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p53 and MDM2 in Germ Cell Cancer Treatment Response

St Bartholomew’s Hospital, Queen Mary’s School of Medicine & Dentistry, London, England

To the Editor:Although we agree with the view of Kersemaekers et al¹ that mutation of p53 is not a common cause of chemotherapy resistance in germ cell cancer, we would be less supportive of their view that ". . . MDM2 does not seem to interfere with the chemoresponsiveness in these tumors." As they themselves demonstrate, 63% (five of eight) chemosensitive versus 77% (13 of 17) chemotherapy-resistant, nonseminomas showed strong immunochemical expression of MDM2 (more than 10% of cells staining). Clearly the numbers tested are insufficient to exclude that there was a 14% higher expression of MDM2 in chemotherapy-resistant tumors, because 334 patients would be needed to prove such a difference was significant at 5% level.

However, much more significant in respect to the chemoresponsiveness issue is their observation that overall none of 26 seminomas versus 36 of 48 (75%) nonseminomas showed strong expression. This significant observation (² = 37.97, P = .000) has been confirmed by at least one other author.² They showed that only four (15%) of 26 seminoma versus 30 (55%) of 55 nonseminomas had strong expression of MDM2. Our own as yet unpublished observations show a similar trend (Waterfall and Berney, manuscript in preparation). Five (29%) of 17 seminoma versus 14 (52%) of 27 nonseminoma showed strong MDM2 expression. It has long been known and accepted that seminoma is more radiosensitive than nonseminoma.³ However, it is less accepted that seminoma is more chemosensitive than nonseminoma, although it is now nearly 20 years since the first reports⁴ that metastatic seminoma had a substantially higher durable primary relapse-free survival⁵ with single-agent cisplatin than nonseminoma,⁶ something that has also been demonstrated using carboplatin.⁵

These observations lead one to conclude that MDM2 could be contributing to the differential chemosensitivity of seminoma and nonseminoma. MDM2’s role in dampening down p53-controlled apoptotic mechanisms is well established and supported by Kersemaeker et al’s¹ observations that most of the p53 in embryonal carcinomas was bound to MDM2. It may well be that it is the nonbound p53 that is critical to the chemosensitivity of germ cell cancer. Possible justification for re-examination of this issue comes from our work on p53.^7,8 These authors used a series of novel monoclonal antibodies to different epitopes on the p53 molecule^9,10 on snap-frozen germ cell tumors. They found that the PAb240 epitope, though identified initially in mutant p53⁹ but also expressed under special circumstances in wild-type p53,¹¹ was more frequently detected in germ cell cancers than other adult cancers such as bladder and head and neck cancers. In addition, it was more frequent in seminoma than nonseminoma.^7,8 In contrast, the p53 determinant defined by monoclonal Bp53-12 is less frequently expressed in germ cell cancers and more frequently detected in tumors with mutant p53 such as bladder and head and neck cancer.

We conclude that a more detailed study of the subtlety of MDM2/p53 interactions in different types of germ cell cancers and compared with non–germ cell cancers could provide further insights into mechanisms of germ cell chemosensitivity and could lead to treatments to enhance chemosensitivity of non–germ cell cancers.

REFERENCES

1. Kersemaekers AM, Mayer F, Molier M, et al: Role of P53 and MDM2 in treatment response of human germ cell tumors. J Clin Oncol 20: 1551-1561, 2002[Abstract/Free Full Text]

2. Eid H, Institoris E, Geczi , et al: mdm-2 expression in human testicular germ-cell tumours and its clinical value. Anticancer Res 19: 3485-3490, 1999[Medline]

3. Friedman M: Tumors of testis; relation of histiogenic classification to radiosensitivity and prognosis. Proc N Y Path Soc 1: 33-41, 1950

4. Oliver RTD, Hope-Stone HF, Blandy JP: Possible new approaches to the management of seminoma of the testis. Br J Urol 56: 729-733, 1984[Medline]

5. Ravi R, Oliver R, Ong J, et al: A single-centre observational study of surgery and late malignant events after chemotherapy for germ cell cancer. B J Urol 80: 647-652, 1997

6. Higby DJ, Wallace HJ, Albert DJ, et al: Diaminedichloroplatinum: A phase I study showing responses in testicular and other tumors. Cancer 33: 1219-1255, 1974[CrossRef][Medline]

7. Nouri A, Oliver R: Tetraploid arrest with over expressed non-mutated p53 in germ cell cancers: Relevance to their chemosensitivity and possible application in non germ cell cancers. Int J Oncol 11: 1167-1371, 1997

8. Dabare M: Development of Monoclonal Antibodies for Detection of Testicular Tumours. London, United Kingdom, University of London, 1999

9. Bartek J, Bartkova J, Lukas J, et al: Immunohistochemical analysis of the p53 oncoprotein on paraffin sections using a series of novel monoclonal antibodies. J Pathol 169: 27-34, 1993[CrossRef][Medline]

10. Gannon JV, Greaves R, Iggo R, et al: Activating mutations in p53 produce a common conformational effect: A monoclonal antibody specific for the mutant form. EMBO J 9: 1595-1602, 1990[Medline]

