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Disrupted p53 Function as Predictor of Treatment Failure and Poor Prognosis in B- and T-Cell Non-Hodgkin’s Lymphoma¹

Departments of Pathology [M. B. M., N. T. P.], Clinical Genetics [A-M. G.], and Medical Microbiology [K. S.], Odense University, DK-5000 Odense, and Department of Medical Statistics, Danish Computing Centre for Research and Education, DK-8200 Aarhus [L. S. M.], Denmark

	ABSTRACT

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Mutation of the p53 gene has been associated with treatment failure and poor outcome in various malignancies. It has been suggested that immunohistochemical analysis of p53 and p21^Waf1, a downstream target, can be used to screen for p53 gene mutations. We determined the value of immunohistochemical screening for p53 gene mutations as a prognostic marker in a population-based group of B- and T-cell non-Hodgkin’s lymphomas (NHLs). On the basis of p53 gene mutation status and immunohistochemically detected p53 and p21^Waf1 expression in 34 lymphomas, we established an immunophenotype (p53) correlating with p53 gene mutation. The immunohistochemical analysis was extended to encompass 199 lymphomas from a population-based registry and was correlated with clinical parameters. p53 showed 100% concordance with p53 gene mutation and was detected in 42 cases (21%). Multivariate analysis of advanced stage lymphomas showed that p53 was independently associated with treatment failure (relative risk, 3.8; P = 0.001). p53 predicted poor survival when analyzing all patients (P = 0.0001), as well as B-cell (P = 0.04) and T-cell NHL (P = 0.000002). In multivariate analysis, p53 (relative risk, 2.2; P = 0.001) maintained prognostic significance. The impact on prognosis of p53 was highly significant in the low-intermediate-risk group (P = 0.00002). Comparing survival of the aggressive lymphoma patients in this group showed that the 8 p53 patients died within 1 year, whereas the median survival of the 28 non-p53 patients was 36 months. These results suggest that immunohistochemically assessed p53 status may predict treatment response and outcome in B- and T-cell NHL patients.

	INTRODUCTION

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NHL³ is becoming an increasing clinical problem because of a steady annual increase in incidence. The age-adjusted incidence increased 85% in the United States from 1973 to 1995 (1) . Only four cancer types cause more person-years of life to be lost (1) . It is, therefore, highly important to improve diagnosis and therapy of this disease. One important aspect of this is to identify patients with a poor prognosis to plan the treatment strategy accordingly, be it intensified standard treatment or an experimental regimen. Since the publication of the IPI (2) , it has been widely used to categorize patients into risk groups. Although the IPI was constructed for aggressive NHL, it has been shown also to be valuable in other NHL subtypes (3, 4, 5, 6) . The IPI is based on patient characteristics related to patient constitution (age, performance status) and variables indirectly reflecting the tumors biology (LDH, extranodal disease, stage). To improve on the index, biological factors more directly relating to clinical characteristics of the individual tumor, such as chemo- or radio-sensitivity, will be needed. Efforts have been made to associate molecular factors related to such important tumor biology functions as proliferation (7) , cell cycle progression (8) , apoptosis (9) , and invasion (10) with a predictive value in NHL.

The p53 tumor suppressor gene is one of the most frequently mutated genes in human cancer (11) . It functions as an integrator of cellular responses to DNA damage (12 , 13) , and is vital in assuring genome stability (14) . Mutation of the p53 gene is associated with poor prognosis in patients with aggressive B-cell NHL (15) . Most p53 gene mutations in NHL are missense mutations stabilizing—possibly mediated by interaction with MDM2 (16) —the functionally defect protein (17, 18, 19, 20) . As a result, the mutated p53 protein is unable to induce downstream targets such as p21^Waf1. Immunohistochemical detection of p53 and its downstream target p21^Waf1 has been shown to predict presence of p53 gene mutations (18) . This population-based study addresses the value of an immunophenotype indicative of p53 gene mutation (p53) in predicting outcome in B- and T-cell NHL. The optimal criteria for defining p53 was established by immunohistochemically analyzing 34 lymphomas with known p53 gene status from our previous molecular biological studies (21) . We found that p53, identified by simple and low-cost immunohistochemistry assays applicable in routine diagnostic laboratories, independently predicted poor survival in both B- and T-cell NHL.

