significantlyincreased risk of recurrence and death, independently of tumorgrade, stage, and lymph-node status. Patients with transitional-cellcarcinoma confined to the bladder that demonstrates nuclearp53 reactivity should be considered for protocols of adjuvanttreatment.
Mutations of the p53 gene are the most common genetic defectin human tumors1. The p53 gene functions as a tumor-suppressorgene and more specifically as a cell-cycle regulator2. Levelsof p53 protein increase in response to damage to DNA, arrestingthe cell cycle and allowing time for the repair of DNA.
Mutations of the p53 gene occur in a high percentage of invasivetransitional-cell carcinomas of the bladder3 and appear to bean early event in the formation of carcinoma in situ4. Theyare much less frequent in noninvasive papillary tumors5,6. Mutationsof the p53 gene and nuclear accumulation of p53 protein areassociated with the grade and stage of bladder cancer5 and maybe important in the multistep progression of bladder cancer7,8,9.The immunohistochemical detection of the protein, which exploitsthe difference in life span between mutated and wild-type p53,has been shown to correlate strongly with mutations of the p53gene in bladder cancer5.
The primary factors used in determining the clinical treatmentof patients with early-stage bladder cancer are the depth oftumor invasion, the tumor grade, and the presence or absenceof lymph-node metastases. Radical cystectomy is a generallyaccepted treatment for patients with invasive cancer confinedto the bladder, particularly when there is evidence of muscleinvasion10. Surgical treatment is curative in a substantialproportion of such patients, but in a large number incurablemetastatic disease appears after surgery. Adjuvant therapy (includingchemotherapy and radiation therapy) is under investigation inthis setting, and shows encouraging results11,12. It may thusbe important to distinguish patients for whom surgery aloneis adequate and who can avoid the morbidity and expense of adjuvanttherapy from patients who might benefit from both surgery andadditional treatment.
In the present study we sought to determine whether a nuclearaccumulation of p53 is an important factor in predicting theclinical behavior of bladder cancer. Previous work has suggestedthat alterations of p53 can predict disease progression in superficiallyinvasive bladder cancer13. However, a study of patients withbladder cancer who received a variety of treatments suggestedthat nuclear accumulation of p53 is not a predictor of diseaseprogression that is independent of clinical stage and the rateof proliferation of the tumor cells14. We demonstrate, in 243patients with bladder cancer treated by radical cystectomy,that nuclear accumulation of p53 identifies transitional-cellcarcinomas with a propensity for progression that is independentof tumor grade and stage.
Methods
Population of Patients
We studied 243 patients who underwent radical cystectomy, pelvic-lymph-nodedissection, and urinary diversion at the Kenneth Norris Jr.Comprehensive Cancer Center. To assess the association betweennuclear accumulation of p53 and clinical outcome, we includedall patients with transitional-cell carcinoma treated by radicalcystectomy from April 1983 through June 1987 for whom follow-updata and tumor samples from the cystectomy specimens (preservedin archival paraffin-embedded tissue blocks) were available.An additional 33 patients who underwent cystectomy between July1987 and December 1988 were studied in order to increase thenumber of patients with cancer confined to the bladder. Thestudy also included 53 patients described previously whose tumorsunderwent both molecular and immunohistochemical analysis forp535. Thus, of the entire group of 243 patients, 190 had notpreviously been evaluated for nuclear accumulation of p53. Patientswith pure adenocarcinoma, squamous-cell carcinoma, or small-cellcarcinoma of the bladder were excluded. The median age of allpatients was 63 years (range, 49 to 83); 77 percent were men,and 23 percent were women.
Clinical and Pathological Evaluation
The indications for radical cystectomy included invasion ofmuscle or prostate stroma by the tumor; high-grade, superficiallyinvasive tumors associated with carcinoma in situ; carcinomain situ refractory to intravesical chemotherapy or immunotherapy;and recurrent multifocal disease after conservative therapy.None of the patients received pelvic irradiation or systemicchemotherapy before surgery. All the specimens included in thisstudy were transitional-cell carcinomas; a minority demonstratedglandular or squamous differentiation. The histologic gradingwas performed according to the method of Bergkvist et al.,15and the pathological staging was done according to the tumor-node-metastasisclassification16. All tumors were reevaluated for histologicgrade by two of the investigators. Among the 243 tumors, 11were classified histologically as grade 2, 157 as grade 3, and75 as grade 4. Five tumors were classified as stage Pa (noninvasivepapillary tumors), 11 as stage Pis (carcinoma in situ), 50 asstage P1 (superficial invasion), 32 as stage P2 (superficialinvasion into muscularis propria), 35 as stage P3a (deep invasioninto muscularis propria), 68 as stage P3b (invasion into perivesicularfat), and 42 as stage P4 (direct extension into adjacent organsor structures). Sixty-six patients were found on pathologicalexamination to have metastatic disease in the pelvic lymph nodes.None of the patients had distant metastatic disease at the timeof cystectomy. Forty-one patients received systemic chemotherapyafter surgery, either cisplatin, cyclophosphamide, and doxorubicinor methotrexate, vinblastine, doxorubicin, and cisplatin. Themedian follow-up for the 243 patients was 6.0 years, with 81percent having at least 3 years of follow-up. The patients wereseen at three-month intervals during the first postoperativeyear, every four months during the second year, and every yearthereafter. Follow-up consisted of a biochemical profile, chestradiography, and physical examination. A computed tomographicscan or bone scan was performed to confirm suspected recurrencesof disease. Data on recurrences of transitional-cell carcinomaand causes of death were obtained from office and hospital records.
