NanoString profiling of DNA repair and apoptosis genes in testicular germ cell tumours with divergent chemotherapy outcomes.

BACKGROUND

Platinum-based chemotherapy cures most patients with advanced testicular germ cell tumours (TGCTs), yet a subset develops resistance or relapse. The molecular basis of platinum sensitivity and resistance remains unclear, particularly in archival formalin-fixed paraffin-embedded (FFPE) samples that limit broad genomic analyses.

OBJECTIVES

To evaluate whether differential expression of genes involved in apoptosis, DNA repair, and cell-cycle regulation distinguish platinum-resistant TGCTs.

DESIGN

Retrospective exploratory molecular profiling study using archival TGCT tissue specimens.

METHODS

We profiled the expression of 30 genes related to apoptosis, DNA repair, and cell cycle regulation in 50 archival TGCT samples from 41 patients using the NanoString nCounter platform. Samples included platinum-sensitive, platinum-resistant, and post-chemotherapy teratomas. Platinum-resistant disease was defined as radiological progression and/or rising tumour markers after first line platinum-based chemotherapy. Platinum-sensitive cases included patients achieving complete response as well as those with residual teratoma requiring post-chemotherapy resection. Differential expression analysis and principal component analysis (PCA) were performed to compare transcriptional patterns across groups.

RESULTS

Post-chemotherapy teratomas demonstrated a distinct expression profile, characterised by lower POU5F1 (encodes OCT4 protein) expression and higher levels of apoptosis and cell-cycle related genes. In contrast, platinum-resistant and platinum-sensitive primary TGCTs showed substantial overlap in global expression patterns, and no individual gene met thresholds for differential expression. These findings suggest that the transcriptional features of teratoma differentiation are readily detectable with targeted profiling, while platinum resistance is not captured by this gene set.

CONCLUSIONS

NanoString-based targeted expression profiling identifies biologically distinct expression patterns in post-chemotherapy teratomas but did not reveal a unifying transcriptional signature associated with platinum resistance in TGCTs. These negative results underscore the multifactorial and heterogenous nature of platinum resistance and highlight the need for broader genomic, immune and epigenomic profiling to better elucidate mechanisms of platinum resistance.