	PATIENTS AND METHODS

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Patients and Tumors.
Since January 1, 1983, the LYFO has registered clinical and pathoanatomical data on all newly diagnosed primary NHL patients 15 years of age in a population-based registry covering western Denmark (2.8 million inhabitants). We previously described the LYFO registry, including exclusion criteria, hematopathological analysis, staging, and follow-up procedures (22, 23, 24) . Briefly, from the 3212 consecutive cases in the LYFO registry diagnosed between January 1, 1984, and December 31, 1994, we retrieved 206 previously untreated patients from Odense University Hospital by obtaining consecutive cases from each of a number of selected major histological entities. Of these 206 patients, 7 were excluded because no tissue from the time of initial diagnosis was available for analysis. For the present study, all specimens were reviewed and reclassified based on morphological examination of paraffin sections, as well as immunophenotyping using flow cytometry and immunohistochemistry on paraffin and frozen sections, according to the Revised European-American Lymphoma classification (25) . For clinical grading, the scheme proposed by Hiddemann et al. (26) was used. Our final study population (n = 199) consisted of 72 indolent B-lymphomas [B-cell chronic lymphocytic lymphoma (14 cases), immunocytoma (17 cases), FCL grade I/II (21 cases), and extranodal marginal zone lymphoma (20 cases)], 74 aggressive B-lymphomas [FCL III (4 cases), FCL diffuse (4 cases), mantle cell lymphoma (15 cases), and DLCL (51 cases)], 37 aggressive T-lymphomas [peripheral T-cell lymphoma (21 unspecified, 6 angioimmunoblastic, 1 angiocentric, and 1 intestinal T-cell lymphoma) and anaplastic large T- or Null-cell lymphoma (8 cases)], and 16 very aggressive lymphomas [B-lymphoblastic lymphoma (5 cases), Burkitt’s lymphoma (3 cases), and T-lymphoblastic lymphoma (8 cases)]. The observation period analyzed was up to 5 years (until December 31, 1996) or death, whichever came first. No patients were lost to follow-up. The median follow-up period for patients alive at the end of the observation period was 60 months (range, 36–60).

The 72 indolent lymphomas were treated with combination chemotherapy in 25 cases (including anthracycline in 19 cases), single alkylating agents in 24 cases, radiotherapy and/or surgery in 21 cases, and no treatment in 2 cases. Forty-two patients treated with chemotherapy had advanced stage NHL, whereas 19 of 21 patients treated with radiotherapy and/or surgery had stage I or II disease. Treatment of the 74 aggressive B-lymphomas consisted of combination chemotherapy in 58 cases (anthracycline-containing in 46 cases, primarily cyclophosphamide, doxorubicin, vincristine, and prednisone), single alkylating agents in 5 cases, and other approaches in 11 cases. The 37 aggressive T-lymphomas primarily received combination chemotherapy with (24 cases) or without (4 cases) anthracycline. Two patients received radiotherapy, four patients were treated with interferon or prednisone, and three patients had no initial therapy. Fifteen of 16 very aggressive lymphomas were treated with high-dose combination chemotherapy with central nervous system prophylaxis in 12 cases. One patient died before therapy was instigated.

Data allowing allocation of the patients to the IPI risk groups (2) , which are based on age (>60 years), LDH (>1 x normal), Eastern Cooperative Oncology Group performance status (2, 3, 4) , number of extranodal sites (>1), and stage (III or IV), were available for 193 patients.

We compared the clinical characteristics of our study population with those of the remaining patients (n = 3013) of the LYFO population from the study period for each histological entity separately, as well as the two populations overall. There were no significant differences in age, sex, stage, PS, B symptoms, LDH, number of extranodal sites involved, CR rates (27) , and OS. Furthermore, the distribution of IPI risk group assignment was not significantly different between the study population and the remaining LYFO patients.

Laboratory Assays.
Using sections from two compound paraffin blocks, one composed of numerous benign and malignant tissues of various histiogenesis and the other containing various lymphoma subtypes as well as benign lymphoid tissue, we established optimal conditions for immunostaining for p21^Waf1 with the monoclonal antibodies 4D10 (Novocastra, Newcastle, United Kingdom), EA10 (Oncogene Research, Cambridge, MA), and 6B6 (PharMingen, San Diego, CA). The antibodies showed nearly identical reaction patterns, but because it had a superior signal-to-noise relation, EA10 was chosen for the study. We used the same material to optimize the conditions for the anti-p53 antibody DO-7 (DAKO, Glostrup, Denmark), which recognizes both wild-type and mutant p53 (28) . Optimal dilution for EA10 and DO-7 was 1:25 and 1:100, respectively. Briefly, deparaffinized 4-µm sections were submitted to microwave oven antigen retrieval in T-EG buffer [10 mM Tris (Sigma Chemical Co., St. Louis, MO) and 0.5 mM EGTA (pH 9.0; Sigma Chemical Co.)] or 10 mM citrate buffer (DO-7; pH 6.0), followed by incubation overnight at 4°C with primary antibody. TechMate 1000 (DAKO) was used for automated staining using the LSAB+ kit (DAKO) with diaminobenzidine as chromogen and brief counterstaining in Mayer’s hematoxylin. Sections from the compound blocks served as positive and negative (omitted primary antibody) controls.