Monoclonal Antibodies and Immunohistochemical Analysis
Five-microm sections of archival formalin-fixed, paraffin-embeddedtissue were placed on slides coated with poly-l-lysine (Sigma,St. Louis). The immunohistochemical procedure was performedas described elsewhere5. In brief, after deparaffinization andblocking of endogenous peroxidase, the anti-p53 mouse monoclonalantibody PAb1801 (IgG1 class, 1:10 dilution, Biogenex, San Ramon,Calif.) was incubated overnight with tissue at 4 °C. PAb1801recognizes the p53 protein at a denaturation-resistant epitopecorresponding to amino acids 32 through 79. Tissues were thenincubated with a biotinylated horse antimouse secondary antibody(Vector Labs, Burlingame, Calif.), and reactivity was visualizedwith an avidin-biotin-immunoperoxidase system (Vector) usingdiaminobenzidine (0.03 percent) as the chromogen and hematoxylinas the counterstain. Samples of bladder carcinoma with knownp53 mutations and documented accumulations of p53 protein byimmunohistochemical analysis were used as positive controls.Normal urothelium and nonepithelial cells (lymphocytes, stromalcells, and endothelial cells), used as internal negative controls,demonstrated no immunoreactivity. Only nuclear localizationof immunoreactivity was evaluated. The extent of nuclear reactivitywas classified in four categories: no nuclear reactivity; afew focally positive nuclei (1 to 9 percent of tumor cells);heterogeneous nuclear reactivity (10 to 49 percent of tumorcells); and intense homogeneous nuclear reactivity (50 to 100percent of tumor cells) (Figure 1). Only samples demonstratingat least 10 percent nuclear reactivity were considered to bep53-positive (to have an alteration in p53). We based this criterionon our demonstration of a strong correlation of mutations inthe p53 gene with the accumulation of p53 protein in 10 percentor more of the tumor-cell nuclei5. The immunohistochemical analysiswas performed without knowledge of the tumor stage or the resultsof clinical follow-up.
Figure 1. Immunohistochemical Detection of p53 Protein in the Nuclei of Transitional-Cell Carcinomas of the Bladder with the Anti-p53 Monoclonal Antibody PAb1801.
No detectable nuclear staining is seen in Panel A, only a few cells (1 to 9 percent) with nuclear reactivity are seen in Panel B, heterogeneous nuclear reactivity is seen in 10 to 49 percent of tumor cells in Panel C, and intense homogeneous nuclear reactivity is seen in 50 to 100 percent of tumor cells in Panel D (all panels x105). Tumors with 0 to 9 percent nuclear staining were considered p53-negative, whereas tumors with 10 to 100 percent nuclear staining were considered p53-positive.
Statistical Analysis
Survival was calculated from cystectomy to the date of deathor the date of the last follow-up (either a clinical visit ora discussion with the patient's referring physician); deathsdue to any cause were considered to represent treatment failures.Time to recurrence was calculated from cystectomy to the dateof the first documented clinical recurrence or the last follow-up;data on patients who died free of disease before any recurrencewere censored at the time of death. One patient was known tohave died of disease, but the date of recurrence was unknownand therefore a date midway between the last clinic visit andthe date of death was used. For the purpose of the statisticalanalysis, nuclear accumulations of p53 were classified as eitherpositive (accumulation in 10 percent or more of tumor cells)or negative.
