In a study reported in the Journal of Clinical Oncology, Timmerman et al found that chromosome 3p25.3 gain was present in all cisplatin-resistant germ cell tumor (GCT) lines in vitro; was more common in patients with relapsed or cisplatin-resistant male type II GCTs; and was associated with poorer outcomes in patients with nonseminoma histology.
The study involved analysis of cisplatin-resistant GCT cell line models in vitro, as well as assessment of the investigators’ cohort (Erasmus Medical Center) and publicly available cohorts (TGCA, MSKCC-2016, MSKCC-2008) of patients with type II GCT for chromosome 3p25.3 gain (defined as a log2 copy number ratio > 0.1) and association with outcomes.
Key Findings
In in vitro studies, chromosome 3p25.3 gain was detected in all cisplatin-resistant GCT cell lines, with copy number of this region being correlated with level of resistance (R = 0.96, P = 1.5e-04).
In the investigators’ cohort, gain was detected in 15 (6.8%) of 221 primary tumors and in 2 (29%) of 7 metastasized or cisplatin-resistant tumors. Gain was detected in several relapses/metastases, whereas it was absent or present at lower copy number in matched primary tumors. In the TCGA cohort of untreated primary tumors, gain was found in 13 (9.7%) of 133. In the MSKCC-2016 cohort of tumors classified as cisplatin-sensitive or cisplatin-resistant on the basis of treatment response, gain was detected in 13 (17.1%) of 76 chemotherapy-sensitive tumors and 35 (33.7%) of 104 chemotherapy-resistant tumors. In the MSKCC-2008 cohort—which contains primary GCTs, treated samples, and metastases—gain was identified in 9 (12.2%) of 74 tumors. Findings indicated that gain vs wild-type was more frequently associated with platinum resistance in nonseminomas vs seminomas (eg, P = .02 vs P = nonsignificant in MSKCC-2016 cohort).
The presence of chromosome 3p25.3 gain was associated with poorer outcomes in patients with nonseminomas. For example, for patients with gain vs wild-type in nonseminomas, progression-free survival was significantly poorer in the MSKCC-2016 cohort (P = 3.3e-04) and overall survival was significantly poorer in the MSKCC-2008 cohort (P = 8.8e-03).
Chromosome 3p25.3 gain was more frequently observed in tumors with yolk sac tumor histology and was predictive of poorer outcomes—independent of the International Germ Cell Cancer Collaborative Group risk classification and the presence of TP53/MDM2 alterations.
The investigators concluded, “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.”
Leendert H.J. Looijenga, PhD, of the Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands, is the corresponding author for the Journal of Clinical Oncology article.
Disclosure: The study was supported by the Princess Máxima Center for Pediatric Oncology and the Bergh in het Zadel Foundation. For full disclosures of the study authors, visit ascopubs.org.