Brown nuclear coloration was considered positive immunoreaction. The reactivity was quantified using the image analysis software ImagePro Plus (Media Cybernetics, Silver Spring, MD). Briefly, in areas with highest expression of p53 and p21^Waf1, respectively, the number of immunopositive cells was counted among the total number of cells. Typically 1000–3000 cells were counted. The quantification was done by a single observer, who had no previous knowledge of clinical outcome or other clinical variables.

Statistical Analysis.
Univariate association was analyzed using Fisher’s exact test, Pearsons ² test, or McNemar’s test (29) . OS was calculated from the time from definitive diagnosis to death from any cause in or to the end of the observation. RFS of patients with CR was calculated from the time from achievement of CR to relapse, death, or end of the follow-up period. Survival curves were calculated using the method of Kaplan and Meier (30) and compared using the log-rank test (31) stratified by clinical grade (indolent B-NHL, aggressive B-NHL, aggressive T-NHL, and very aggressive NHL), unless stated otherwise. Factors independently affecting CR, OS, and RFS were identified using a Cox proportional hazards regression model (Ref. 32 ; P 0.10 for entry into model, P 0.10 to remain in model) stratified by grade. All Ps are two-sided and considered significant if <0.05. SPSS for Windows, version 8.0.0 (SPSS Ltd., Chicago, IL), was used for all calculations.

	RESULTS

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Association of p53 Gene Mutations with p53 and p21^Waf1 Expression.
The seven mutations found in the p53 gene in 7 of the 34 primary DLCLs analyzed were single nucleotide missense mutations (Table 1) and were described previously (21) . The results of immunostaining of these seven tumors are shown in Table 1 . On the basis of this, we wanted to establish which p53/p21^Waf1 phenotype predicted p53 gene mutation status best. All mutated tumors would be included if a cutoff value for p53 of >5% was chosen. However, 8 of 27 of the remaining nonmutated tumors would also be included. A cutoff value of 20% excluded nonmutated tumors, but left out two of seven mutated tumors. To distinguish between mutated and nonmutated tumors with p53 expression ranging from 6–20%, p21^Waf1 expression was very helpful. Mutated tumors, and only mutated tumors in this group, were p21^Waf1-negative. An immunophenotype satisfying at least one of two criteria (p53 20% or a combination of p53 >5% and negative p21^Waf1), p53, showed both 100% specificity and 100% sensitivity in predicting p53 gene mutations in DLCL.

Characteristics of Patients with p53.

Analysis of Survival.
p53 status was significantly associated with poor OS in our study population (P = 0.0001; Fig. 1 ). When considering the different clinical grades of NHL, differences emerge. The association of p53 with poor survival is highly significant in aggressive T-NHL (P = 0.000006; P = 0.0001 if stratified by peripheral T-cell lymphoma versus anaplastic large cell lymphoma), but also significant in lymphomas not included in this group (P = 0.03). For both B-NHL (P = 0.04) and T/Null-NHL (P = 0.000002), p53 was associated with shorter survival. Multivariate analysis of OS of all patients with the IPI prognostic factors, treatment (combination chemotherapy versus single alkylating agent versus other treatments), and p53 in a Cox model showed that p53 maintained prognostic significance (Table 3) . Furthermore, in Cox analysis excluding the stratum of aggressive T-NHL, where p53 is highly significant, p53 maintained independent prognostic significance (RR = 1.7; P = 0.05).

View larger version (15K): [in this window] [in a new window] [Download PPT slide]   Fig. 1. OS of lymphoma patients according to p53 status. A, the survival of all 199 lymphoma patients, illustrating the poorer survival of the patients with disrupted p53 phenotype (P = 0.0001). B, the dismal survival of the 6 T-cell lymphoma patients with altered p53 as compared with the 31 T-cell lymphoma patients with normal p53 (P = 0.000006). C, survival of the 162 patients with indolent, aggressive, or very aggressive lymphomas, other than aggressive T-cell lymphoma patients, is seen, showing shorter survival of the patients with disrupted p53 (P = 0.03). The number of patients at risk at time 0 and 30 and 60 months is shown for each group.