Contingency tables, Pearson's chi-square test, and logisticregression17 were used to evaluate the association of p53 accumulationwith lymph-node status, pathological stage of the primary tumor,and histologic grade. Kaplan-Meier plots18 and the log-ranktest19 were used to evaluate the association of these threestandard clinical prognostic variables, as well as the expressionof p53, with the time to recurrence and with survival. Greenwood'sformula19 was used to estimate the standard errors of the Kaplan-Meierestimates of the probability of survival or recurrence. To determinewhether an accumulation of p53 provided prognostic informationbeyond that provided by the three standard clinical variables,a stratified log-rank test was used. All P values reported aretwo-sided.
The statistical analyses were performed for the entire cohortof 243 patients and were performed separately for the 190 patientsnot previously tested for accumulation of p53.
Results
Of the 190 bladder tumors not previously examined for accumulationof p53, 112 had no nuclear reactivity and 7 had a few focallypositive tumor nuclei but less than 10 percent. These 119 tumorswere considered p53-negative. In 54 of the remaining 71 tumors,p53 protein was detected in 10 to 49 percent of tumor-cell nuclei,and in 17 tumors p53 was seen in 50 to 100 percent of tumor-cellnuclei. These 71 bladder cancers were considered p53-positive.In all 243 patients, 142 tumors were classified as p53-negativeand 101 as p53-positive.
Association of p53 Nuclear Reactivity with Tumor Grade, Pathological Stage, and Lymph-Node Status
Analysis of the 190 tumors not previously tested for p53 revealedthat nuclear p53 was identified more frequently in grade 4 tumorsthan in grade 2 or 3 tumors, but this association was not statisticallysignificant (P = 0.20) (Table 1). By contrast, the presenceof nuclear p53 was significantly associated with pathologicalstage (P = 0.003); 32 percent of the patients with negativelymph nodes, as compared with 55 percent of the patients withpositive lymph nodes, had nuclear accumulation of p53 (P = 0.008).In patients with no evidence of lymph-node metastases, the presenceof nuclear p53 was associated with greater depth of invasion;22 percent of the patients with superficial disease (stage Pa,Pis, or P1), as compared with 38 percent of the patients withdisease invasive of muscle (stages P2 through P4), had nuclearp53 in the tumor cells (P = 0.044). Similar results were obtainedfor the entire cohort of 243 patients.
Table 1. Association of p53 Immunoreactivity with Grade and Pathological Stage of Bladder Cancer and Presence or Absence of Lymph-Node Metastases in 190 Patients Not Previously Tested for p53 Alterations.
Association of p53 Immunoreactivity with Recurrence and Overall Survival
In the group of 190 patients not previously tested for p53 alterations,nuclear accumulation of p53 was significantly associated withan increased probability of tumor recurrence (P<0.001) anda decreased probability of survival (P<0.001). Identicalresults were obtained for the entire cohort of 243 patients;Figure 2 and Figure 3 show curves for recurrence and survivalfor all patients.
Figure 2. Probability of Remaining Relapse-free in 243 Patients with Bladder Cancer and either p53-Positive or p53-Negative Tumors.
Identical results were obtained for the subgroup of 190 patients not previously tested for p53 alterations. Each tick mark represents a patient who had not had a recurrence of disease at the time of the last follow-up.
Figure 3. Probability of Survival in Patients with Bladder Cancer and either p53-Positive or p53-Negative Tumors.
Each tick mark represents a patient who was alive at the time of the last follow-up.
Among the patients with no evidence of lymph-node involvement,nuclear accumulation of p53 was significantly associated withrecurrence in those with disease confined to the bladder (stageP1, P2, or P3a). However, this association was not statisticallysignificant among the patients with extravesical extension oftumor (stage P3b or P4) (Table 2). The five-year recurrencerates for patients with stage P1, P2, and P3a tumors that werep53-negative were 7, 12, and 11 percent, respectively. In contrast,the five-year recurrence rates were 62, 56, and 80 percent forstage P1, P2, and P3a tumors that were p53-positive (Table 2).In all subgroups of tumors confined to the bladder, the recurrencerates at five years for p53-negative and p53-positive tumorsdiffered significantly. Significant differences in estimatedfive-year survival rates were also found among patients withtumors confined to the bladder (except stage P3a tumors) (Table 2).Identical results were obtained for the entire cohort of243 patients. Figure 4 and Figure 5 show the Kaplan-Meier curvesfor recurrence and survival in all 243 patients, stratifiedaccording to the depth of tumor invasion.
Table 2. Estimated Rates of Recurrence and Survival at Five Years in 190 Patients with Bladder Cancer, According to p53 Status of Tumors and Pathological Stage.
Figure 4. Probability of Remaining Relapse-free According to Pathological Stage in Patients with Organ-Confined Bladder Cancer but No Regional Lymph-Node Metastases.
