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Lookup NU author(s): Dr Christoph OingORCiD
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND).
© American Society of Clinical Oncology. 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.
Author(s): Timmerman DM, Eleveld TF, Sriram S, Dorssers LCJ, Gillis AJM, Schmidtova S, Kalavska K, Van De Werken HJG, Oing C, Honecker F, Mego M, Looijenga LHJ
Publication type: Article
Publication status: Published
Journal: Journal of Clinical Oncology
Year: 2022
Volume: 40
Issue: 26
Pages: 3077-3088
Print publication date: 01/09/2022
Online publication date: 20/04/2022
Acceptance date: 14/03/2022
Date deposited: 24/07/2024
ISSN (print): 0732-183X
ISSN (electronic): 1527-7755
Publisher: American Society of Clinical Oncology
URL: https://doi.org/10.1200/JCO.21.02809
DOI: 10.1200/JCO.21.02809
Data Access Statement: WGS Sequencing data ENA PRJEB38262. Methylation data, Array Express, accession number E-MTAB-9114 and GSA data, Array Express, accession number E- MTAB-9266. The primary data sets are available via the various repositories.
PubMed id: 35442716
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