View larger version (16K): [in this window] [in a new window] [Download PPT slide]   Fig. 2. OS of the 65 indolent and aggressive lymphoma patients in the low-intermediate-risk IPI group according to p53 status. The 13 patients with altered p53 status had a significantly poorer outcome as compared with the 52 patients with a normal p53 phenotype (P = 0.00002). The number of patients at risk at time 0 and 30 and 60 months is shown for each group.

	DISCUSSION

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This study of a population-based group of NHL patients is the first to show that an immunohistochemical phenotype indicative of altered p53 function, p53, is independently associated with poor outcome in both B- and T-cell NHL. p53 predicts poor OS in indolent and aggressive NHL and, furthermore, is associated with treatment failure and shortened RFS.

Previous studies have also linked p53 with prognosis in selected NHL entities (20 , 33 , 34) . However, only in aggressive B-cell NHL has an independent prognostic value of p53 gene mutation been demonstrated (15) . The approach used was to identify p53 gene mutations in fresh tissue using a PCR-based single-strand confirmation polymorphism assay, followed by direct sequencing. Our approach of immunohistochemistry on paraffin-embedded formalin-fixed tissue has several advantages. Immunohistochemistry is inexpensive, nonradioactive, nonlabor-intensive, and readily applicable in routine diagnostic laboratories. Reproducibility of the immunostaining was ensured by using a semiautomated staining instrument. Furthermore, our method does not require fresh tissue, making it feasible in cases where only fixed tissue is available.

Studies correlating p53 gene mutation with p53 (and, in some reports, p21^Waf1) expression in NHL show that a stronger correlation with p53 gene mutation is obtained with the DO-7 (20 , 33, 34, 35, 36, 37) or DO-1 (18 , 38) anti-p53 antibodies as compared with studies of other antibodies (39, 40, 41) . p21^Waf1 expression is helpful in predicting the functional status of p53, but it is not an absolute measure. Patient 2 (Table 1) expressed high levels of p21^Waf1 despite that the p53 gene showed a 175His mutation. This supports the presence of a p53-independent way of inducing p21^Waf1 (42) because this particular apoptosis-disruptive mutation is not among those with intact p21^Waf1-inducing capacity (43) .

The optimal cutoff values for p53 and p21^Waf1 expression vary among laboratories (18 , 20 , 33, 34, 35, 36, 37, 38) . This reflects differences in fixation and processing of samples. It is, therefore, important for a laboratory introducing this immunohistochemical assay to establish which conditions are the most predictive in that particular laboratory setting, preferably by analyzing a sample of tumors with known p53 gene status.

An underlying assumption in our extrapolation from p53 gene mutation in DLCL to other NHL entities is that the types of mutations and their association with protein expression are comparable throughout the lymphoma entities. Previous studies justify this assumption (18 , 20 , 33, 34, 35, 36 , 38) . A review of the 113 published p53 gene mutations with data on p53 expression using DO-7 or DO-1 antibodies available showed that among the 67 mutations identified in DLCL only 7 (10%) were not missense mutations or other mutation types with p53 expression. In lymphomas other than DLCL, the number was 4 (9%) of 46 mutations. A limitation to the immunohistochemical approach to identify disrupted p53 function is shown, however, by the fact that the reviewed five (4%) nonsense mutations producing a stop codon consistently were p53-negative.

Disruption of p53-dependent apoptosis could contribute significantly to the poor prognosis of NHL with p53. Previous studies have shown that apoptosis induction, efficacy of anticancer agents of different classes, and radiotherapy are reduced in cell lines and tumors with p53 gene mutations (44, 45, 46) , including Burkitt’s lymphoma cell lines (47 , 48) . An exception from this pattern is provided by antimitotic agents, the apoptosis-inducing capacity of which is not affected by p53 gene status (46 , 49 , 50) . These results are in agreement with the finding in this and other studies (15 , 35) of an association between p53 malfunction and treatment failure in NHL. This association is not absolute and, therefore, suggests that in cases with wild-type p53 and poor response to treatment apoptosis is circumvented by defects either of other components of the p53 pathway or of p53-independent apoptosis-inducing pathways. Furthermore, our finding of the adverse clinical impact of p53 being present primarily in the low-intermediate-risk IPI group and not in the higher risk groups, which is in agreement with a previous study (15) , suggests that the tumors in the higher-risk groups have accumulated sufficient genetic changes to make p53 disruption less important.