All patients with P1, P2, or P3a disease from the entire cohort of 243 patients were included in this analysis. Identical results were obtained for the patients with P1, P2, or P3a disease in the subgroup of 190 patients not previously tested for p53 alterations.
Figure 5. Probability of Survival According to Pathological Stage in Patients with Organ-Confined Bladder Cancer but No Regional Lymph-Node Metastases.
In a multivariable analysis stratified according to grade, pathologicalstage, and presence or absence of lymph-node metastases nuclearp53 status was an independent predictor of the recurrence ofbladder cancer and of overall survival (P<0.001). When patientswith lymph-node-negative cancers confined to the bladder werestratified according to p53 status, pathological stage (i.e.,depth of invasion) was not an independent predictor of eitherrecurrence (P = 0.62) or survival (P = 0.23).
Forty-one of the 243 patients received postoperative adjuvantsystemic chemotherapy. When these patients were removed fromthe analysis, the presence of nuclear p53 remained highly associatedwith recurrence and death. This analysis demonstrates the predictivevalue of nuclear p53 reactivity in a cohort of patients uniformlytreated with radical cystectomy and pelvic-lymph-node dissectionbut no adjuvant therapy.
Discussion
We found that the immunohistochemical detection of p53 proteinin the nuclei of tumor cells can provide prognostic informationin patients with bladder cancer. In patients with transitional-cellcarcinoma of the bladder treated by cystectomy, the nuclearaccumulation of p53 correlated with a significantly increasedrisk of recurrence and decreased overall survival. The linkbetween nuclear p53 and prognosis was independent of tumor grade,pathological stage, and lymph-node status. The strongest associationbetween p53 immunoreactivity in tumor-cell nuclei and tumorprogression was observed when the disease was confined to thebladder. The presence of nuclear p53 was strongly associatedwith an increased risk of recurrence among patients with P1,P2, or P3a disease and with decreased overall survival amongthose with P1 or P2 disease. It was the only independent predictorof disease progression in a multivariable comparison of p53status, pathological stage, and histologic grade.
The product of a mutated p53 gene can be a metabolically stableprotein with a long half-life20. In contrast, wild-type p53has a short half-life, only 6 to 30 minutes, and thus it doesnot generally accumulate in high enough levels to be detectedby standard immunohistochemical methods. A long-lived mutatedp53 protein, in contrast, is usually detectable by such techniques.We have previously demonstrated a significant association ofp53 mutations with the immunohistochemical detection of p53protein in tumor-cell nuclei5. Immunohistochemical techniquesidentified most cases in which the cells had mutated p53 genes,but 15 to 20 percent of tumors with demonstrable mutations ofthe p53 gene were negative by immunohistochemical analysis5.Moreover, a substantial proportion of tumors with nuclear accumulationof p53 lacked evidence of p53 gene mutation. Alterations thatrender the p53 protein detectable by immunohistochemical analysismay not require a mutation in the p53 gene. For example, cellularoncogene products that bind to and inactivate wild-type p53protein, such as MDM2,21 may prolong the half-life of p53, allowingit to accumulate in the nucleus. Although this phenomenon hasnot been shown directly, recent studies indicate that cellsthat overexpress MDM2 can also overexpress p53 protein in theabsence of a p53 gene mutation22. Moreover, the level of wild-typep53 protein can increase in response to DNA damage23. Thus,increases in the level of the p53 protein and mutation of thep53 gene occur together in most cases but can be separate events.Although we have shown that the presence of p53 alterationsas detected by immunohistochemical methods is clinically relevant,it may also be important to assess mutations of the p53 genedirectly as a prognostic indicator in bladder cancer.
The most important finding of this study is that in patientswith transitional-cell carcinoma confined to the bladder (stagesP1, P2, and P3a), and no evidence of lymph-node metastases,p53 nuclear reactivity identifies tumors with a tendency toprogress. In these cases, the detection of nuclear p53 is morestrongly associated with tumor recurrence and decreased survivalthan is the depth of invasion or histologic grade. Patientswith p53-negative tumors had relatively low rates of recurrence,whereas metastases developed in the majority of patients withp53-positive tumors, regardless of depth of invasion. Althoughdepth of invasion is clearly associated with the progressionof disease in patients with bladder cancer, this may reflectthe proportion of tumors in each stage that have p53 alterations.
