Human male germ cell tumor resistance to cisplatin is linked to TP53 gene mutation

• Published in: Oncogene Vol. 16; no. 18; pp. 2345 - 2349
• Main Authors: HOULDSWORTH, J, HAN XIAO, MURTY, V. V. V. S, WEIYI CHEN, RAY, B, REUTER, V. E, BOSL, G. J, CHAGANTI, R. S. K
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing 07.05.1998; Nature Publishing Group
• Subjects: Antineoplastic Agents - therapeutic use; Apoptosis; Biological and medical sciences; Cell death; Cell physiology; Cell Survival; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Chemotherapy; Cisplatin; Cisplatin - therapeutic use; Cyclin-dependent kinase inhibitor p21; Drug Resistance; Exons; Fundamental and applied biological sciences. Psychology; Genes, p53; Genotoxicity; Humans; Male; MDM2 protein; Metastases; Molecular and cellular biology; Mutation; Neoplasms, Germ Cell and Embryonal - genetics; p53 Protein; Point mutation; Polymorphism, Single-Stranded Conformational; Rhabdomyosarcoma - genetics; Sequence Analysis, DNA; Solid tumors; Spermatozoa - pathology; Teratoma - genetics; Transcription; Tumor Cells, Cultured; Tumors; Antineoplastic agent; Human; Resistance; Chemotherapy; TP53 Gene; Male; Tumor; Mutation; Germinal cell; Tumor cell; Cisplatin
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/sj.onc.1201770

Male germ cell tumors (GCTs) are uniquely sensitive to cisplatin-based chemotherapy, with more than 90% of newly diagnosed cases cured. The underlying cause for resistance to treatment in 20-30% of metastatic lesions remains to be identified. Unlike other solid tumors, no mutations in the TP53 gene have been identified to date in random panels of GCT specimens, which could account for the exquisite sensitivity of these tumors to genotoxic insult. However, in a panel of resistant GCTs that did either not respond to cisplatin-based chemotherapy or subsequently relapsed and resulted in the death of the patient, we have now identified a subset of tumors to contain TP53 mutations within exons 6-9. A cell line derived from one of these tumors (228A) displayed the same TP53 mutation as the tumor specimen, expressed only mutant TP53 mRNA, and exhibited a relative resistance to cisplatin in vitro in comparison to a cell line (218A) derived from a responsive tumor with wild-type TP53. The resistant cell line displayed a much reduced apoptotic cell death and did not exhibit an induction of transcription of the p53-responsive genes WAF1 and MDM2 following cisplatin treatment, compared to that observed in the sensitive cell line. The levels of bax, an agonist of apoptosis, were found to be reduced in the resistant cell line. The simplest explanation for the resistance of this subset of GCTs that are resistant to cisplatin-based chemotherapy, is the inability of the cells to mount an apoptotic response following exposure due to a functionally inactivating mutation in the TP53 gene.