CORRESPONDENCE p53 and MDM2 in Germ Cell Cancer Treatment Response To the Editor: Although we agree with the view of Kersemaekers et al 1 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 chemo- responsiveness in these tumors.” As they themselves demonstrate, 63% (five of eight) chemosensitive versus 77% (13 of 17) chemo- therapy-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 chemorespon- siveness issue is their observation that overall none of 26 semino- mas versus 36 of 48 (75%) nonseminomas showed strong expres- sion. 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 Our own as yet unpublished observa- tions show a similar trend (Waterfall and Berney, manuscript in preparation).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 reports 4 that metastatic seminoma had a substantially higher durable primary relapse-free survival 5 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 Kerse- maeker et al’s 1 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 p53 9 but also expressed under special circumstances in wild-type p53, 11 was more fre- quently 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. R.T.D. Oliver J. Shamash D.M. Berney St Bartholomew’s Hospital Queen Mary’s School of Medicine & Dentistry London, England 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 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 3. Friedman M: Tumors of testis; relation of histiogenic classifica- tion to radiosensitivity and prognosis. Proc N Y Path Soc 1:33-41, 1950 4. Oliver RTD, Hope-Stone HF, Blandy JP: Possible new ap- proaches to the management of seminoma of the testis. Br J Urol 56:729-733, 1984 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: Diaminedichloroplati- num: A phase I study showing responses in testicular and other tumors. Cancer 33:1219-1255, 1974 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 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 11. McLure KG, Lee PW: A PAb240+ conformation of wild type p53 binds DNA. Oncogene 13:1297-1303, 1996 In Reply: The main objective of the work described in our article 1 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 3928 Journal of Clinical Oncology, Vol 20, No 18 (September 15), 2002: pp 3928-3939 Downloaded from jco.ascopubs.org on October 8, 2016. For personal use only. No other uses without permission. Copyright © 2002 American Society of Clinical Oncology. All rights reserved.