This study may influence the selection of patients for adjuvanttreatment of bladder cancer, which currently depends on thedepth of tumor invasion and the detection of regional lymph-nodemetastases. The results of two recent studies are encouraging,11,12but the role of adjuvant chemotherapy after cystectomy, particularlyin patients with disease confined to the bladder, remains unresolved.Patients with p53-negative tumors confined to the bladder havea low rate of disease progression (even when there is deep muscleinvasion) and may not require adjuvant treatment after radicalcystectomy. In contrast, patients with p53-positive cancer confinedto the bladder (including those with only superficially invasivetumors) have a poor prognosis. They may benefit from adjuvanttreatment. This study and the study by Sarkis et al.13 are alsorelevant to the controversial issue of surgical treatment ofsuperficially invasive bladder cancer. Patients with superficiallyinvasive p53-positive tumors have a high rate of disease progressionand may therefore benefit from early radical cystectomy. Moreover,our study indicates that patients with p53-positive tumors areat high risk of progression despite radical cystectomy and maytherefore benefit from adjuvant treatment. Thus, the immunohistochemicaldetection of p53 may identify patients with cancer confinedto the bladder who could benefit from radical surgery and adjuvanttherapy. Furthermore, the absence of detectable p53 may be anindication for conservative therapy, even in the presence oflocally advanced disease.
Supported in part by grants (R35 CA49758 and P30 CA14089) fromthe National Cancer Institute, by the American Foundation forUrologic Disease-National Kidney Foundation Fellowship, andby the Firestein-Gertz Cancer Research Fund.
We are indebted to Drs. Gary Lieskovsky and Stuart Boyd forproviding some of the patients included in this study, and toDrs. Ron Natale and Clive Taylor for their critical review ofthis work.
Source Information
From the Departments of Urology (D. Esrig, D. Elmajian, J.A.F., J.P.S., D.G.S., P.A.J.), Preventive Medicine (S.G., S.-C.C.), and Pathology (P.W.N., R.J.C.), University of Southern California School of Medicine and Kenneth Norris Jr. Comprehensive Cancer Center, Los Angeles.
Address reprint requests to Dr. Cote at the Department of Pathology, University of Southern California School of Medicine, Kenneth Norris Jr. Cancer Center, 1441 Eastlake Ave., Los Angeles, CA 90033.
References
Hollstein M, Sidransky D, Vogelstein B, Harris CC. p53 Mutations in human cancers. Science 1991;253:49-53. [Free Full Text]
Lane DP. Cancer: p53, guardian of the genome. Nature 1992;358:15-16. [CrossRef][Medline]
Sidransky D, Von Eschenbach A, Tsai YC, et al. Identification of p53 gene mutations in bladder cancers and urine samples. Science 1991;252:706-709. [Free Full Text]
Spruck CH III, Ohneseit PF, Gonzalez-Zulueta M, et al. Two molecular pathways to transitional cell carcinoma of the bladder. Cancer Res 1994;54:784-788. [Free Full Text]
Esrig D, Spruck CH III, Nichols PW, et al. p53 Nuclear protein accumulation correlates with mutations in the p53 gene, tumor grade, and stage in bladder cancer. Am J Pathol 1993;143:1389-1397. [Abstract]
Sarkis AS, Zhang Z, Cordon-Cardo C, et al. p53 Nuclear overexpression and disease progression in Ta bladder carcinoma. Int J Oncol 1993;3:355-360.
Sidransky D, Messing E. Molecular genetics and biochemical mechanisms in bladder cancer: oncogenes, tumor suppressor genes, and growth factors. Urol Clin North Am 1992;19:629-639. [Medline]
Cordon-Cardo C, Wartinger D, Petrylak D, et al. Altered expression of retinoblastoma gene product: prognostic indicator in bladder cancer. J Natl Cancer Inst 1992;84:1251-1256. [Free Full Text]
Logothetis CJ, Xu HJ, Ro JY, et al. Altered expression of retinoblastoma protein and known prognostic variables in locally advanced bladder cancer. J Natl Cancer Inst 1992;84:1256-1261. [Free Full Text]
Skinner DG. Management of invasive bladder cancer: a meticulous pelvic node dissection can make a difference. J Urol 1982;128:34-36. [Medline]
Skinner DG, Daniels JR, Russell CA, et al. The role of adjuvant chemotherapy following cystectomy for invasive bladder cancer: a prospective comparative trial. J Urol 1991;145:459-467. [Medline]
Stockle M, Meyenburg W, Wellek S, et al. Advanced bladder cancer (stages pT3b, pT4a, pN1 and pN2): improved survival after radical cystectomy and 3 adjuvant cycles of chemotherapy: results of a controlled prospective study. J Urol 1992;148:302-307. [Medline]
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. [Free Full Text]
Lipponen PK. Over-expression of p53 nuclear oncoprotein in transitional-cell bladder cancer and its prognostic value. Int J Cancer 1993;53:365-370. [Medline]
Bergkvist A, Ljungqvist A, Moberger G. Classification of bladder tumours based on the cellular pattern. Acta Chir Scand 1965;130:371-378. [Medline]
Hermanek P, Sobin LH, eds. TNM classification of malignant tumors. 4th ed. New York: Springer-Verlag, 1987:133-4.