These results must necessarily be confirmed on larger prospective series of NHL patients, making analysis of clinical impact of p53 status in individual NHL entities possible. Our finding, however, of p53 as an independent marker of poor prognosis and treatment failure, even abolishing the difference between the low-intermediate- and high-intermediate-risk groups in aggressive NHL, suggests that p53 status could be important to consider when treatment strategies for individual patients are selected. Likewise, p53 status should be considered when planning and analyzing clinical trials. To significantly improve the treatment of patients with disrupted p53 function, it is imperative that alternative treatment strategies, not relying on p53-dependent apoptosis, are developed.

	ACKNOWLEDGMENTS

 
We are grateful to Dr. David N. Louis (Massachusetts General Hospital, Boston, MA) for help with image analysis. We, furthermore, thank the Research Unit at the Department of Pathology (Odense University Hospital, Odense, Denmark) and Marianne Christensen for technical assistance.

	FOOTNOTES

 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported by grants from the Danish Medical Research Council, the Danish Cancer Research Foundation, the Karen Krieger Foundation, and Odense University.

² To whom requests for reprints should be addressed, at Department of Pathology, Odense University, Winsløwparken 15, DK-5000 Odense C, Denmark. Phone: 45-6541-4813; Fax: 45-6591-2943; E-mail: m.moeller{at}imbmed.ou.dk

³ The abbreviations used are: NHL, non-Hodgkin’s lymphoma; IPI, International Prognostic Index; LDH, serum lactate dehydrogenase; LYFO, Danish Lymphoma Group; FCL, follicular center lymphoma; DLCL, diffuse large B-cell lymphoma; CR, complete response; OS, overall survival; RFS, relapse-free survival; RR, relative risk; PS, performance score.

Received 11/ 2/98; accepted 2/ 1/99.

