Purpose Owing to its exquisite
chemotherapy sensitivity, most patients with metastatic
germ cell tumors (GCTs) are cured with
cisplatin-based
chemotherapy. However, up to 30% of patients with advanced GCT exhibit
cisplatin resistance, which requires intensive
salvage treatment, and have a 50% risk of
cancer-related death. To identify a genetic basis for
cisplatin resistance, we performed whole-exome and targeted sequencing of
cisplatin-sensitive and
cisplatin-resistant GCTs. Methods Men with GCT who received a
cisplatin-containing
chemotherapy regimen and had available
tumor tissue were eligible to participate in this study. Whole-exome sequencing or targeted exon-capture-based sequencing was performed on 180
tumors. Patients were categorized as
cisplatin sensitive or
cisplatin resistant by using a combination of postchemotherapy parameters, including serum
tumor marker levels, radiology, and pathology at surgical resection of residual disease. Results TP53 alterations were present exclusively in
cisplatin-resistant
tumors and were particularly prevalent among primary mediastinal nonseminomas (72%). TP53 pathway alterations including MDM2 amplifications were more common among patients with adverse clinical features, categorized as poor risk according to the International
Germ Cell Cancer Collaborative Group (IGCCCG) model. Despite this association, TP53 and MDM2 alterations predicted adverse prognosis independent of the IGCCCG model. Actionable alterations, including novel RAC1 mutations, were detected in 55% of
cisplatin-resistant GCTs. Conclusion In GCT, TP53 and MDM2 alterations were associated with
cisplatin resistance and inferior outcomes, independent of the IGCCCG model. The finding of frequent TP53 alterations among mediastinal primary nonseminomas may explain the more frequent chemoresistance observed with this
tumor subtype. A substantial portion of
cisplatin-resistant GCTs harbor actionable alterations, which might respond to targeted
therapies. Genomic profiling of patients with advanced GCT could improve current risk stratification and identify novel therapeutic approaches for patients with
cisplatin-resistant disease.