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

TY - JOUR

T1 - Chromosome 3p25.3 Gain Is Associated With Cisplatin Resistance and Is an Independent Predictor of Poor Outcome in Male Malignant Germ Cell Tumors

AU - Timmerman, Dennis M

AU - Eleveld, Thomas F

AU - Sriram, Sruthi

AU - Dorssers, Lambert C J

AU - Gillis, Ad J M

AU - Schmidtova, Silvia

AU - Kalavska, Katarina

AU - van de Werken, Harmen J G

AU - Oing, Christoph

AU - Honecker, Friedemann

AU - Mego, Michal

AU - Looijenga, Leendert H J

PY - 2022/9/10

Y1 - 2022/9/10

N2 - 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.

AB - 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.

U2 - 10.1200/JCO.21.02809

DO - 10.1200/JCO.21.02809

M3 - SCORING: Journal article

C2 - 35442716

VL - 40

SP - 3077

EP - 3087

JO - J CLIN ONCOL

JF - J CLIN ONCOL

SN - 0732-183X

IS - 26

ER -