Chromosome 3p25.3 Gain Is Associated With Cisplatin Resistance and Is an Independent Predictor of Poor Outcome in Male Malignant Germ Cell Tumors

Abstract

PURPOSE Cisplatin is the main systemic treatment modality for male type II germ cell tumors (GCTs). Although generally very effective, 5%-10% of patients suffer from cisplatin-resistant disease. Identification of the driving mechanisms of resistance will enable improved risk stratification and development of alternative treatments. METHODS We developed and characterized cisplatin-resistant GCT cell line models and compared their molecular characteristics with patient samples with cisplatin resistance and/or a poor clinical outcome. Subsequently, the association between the overlapping genetic features and clinical data was assessed. Finally, we used Cox regression to determine the prognostic relevance of these features within the currently used risk classification. RESULTS Gain of chromosome 3p25.3 was detected in all cisplatin-resistant cell lines, and copy number of this region correlated with the level of resistance (R = 0.96, P = 1.5e-04). Gain of this region was detected at low frequencies in primary tumors and at higher frequencies in relapsed and/or cisplatin-resistant tumors. Chromosome 3p25.3 gain was associated with shorter progression-free survival and overall survival, with the strongest association observed in nonseminomas excluding pure teratomas. 3p25.3 gain was more frequently observed in tumors with yolk sac tumor histology and predicted adverse outcome independent of the International Germ Cell Cancer Collaborative Group risk classification and the presence of TP53/ MDM2 alterations. CONCLUSION On the basis of both in vitro analyses and clinical data, we found 3p25.3 to be strongly associated with cisplatin resistance and poor clinical outcome in male type II GCTs. Using genomic profiling, 3p25.3 status could help to improve risk stratification in male patients with type II GCT. Further characterization of this locus and underlying mechanisms of resistance is warranted to guide development of novel treatment approaches for cisplatin-resistant disease.

Evolution of Testicular Germ Cell Tumors in the Molecular Era With Histogenetic Implications

“…55 Higher frequencies of Gain of chromosome 3p25.3 have been shown in cisplatin-resistant cell lines, and higher resistance relates to higher copy numbers. 56 Receptor tyrosine kinase (RTK) pathway, RAS/ERK pathway mutations, RAC1, and mutations in several other pathways have been identified and need further exploration of their role in the mechanism of resistance in germ cell tumors. 55,57 Molecular Diagnostics Update Testicular germ cell serum biomarkers are widely used for the initial diagnosis, management, follow-up, and clinical staging, as well as predictors of the disease.…”

“…Higher frequencies of Gain of chromosome 3p25.3 have been shown in cisplatin-resistant cell lines, and higher resistance relates to higher copy numbers 56 . Receptor tyrosine kinase (RTK) pathway, RAS/ERK pathway mutations, RAC1, and mutations in several other pathways have been identified and need further exploration of their role in the mechanism of resistance in germ cell tumors 55,57 …”

Children's Oncology Group's 2023 blueprint for research: Germ cell tumors

“…50 A phase 1 study of codrituzumab, a recombi- recently implicated a gain in chromosome 3p25.3 as a predictor of poor outcome associated with cisplatin resistance in type II GCTs. 54 However, the role these alterations play in type I tumors and ovarian GCTs needs to be further explored. The proposed PANTHER trial (phase 3 randomized trial of adaptive dose-intense treatment for highrisk GCTs) will evaluate for TP53 alteration as part of its treatment assignment.…”

“…Timmerman et al. recently implicated a gain in chromosome 3p25.3 as a predictor of poor outcome associated with cisplatin resistance in type II GCTs 54 . However, the role these alterations play in type I tumors and ovarian GCTs needs to be further explored.…”

Biomarkers for risk-based treatment modifications for CNS germ cell tumors: Updates on biological underpinnings, clinical trials, and future directions

“…A recent study in patients with testicular GCTs found that 3p25.3 gain was a poor prognostic factor among patients with non-seminomatous GCTs ( 38 ). This gain was present in 6.8% of cases, and those that harbored this gain showed shorter PFS and OS than those without.…”