Fienberg SE. The analysis of cross-classified categorical data. Cambridge, Mass.: MIT Press, 1977:9-86.
Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958;53:457-81.
Miller RG Jr. Survival analysis. New York: John Wiley, 1981:44-102.
Finlay CA, Hinds PW, Tan TH, Eliyahu D, Oren M, Levine MJ. Activating mutations for transformation by p53 produce a gene product that forms an hsc70-p53 complex with an altered half-life. Mol Cell Biol 1988;8:531-539. [Free Full Text]
Oliner JD, Kinzler KW, Meltzer PS, George DL, Vogelstein B. Amplification of a gene encoding a p53-associated protein in human sarcomas. Nature 1992;358:80-83. [CrossRef][Medline]
Cordon-Cardo C, Latres E, Drobjnak M, et al. Molecular abnormalities of mdm2 and p53 genes in adult soft tissue sarcomas. Cancer Res 1994;54:794-799. [Free Full Text]
Kastan MB, Onyekwere O, Sidransky D, Vogelstein B, Craig RW. Participation of p53 protein in the cellular response to DNA damage. Cancer Res 1991;51:6304-6311. [Medline]
p53 and Bladder Cancer
Li W. W., Li V. W., Tsakayannis D., Xing X., Wood L. L., Cote R. J., Skinner D. G., Jones P. A.
Extract |
Full Text
N Engl J Med 1995;
332:957-958, Apr 6, 1995.
Correspondence
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[Abstract][Full Text]
Takata, R., Katagiri, T., Kanehira, M., Tsunoda, T., Shuin, T., Miki, T., Namiki, M., Kohri, K., Matsushita, Y., Fujioka, T., Nakamura, Y.
(2005). Predicting Response to Methotrexate, Vinblastine, Doxorubicin, and Cisplatin Neoadjuvant Chemotherapy for Bladder Cancers through Genome-Wide Gene Expression Profiling. Clin. Cancer Res.
11: 2625-2636
[Abstract][Full Text]
Goebell, P. J., Groshen, S., Schmitz-Drager, B. J., Sylvester, R., Kogevinas, M., Malats, N., Sauter, G., Grossman, H. B., Dinney, C. P.N., Waldman, F., Cote, R. J.
(2005). Concepts for Banking Tissue in Urologic Oncology--The International Bladder Cancer Bank. Clin. Cancer Res.
11: 413-415
[Full Text]
Schultz, I. J., Kiemeney, L. A., Karthaus, H. F.M., Witjes, J. A., Willems, J. L., Swinkels, D. W., Gunnewiek, J. M.T. K., de Kok, J. B.
(2004). Survivin mRNA Copy Number in Bladder Washings Predicts Tumor Recurrence in Patients with Superficial Urothelial Cell Carcinomas. Clin. Chem.
50: 1425-1428
[Full Text]
Kawamura, K., Izumi, H., Ma, Z., Ikeda, R., Moriyama, M., Tanaka, T., Nojima, T., Levin, L. S., Fujikawa-Yamamoto, K., Suzuki, K., Fukasawa, K.
(2004). Induction of Centrosome Amplification and Chromosome Instability in Human Bladder Cancer Cells by p53 Mutation and Cyclin E Overexpression. Cancer Res.
64: 4800-4809
[Abstract][Full Text]
Shariat, S. F., Tokunaga, H., Zhou, J., Kim, J., Ayala, G. E., Benedict, W. F., Lerner, S. P.
(2004). p53, p21, pRB, and p16 Expression Predict Clinical Outcome in Cystectomy With Bladder Cancer. JCO
22: 1014-1024
[Abstract][Full Text]
Chatterjee, S. J., Datar, R., Youssefzadeh, D., George, B., Goebell, P. J., Stein, J. P., Young, L., Shi, S.-R., Gee, C., Groshen, S., Skinner, D. G., Cote, R. J.
(2004). Combined Effects of p53, p21, and pRb Expression in the Progression of Bladder Transitional Cell Carcinoma. JCO
22: 1007-1013
[Abstract][Full Text]
Catto, J. W. F., Linkens, D. A., Abbod, M. F., Chen, M., Burton, J. L., Feeley, K. M., Hamdy, F. C.