	REFERENCES

Top ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 

1. Ries L. A. G., Kosary C. L., Hankey B. F., Miller B. A., Edwards B. K. SEER Cancer Statistics Review, 1973–1995 National Cancer Institute Bethesda, MD 1998.
2. Shipp M. A., Harrington D. P., Anderson J. R., Armitage J. O., Bonadonna G., Brittinger G., Cabanillas F., Canellos G. P., Coiffier B., Connors J. M., Cowan R. A., Crowther D., Dahlberg S., Engelhard M., Fisher R. I., Gisselbrecht C., Horning S. J., Lepage E., Lister T. A., Meerwald J. H., Montserrat E., Nissen N. I., Oken M. M., Peterson B. A., Tondini C., Velasquez W. A., Yeap B. Y. A predictive model for aggressive non-Hodgkin’s lymphoma. The International Non-Hodgkin’s Lymphoma Prognostic Factors Project. N. Engl. J. Med., 329: 987-994, 1993.[Abstract/Free Full Text]
3. Lopez-Guillermo A., Montserrat E., Bosch F., Terol M. J., Campo E., Rozman C. Applicability of the International Index for aggressive lymphomas to patients with low-grade lymphoma. J. Clin. Oncol., 12: 1343-1348, 1994.[Abstract]
4. Hermans J., Krol A. D. G., van Groningen K., Kluin P. M., Kluin-Nelemans J. C., Kramer M. H. H., Noordijk E. M., Ong F., Wijermans P. W. International Prognostic Index for aggressive non-Hodgkin’s lymphoma is valid for all malignancy grades. Blood, 86: 1460-1463, 1995.[Abstract/Free Full Text]
5. Ansell S. M., Habermann T. M., Kurtin P. J., Witzig T. E., Chen M. G., Li C. Y., Inwards D. J., Colgan J. P. Predictive capacity of the International Prognostic Factor Index in patients with peripheral T-cell lymphoma. J. Clin. Oncol., 15: 2296-2301, 1997.[Abstract/Free Full Text]
6. Bastion Y., Blay J. Y., Divine M., Brice P., Bordessoule D., Sebban C., Blanc M., Tilly T., Lederlin P., Deconinck E., Salles B., Dumontet C., Briere J., Coiffier B. Elderly patients with aggressive non-Hodgkin’s lymphoma: disease presentation, response to treatment, and survival—a Groupe d’Etude des Lymphomes de l’Adulte study on 453 patients older than 69 years. J. Clin. Oncol., 15: 2945-2953, 1997.[Abstract]
7. Miller T. P., Grogan T. M., Dahlberg S., Spier C. M., Braziel R. M., Banks P. M., Foucar K., Kjeldsberg C. R., Levy N., Nathwani B. N., Schnitzer B., Tubbs R., Gaynor E. R., Fisher R. I. Prognostic significance of the Ki-67-associated proliferative antigen in aggressive non-Hodgkin’s lymphomas: a prospective Southwest Oncology Group trial. Blood, 83: 1460-1466, 1994.[Abstract/Free Full Text]
8. Erlanson M., Portin C., Linderholm B., Lindh J., Roos G., Landberg G. Expression of cyclin E and the cyclin-dependent kinase inhibitor p27 in malignant lymphomas: prognostic implications. Blood, 92: 770-777, 1998.[Abstract/Free Full Text]
9. Gascoyne R. D., Krajewska M., Krajewski S., Connors J. M., Reed J. C. Prognostic significance of Bax protein expression in diffuse aggressive non-Hodgkin’s lymphoma. Blood, 90: 3173-3178, 1997.[Abstract/Free Full Text]
10. Terol M. J., Lopez-Guillermo A., Bosch F., Villamor N., Cid M. C., Rozman C., Campo E., Montserrat E. Expression of the adhesion molecule ICAM-1 in non-Hodgkin’s lymphoma: relationship with tumor dissemination and prognostic importance. J. Clin. Oncol., 16: 35-40, 1998.[Abstract/Free Full Text]
11. Greenblatt M. S., Bennett W. P., Hollstein M., Harris C. C. Mutations in the p53 tumor suppressor gene: clues to cancer etiology and molecular pathogenesis. Cancer Res., 54: 4855-4878, 1994.[Free Full Text]
12. Kastan M. B., Onyekwere O., Sidransky D., Vogelstein B., Craig R. W. Participation of p53 protein in the cellular response to DNA damage. Cancer Res., 51: 6304-6311, 1991.[Medline]
13. Nelson W. G., Kastan M. B. DNA strand breaks: the DNA template alterations that trigger p53-dependent DNA damage response pathways. Mol. Cell. Biol., 14: 1815-1823, 1994.[Abstract/Free Full Text]
14. Griffiths S. D., Clarke A. R., Healy L. E., Ross G., Ford A. M., Hooper M. L., Wyllie A. H., Greaves M. Absence of p53 permits propagation of mutant cells following genotoxic damage. Oncogene, 14: 523-531, 1997.[Medline]
15. Ichikawa A., Kinoshita T., Watanabe T., Kato H., Nagai H., Tsushita K., Saito H., Hotta T. Mutations of the p53 gene as a prognostic factor in aggressive B-cell lymphoma. N. Engl. J. Med., 337: 529-534, 1997.[Abstract/Free Full Text]
16. Midgley C. A., Lane D. P. p53 protein stability in tumour cells is not determined by mutation but is dependent on Mdm2 binding. Oncogene, 15: 1179-1189, 1997.[Medline]
