HUMAN MALE GERM-CELL TUMOR RESISTANCE TO CISPLATIN IS LINKED TO TP53 GENE MUTATION

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 l esions remains to be identified. Unlike other solid tumors, no mutatio ns in the TP53 gene have been identified to date in random panels of G CT specimens, which could account for the exquisite sensitivity of the se tumors to genotoxic insult. However, in a panel of resistant GCTs t hat did either not respond to cisplatin-based chemotherapy or subseque ntly relapsed and resulted in the death of the patient, we have now id entified a subset of tumors to contain TP53 mutations within exons 6-9 . A cell line derived from one of these tumors (228A) displayed the sa me TP53 mutation as the tumor specimen, expressed only mutant TP53 mRN A, and exhibited a relative resistance to cisplatin in vitro in compar ison to a cell line (218A) derived from a responsive tumor with wild-t ype TP53. The resistant cell line displayed a much reduced apoptotic c ell death and did not exhibit an induction of transcription of the p53 -responsive genes WAF1 and MDM2 following cisplatin treatment, compare d to that observed in the sensitive cell line. The levels of bax, an a gonist of apoptosis, were found to be reduced in the resistant cell li ne. 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.