(2003). Artificial Intelligence in Predicting Bladder Cancer Outcome: A Comparison of Neuro-Fuzzy Modeling and Artificial Neural Networks. Clin. Cancer Res.
9: 4172-4177
[Abstract][Full Text]
Pagliaro, L. C., Keyhani, A., Williams, D., Woods, D., Liu, B., Perrotte, P., Slaton, J. W., Merritt, J. A., Grossman, H. B., Dinney, C. P.
(2003). Repeated Intravesical Instillations of an Adenoviral Vector in Patients With Locally Advanced Bladder Cancer: A Phase I Study of p53 Gene Therapy. JCO
21: 2247-2253
[Abstract][Full Text]
Loukopoulos, P., Thornton, J. R., Robinson, W. F.
(2003). Clinical and Pathologic Relevance of p53 Index in Canine Osseous Tumors. Vet Pathol
40: 237-248
[Abstract][Full Text]
Derenzini, M., Montanaro, L., Chilla, A., Tosti, E., Ceccarelli, C., Dall'Olio, F., Ofner, D., Trere, D.
(2002). Evaluation of Thymidylate Synthase Protein Expression by Western Blotting and Immunohistochemistry on Human Colon Carcinoma Xenografts in Nude Mice. J. Histochem. Cytochem.
50: 1633-1640
[Abstract][Full Text]
Stoeber, K., Swinn, R., Prevost, A. T., de Clive-Lowe, P., Halsall, I., Dilworth, S. M., Marr, J., Turner, W. H., Bullock, N., Doble, A., Hales, C. N., Williams, G. H.
(2002). Diagnosis of Genito-Urinary Tract Cancer by Detection of Minichromosome Maintenance 5 Protein in Urine Sediments. JNCI J Natl Cancer Inst
94: 1071-1079
[Abstract][Full Text]
Lin, H-J, Chen, W-C, Tsai, F-J, Tsai, S-W
(2002). Distributions of p53 codon 72 polymorphism in primary open angle glaucoma. Br. J. Ophthalmol.
86: 767-770
[Abstract][Full Text]
Cheng, H.-L., Trink, B., Tzai, T.-S., Liu, H.-S., Chan, S.-H., Ho, C.-L., Sidransky, D., Chow, N.-H.
(2002). Overexpression of c-met as a Prognostic Indicator for Transitional Cell Carcinoma of the Urinary Bladder: A Comparison With p53 Nuclear Accumulation. JCO
20: 1544-1550
[Abstract][Full Text]
Kuball, J., Wen, S. F., Leissner, J., Atkins, D., Meinhardt, P., Quijano, E., Engler, H., Hutchins, B., Maneval, D. C., Grace, M. J., Fritz, M. A., Storkel, S., Thuroff, J. W., Huber, C., Schuler, M.
(2002). Successful Adenovirus-Mediated Wild-Type p53 Gene Transfer in Patients With Bladder Cancer by Intravesical Vector Instillation. JCO
20: 957-965
[Abstract][Full Text]
Pollack, I. F., Finkelstein, S. D., Woods, J., Burnham, J., Holmes, E. J., Hamilton, R. L., Yates, A. J., Boyett, J. M., Finlay, J. L., Sposto, R., the Children's Cancer Group,
(2002). Expression of p53 and Prognosis in Children with Malignant Gliomas. NEJM
346: 420-427
[Abstract][Full Text]
Murphy, W. M.
(2002). Human Carcinogenesis, the New Genetics, and the Practicing Pathologist. INT J SURG PATHOL
10: 1-5
[Abstract]
Lu, M.-L., Wikman, F., Orntoft, T. F., Charytonowicz, E., Rabbani, F., Zhang, Z., Dalbagni, G., Pohar, K. S., Yu, G., Cordon-Cardo, C.
(2002). Impact of Alterations Affecting the p53 Pathway in Bladder Cancer on Clinical Outcome, Assessed by Conventional and Array-based Methods. Clin. Cancer Res.
8: 171-179
[Abstract][Full Text]
Latronico, A. C., Pinto, E. M., Domenice, S., Fragoso, M. C. B. V., Martin, R. M., Zerbini, M. C., Lucon, A. M., Mendonca, B. B.
(2001). An Inherited Mutation Outside the Highly Conserved DNA-Binding Domain of the p53 Tumor Suppressor Protein in Children and Adults with Sporadic Adrenocortical Tumors. J. Clin. Endocrinol. Metab.
86: 4970-4973
[Abstract][Full Text]
Pollack, I. F., Finkelstein, S. D., Burnham, J., Holmes, E. J., Hamilton, R. L., Yates, A. J., Finlay, J. L., Sposto, R.
