p53 and MDM2 in Germ Cell Cancer Treatment Response
Authors: R.T.D. Oliver, J. Shamash, D.M. Berney, Frank Mayer, Anne-Marie Kersemaekers, J. Wolter Oosterhuis, Carsten Bokemeyer, Leendert H.J. Looijenga
Journal: Journal of Clinical Oncology (2002)

Article Tools SPECIAL DEPARTMENTS Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.2002.02.980 Journal of Clinical Oncology - published online before print September 21, 2016 PMID: 12228213 p53 and MDM2 in Germ Cell Cancer Treatment Response R.T.D. OliverxR.T.D. OliverSearch for articles by this author , J. ShamashxJ. ShamashSearch for articles by this author , D.M. BerneyxD.M. BerneySearch for articles by this author Frank MayerxFrank MayerSearch for articles by this author , Anne-Marie KersemaekersxAnne-Marie KersemaekersSearch for articles by this author , J. Wolter OosterhuisxJ. Wolter OosterhuisSearch for articles by this author , Carsten BokemeyerxCarsten BokemeyerSearch for articles by this author , Leendert H.J. LooijengaxLeendert H.J. LooijengaSearch for articles by this author Show More St Bartholomew's Hospital, Queen Mary's School of Medicine & Dentistry, London, EnglandErasmus MC, University Hospital Rotterdam, Josephine Nefkens Institute, Rotterdam, the Netherlands https://doi.org/10.1200/JCO.2002.02.980 First Page Full Text PDF Figures and Tables © 2002 by American Society of Clinical OncologyjcoJ Clin OncolJournal of Clinical OncologyJCO0732-183X1527-7755American Society of Clinical OncologyResponse15092002In 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.2,3As 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 (rs = 0.26, P = .16), the apoptotic index was correlated with the percentage of p53-positive cells (rs = 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.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:: 1551,2002-1561, Link, Google Scholar2. Alarcon-Vargas D, Ronai Z: p53-Mdm2: The affair that never ends. Carcinogenesis 23:: 541,2002-547, Crossref, Medline, Google Scholar3. Michael D, Oren M: The p53 and Mdm2 families in cancer. Curr Opin Genet Dev 12:: 53,2002-59, Crossref, Medline, Google Scholar4. 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:: 594,1997-603, Link, Google Scholar5. Heidenreich A, Kuczyk M, Albers P: Molecular pathogenesis and prognostic factors in testicular tumor. Urologe A 37:: 593,1998-608, Crossref, Medline, Google Scholar6. Mickisch GH: Prognostic parameters for the management of advanced testis tumours. Curr Opin Urol 10:: 465,2000-471, Crossref, Medline, Google Scholar