11. McLure KG, Lee PW: A PAb240+ conformation of wild type p53 binds DNA. Oncogene 13: 1297-1303, 1996[Medline]

Response

Erasmus MC, University Hospital Rotterdam, Josephine Nefkens Institute, Rotterdam, the Netherlands

In Reply:The main objective of the work described in our article¹ was to clarify the role of p53 in (1) the general chemosensitivity and (2) the rare occurrence of treatment resistance in germ cell tumors of the adult, ie, seminomas and nonseminomas. We demonstrated that the mere level of p53 protein cannot account for the exquisite curability of these tumors. At the same time, inactivating mutations of p53 are not a common means to develop treatment resistance. In their letter, Oliver et al agree with this conclusion. However, they stress the possibility that MDM2 might have a role in treatment resistance of these tumors, in particular regarding the higher treatment sensitivity of seminomas compared with nonseminomas.

The mode of action of MDM2 as a factor conferring chemotherapy resistance would be inactivation and degradation of wild-type p53, thereby interfering with the p53-dependent apoptotic pathway. In this context, it is important to realize, that MDM2 itself is a downstream target of p53 within a complex negative feedback loop. Therefore, a high level of p53 results in upregulation of MDM2. In other words, only a high level of MDM2 independent of p53, for example by gene-amplification, prevents the action of p53. In contrast, MDM2 induction within the feedback loop would result only in a limitation of p53 function.^2,3

As correctly stated by Oliver et al, the number of cases analyzed in our study is not sufficient to rule out subtle, but significant, differences in the level of MDM2 between responding and nonresponding germ cell tumors. However, from a biologic point of view, it is obvious that the high level of MDM2, as demonstrated in 63% of responding cases (predominantly being nonseminomas), is not able to prevent a favorable treatment response in these patients. The role of MDM2 as resistance factor can thus only be limited. We also agree with Oliver et al that, in general, seminomas do respond better to chemotherapy than nonseminomas,⁴ and indeed, we demonstrated a difference in MDM2 positivity between seminomas and nonseminomas. This might partly be explained as a response to a higher p53 level in nonseminomas. However, the MDM2 staining was mainly determined by histology: all embryonal carcinoma components irrespective of treatment response showed a pronounced MDM2 protein staining and expression of the full length transcript, without gene amplification. Thus, a high level of MDM2 seems to be an intrinsic characteristic of embryonal carcinoma. In this context, it is of interest that the percentage of embryonal carcinoma in a primary germ cell tumor is predicting the presence of metastatic spread (unpublished data).⁵ However, its role as an indicator for poor treatment outcome is still not proven,⁶ and the histologic composition of the tumors of the refractory patients as described in our article does not indicate that embryonal carcinoma respond poorly to chemotherapy.

Finally, Oliver et al discuss a possible difference in functionality of p53 in seminomas and nonseminomas. Not having personal experiences with the mentioned antibodies detecting different p53 epitopes, we cannot comment on the usefulness of this approach. However, the presence of the wild-type form suggests at least that the protein can be active. We investigated two of the main downstream effects of p53, p21 and apoptosis (Mayer et al, manuscript submitted for publication). Although no correlation between the presence of p53 and p21 protein was detected (r_s = 0.26, P = .16), the apoptotic index was correlated with the percentage of p53-positive cells (r_s = 0.66, P < .001). This was found both in seminomas and nonseminomas, irrespective of histologic subtype (with the exception of mature teratomas) and treatment response. These data strongly suggest that, in principle, germ cell tumors have an intact p53-dependent apoptotic pathway, despite the high MDM2 level in embryonal carcinoma components.

In conclusion, even though subtle but significant differences in MDM2 levels may exist between responding and nonresponding tumors, we feel that the available data still argue against a major role of p53 and MDM2 in determining the treatment response in germ cell tumors. Both the biologic explanation and the consequence of the high protein level of MDM2 in embryonal carcinoma remains to be assessed.

REFERENCES

1. Kersemaekers AM, Mayer F, Molier M, et al: Role of P53 and MDM2 in treatment response of human germ cell tumors. J Clin Oncol 20: 1551-1561, 2002[Abstract/Free Full Text]

2. Alarcon-Vargas D, Ronai Z: p53-Mdm2: The affair that never ends. Carcinogenesis 23: 541-547, 2002[Abstract/Free Full Text]

3. Michael D, Oren M: The p53 and Mdm2 families in cancer. Curr Opin Genet Dev 12: 53-59, 2002[CrossRef][Medline]

4. International Germ Cell Cancer Collaborative Group: International Germ Cell Consensus Classification: A prognostic factor-based staging system for metastatic germ cell cancers. J Clin Oncol 15: 594-603, 1997[Abstract/Free Full Text]

5. Heidenreich A, Kuczyk M, Albers P: Molecular pathogenesis and prognostic factors in testicular tumor. Urologe A 37: 593-608, 1998[CrossRef][Medline]

6. Mickisch GH: Prognostic parameters for the management of advanced testis tumours. Curr Opin Urol 10: 465-471, 2000[CrossRef][Medline]

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