17. Gaidano G., Ballerini P., Gong J. Z., Inghirami G., Neri A., Nemcomb E. W., Magrath I. T., Knowles D. M., Dalla-Favera R. p53 mutations in human lymphoid malignancies: association with Burkitt lymphoma and chronic lymphocytic leukemia. Proc. Natl. Acad. Sci. USA, 88: 5413-5417, 1991.[Abstract/Free Full Text]
18. Chilosi M., Doglioni C., Magalini A., Inghirami G., Krampera M., Nadali G., Rahal D., Pedron S., Benedetti A., Scardoni M., Macrì E., Lestani M., Menestrina F., Pizzolo G., Scarpa A. p21/WAF1 cyclin-kinase inhibitor expression in non-Hodgkin’s lymphomas: a potential marker of p53 tumor-suppressor gene function. Blood, 88: 4012-4020, 1996.[Abstract/Free Full Text]
19. Finlay C. A., Hinds P. W., Tan T. H., Eliyahu D., Oren M., Levine A. J. Activating mutations for transformation by p53 produce a gene product that forms an hsc70–p53 complex with an altered half-life. Mol. Cell. Biol., 8: 531-539, 1988.[Abstract/Free Full Text]
20. Koduru P. R. K., Raju K., Vadmal V., Menezes G., Shah S., Susin M., Kolitz J., Broome J. D. Correlation between mutation in p53, p53 expression, cytogenetics, histologic type, and survival in patients with B-cell non-Hodgkin’s lymphoma. Blood, 90: 4078-4091, 1997.[Abstract/Free Full Text]
21. Møller M. B., Ino Y., Gerdes A-M., Skjødt K., Louis D. N., Pedersen N. T. Aberrations of the p53 pathway components p53, MDM2, and CDKN2A appear independent in diffuse large B-cell lymphoma. Leukemia, 13: 453-459, 1999.[Medline]
22. Møller M. B., d’Amore F., Christensen B. E. Testicular lymphoma: a population-based study of incidence, clinicopathological correlations and prognosis. Eur. J. Cancer, 30A: 1760-1764, 1994.
23. d’Amore F., Brincker H., Grønbæk K., Thorling K., Pedersen M., Jensen M. K., Andersen E., Pedersen N. T., Mortensen L. S. Non-Hodgkin’s lymphoma of the gastrointestinal tract: a population-based analysis of incidence, geographic distribution, clinicopathologic presentation features, and prognosis. J. Clin. Oncol., 12: 1673-1684, 1994.[Abstract/Free Full Text]
24. d’Amore F., Johansen P., Houmand A., Weisenburger D. D., Mortensen L. S. Epstein-Barr virus genome in non-Hodgkin’s lymphomas occurring in immunocompetent patients: highest prevalence in nonlymphoblastic T-cell lymphoma and correlation with a poor prognosis. Blood, 87: 1045-1055, 1996.[Abstract/Free Full Text]
25. Harris N. L., Jaffe E. S., Stein H., Banks P. M., Chan J. K., Cleary M. L., Delsol G., De Wolf-Peeters C., Falini B., Gatter K. C., Grogan T. M., Isaacson P. G., Knowles D. M., Mason D. Y., Müller-Hermelink H. K., Pileri S. A., Piris M. A., Ralfkiær E., Warnke R. A. A revised European-American classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group. Blood, 84: 1361-1392, 1994.[Free Full Text]
26. Hiddemann W., Longo D. L., Coiffier B., Fisher R. I., Cabanillas F., Cavalli F., Nadler L. M., De Vita V. T., Lister T. A., Armitage J. O. Lymphoma classification—the gap between biology and clinical management is closing. Blood, 88: 4085-4089, 1996.[Free Full Text]
27. Lister T. A., Crowther D., Sutcliffe S. B., Glatstein E., Canellos G. P., Young R. C., Rosenberg S. A., Coltman C. A., Tubiana M. Report of a committee convened to discuss the evaluation and staging of patients with Hodgkin’s disease: Cotswolds Meeting. J. Clin. Oncol., 7: 1630-1636, 1989.[Abstract]
28. Vojtesek B., Bartek J., Midgley C. A., Lane D. P. An immunochemical analysis of the human nuclear phosphoprotein p53. New monoclonal antibodies and epitope mapping using recombinant p53. J. Immunol. Methods, 151: 237-244, 1992.[Medline]
29. Altman D. G. Practical Statistics for Medical Research Chapman and Hall London 1991.
30. Kaplan E. L., Meier P. Nonparametric estimation from incomplete observations. J. Am. Stat. Assoc., 53: 457-481, 1958.
31. Mantel N. Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother. Rep., 50: 163-170, 1966.[Medline]
32. Cox D. R. Regression models and life-tables. J. R. Stat. Soc. B, 34: 187-220, 1972.
33. Hernandez L., Fest T., Cazorla M., Teruya-Feldstein J., Bosch F., Peinado M. A., Piris M. A., Montserrat E., Cardesa A., Jaffe E. S., Campo E., Raffeld M. p53 gene mutations and protein overexpression are associated with aggressive variants of mantle cell lymphomas. Blood, 87: 3351-3359, 1996.[Abstract/Free Full Text]