(2001). Age and TP53 Mutation Frequency in Childhood Malignant Gliomas: Results in a Multi-institutional Cohort. Cancer Res.
61: 7404-7407
[Abstract][Full Text]
Knowles, M A
(2001). What we could do now: molecular pathology of bladder cancer. Mol. Pathol.
54: 215-221
[Abstract][Full Text]
Inoue, K., Slaton, J. W., Karashima, T., Yoshikawa, C., Shuin, T., Sweeney, P., Millikan, R., Dinney, C. P. N.
(2000). The Prognostic Value of Angiogenesis Factor Expression for Predicting Recurrence and Metastasis of Bladder Cancer after Neoadjuvant Chemotherapy and Radical Cystectomy. Clin. Cancer Res.
6: 4866-4873
[Abstract][Full Text]
Schneider, A., Borgnat, S., Lang, H., Régine, O., Lindner, V., Kassem, M., Saussine, C., Oudet, P., Jacqmin, D., Gaub, M. P.
(2000). Evaluation of Microsatellite Analysis in Urine Sediment for Diagnosis of Bladder Cancer. Cancer Res.
60: 4617-4622
[Abstract][Full Text]
McShane, L. M., Aamodt, R., Cordon-Cardo, C., Cote, R., Faraggi, D., Fradet, Y., Grossman, H. B., Peng, A., Taube, S. E., Waldman, F. M., Network, t. N. C. I. B. T. M.
(2000). Reproducibility of p53 Immunohistochemistry in Bladder Tumors. Clin. Cancer Res.
6: 1854-1864
[Abstract][Full Text]
LaRue, H., Allard, P., Simoneau, M., Normand, C., Pfister, C., Moore, L., Meyer, F., Tetu, B., Fradet, Y.
(2000). P53 point mutations in initial superficial bladder cancer occur only in tumors from current or recent cigarette smokers. Carcinogenesis
21: 101-106
[Abstract][Full Text]
Krasna, M. J., Mao, Y. S., Sonett, J. R., Tamura, G., Jones, R., Suntharalingam, M., Meltzer, S. J.
(1999). P53 gene protein overexpression predicts results of trimodality therapy in esophageal cancer patients. Ann. Thorac. Surg.
68: 2021-2024
[Abstract][Full Text]
Qureshi, K. N., Griffiths, T. R. L., Robinson, M. C., Marsh, C., Roberts, J. T., Hall, R. R., Lunec, J., Neal, D. E.
(1999). TP53 Accumulation Predicts Improved Survival in Patients Resistant to Systemic Cisplatin-based Chemotherapy forMuscle-invasive Bladder Cancer. Clin. Cancer Res.
5: 3500-3507
[Abstract][Full Text]
Del Pizzo, J. J., Borkowski, A., Jacobs, S. C., Kyprianou, N.
(1999). Loss of Cell Cycle Regulators p27Kip1 and Cyclin E in Transitional Cell Carcinoma of the Bladder Correlates with Tumor Grade and Patient Survival. Am. J. Pathol.
155: 1129-1136
[Abstract][Full Text]
Lee, C. C. R., Ichihara, T., Yamamoto, S., Wanibuchi, H., Sugimura, K., Wada, S., Kishimoto, T., Fukushima, S.
(1999). Reduced expression of the CDK inhibitor p27KIP1 in rat two-stage bladder carcinogenesis and its association with expression profiles of p21WAF1/Cip1 and p53. Carcinogenesis
20: 1697-1708
[Abstract][Full Text]
PEI, Y., WATNICK, T., HE, N., WANG, K., LIANG, Y., PARFREY, P., GERMINO, G., GEORGE-HYSLOP, P. ST.
(1999). Somatic PKD2 Mutations in Individual Kidney and Liver Cysts Support a "Two-Hit" Model of Cystogenesis in Type 2 Autosomal Dominant Polycystic Kidney Disease. J. Am. Soc. Nephrol.
10: 1524-1529
[Abstract][Full Text]
Yeager, T. R., DeVries, S., Jarrard, D. F., Kao, C., Nakada, S. Y., Moon, T. D., Bruskewitz, R., Stadler, W. M., Meisner, L. F., Gilchrist, K. W., Newton, M. A., Waldman, F. M., Reznikoff, C. A.
(1998). Overcoming cellular senescence in human cancer pathogenesis. Genes Dev.
12: 163-174
[Abstract][Full Text]
Li, W. W., Li, V. W., Tsakayannis, D., Xing, X., Wood, L. L., Cote, R. J., Skinner, D. G., Jones, P. A.
(1995). p53 and Bladder Cancer. NEJM
332: 957-958
[Full Text]
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