34. Greiner T. C., Moynihan M. J., Chan W. C., Lytle D. M., Pedersen A., Anderson J. R., Weisenburger D. D. p53 mutations in mantle cell lymphoma are associated with variant cytology and predict a poor prognosis. Blood, 87: 4302-4310, 1996.[Abstract/Free Full Text]
35. Wilson W. H., Teruya-Feldstein J., Fest T., Harris C., Steinberg S. M., Jaffe E. S., Raffeld M. Relationship of p53, bcl-2, and tumor proliferation to clinical drug resistance in non-Hodgkin’s lymphomas. Blood, 89: 601-609, 1997.[Abstract/Free Full Text]
36. Villuendas R., Pezzella F., Gatter K., Algara P., Sánchez-Beato M., Martínez P., Martínez J. C., Munoz K., García P., Sánchez L., Kocialkowsky S., Campo E., Orradre J. L., Piris M. A. p21^WAF1/CIP1, and MDM2 expression in non-Hodgkin’s lymphoma and their relationship to p53 status: a p53+, MDM2-, p21- immunophenotype associated with missense p53 mutations. J. Pathol., 181: 51-61, 1997.[Medline]
37. Detourmignies L., Coppin M. C., Morel P., Vanrumbeke M., Preudhomme C., Wattel E., Gaulard P., Gisselbrecht C., Gosselin B., Fenaux P. p53 overexpression in diffuse large cell lymphoma (DLCL) and its prognostic value by multiparameter analysis (Abstract). Blood, 88: 383a 1996.
38. Mansukhani M. M., Osborne B. M., Zhong J. Y., Matsushima A. Y. The pattern of p53 and p21^WAF1/CIP1 immunoreactivity in non-Hodgkin’s lymphomas predicts p53 gene status. Diagn. Mol. Pathol., 6: 222-228, 1997.[Medline]
39. Nakamura H., Said J. W., Miller C. W., Koeffler H. P. Mutation and protein expression of p53 in acquired immunodeficiency syndrome-related lymphomas. Blood, 82: 920-926, 1993.[Abstract/Free Full Text]
40. Villuendas R., Piris M. A., Algara P., Sánchez-Beato M., Sánchez-Verde L., Martinez J. C., Orradre J. L., García P., Lopez C., Martinez P. The expression of p53 protein in non-Hodgkin’s lymphomas is not always dependent on p53 gene mutations. Blood, 82: 3151-3156, 1993.[Abstract/Free Full Text]
41. Kocialkowski S., Pezzella F., Morrison H., Jones M., Laha S., Harris A. L., Mason D. Y., Gatter K. C. Mutations in the p53 gene are not limited to classic "hot spots" and are not predictive of p53 protein expression in high-grade non-Hodgkin’s lymphoma. Br. J. Haematol., 89: 55-60, 1995.[Medline]
42. Schwaller J., Koeffler H. P., Niklaus G., Loetscher P., Nagel S., Fey M. F., Tobler A. Posttranscriptional stabilization underlies p53-independent induction of p21^{WAF1/CIP1/SDI1} in differentiating human leukemic cells. J. Clin. Invest., 95: 973-979, 1995.
43. Friedlander P., Haupt Y., Prives C., Oren M. A mutant p53 that discriminates between p53-responsive genes cannot induce apoptosis. Mol. Cell. Biol., 16: 4961-4971, 1996.[Abstract]
44. Lowe S. W., Ruley H. E., Jacks T., Housman D. E. p53-dependent apoptosis modulates the cytotoxicity of anticancer agents. Cell, 74: 957-967, 1993.[Medline]
45. Lowe S. W., Bodis S., McClatchey A., Remington L., Ruley H. E., Fisher D. E., Housman D. E., Jacks T. p53 status and the efficacy of cancer therapy in vivo. Science (Washington DC), 266: 807-810, 1994.[Abstract/Free Full Text]
46. O’Connor P. M., Jackman J., Bae I., Myers T. G., Fan S. J., Mutoh M., Scudiero D. A., Monks A., Sausville E. A., Weinstein J. N., Friend S., Fornace A. J., Jr., Kohn K. W. Characterization of the p53 tumor suppressor pathway in cell lines of the National Cancer Institute anticancer drug screen and correlations with the growth-inhibitory potency of 123 anticancer agents. Cancer Res., 57: 4285-4300, 1997.[Abstract/Free Full Text]
47. O’Connor P. M., Jackman J., Jondle D., Bhatia K., Magrath I., Kohn K. W. Role of the p53 tumor suppressor gene in cell cycle arrest and radiosensitivity of Burkitt’s lymphoma cell lines. Cancer Res., 53: 4776-4780, 1993.[Abstract/Free Full Text]
48. Fan S., El-Deiry W. S., Bae I., Freeman J., Jondle D., Bhatia K., Fornace A. J., Jr., Magrath I., Kohn K. W., O’Connor P. M. p53 gene mutations are associated with decreased sensitivity of human lymphoma cells to DNA damaging agents. Cancer Res., 54: 5824-5830, 1994.[Abstract/Free Full Text]
49. Delia D., Mizutani S., Lamorte G., Goi K., Iwata S., Pierotti M. A. p53 activity and chemotherapy. Nat. Med., 2: 724-725, 1996.[Medline]
50. Fan S., Cherney B., Reinhold W., Rucker K., O’Connor P. M. Disruption of p53 function in immortalized human cells does not affect survival or apoptosis after Taxol or vincristine treatment. Clin. Cancer Res., 4: 1047-1054, 1998.[Abstract]

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