Researchers have identified specific genetic mutations in germ cell tumors (GCTs) that are associated with sensitivity to platinum-based chemotherapy, potentially paving the way for more personalized treatment approaches. The study, which involved comprehensive molecular profiling of 138 GCT samples, sought to identify biomarkers that could predict a patient's response to platinum therapy.
The research team, utilizing data from Caris Life Sciences, classified tumors as either chemo-naïve or post-chemo based on histopathological features observed in hematoxylin and eosin (H&E)-stained slides. This classification allowed for a comparative analysis of the genetic profiles of tumors with known responses to chemotherapy.
Genomic Analysis and Platinum Sensitivity
DNA next-generation sequencing (NGS) was performed using a targeted 592-gene panel or whole exome sequencing (WES) on genomic DNA isolated from formalin-fixed paraffin-embedded (FFPE) tumor tissue. The analysis revealed several key mutations and their correlation with platinum sensitivity. Genetic somatic variants identified were interpreted and categorized according to the American College of Medical Genetics and Genomics (ACMG) standards.
Whole transcriptome RNA-sequencing was also conducted on FFPE specimens to assess gene expression levels. Immune cell fractions were calculated using the quanTIseq algorithm to deconvolute bulk RNA sequencing data and predict immune cell fractions. A T cell-inflamed score was also calculated.
Platinum Sensitivity Score (PSS) and Resistance Alterations
A previously published gene set of 23 genes associated with platinum resistance in ovarian cancer was used to estimate a platinum sensitivity score (PSS). Tumors with KRAS amplification tended to have higher PSS scores, indicating greater sensitivity to platinum therapy. Platinum resistance alterations (PRAs) included TP53 and KIT mutations, and MDM2 amplification.
Statistical Significance
Statistical analyses were conducted using Mann–Whitney U and X2/Fisher-Exact tests. P-values were adjusted for multiple comparisons using the Bonferroni correction, with p < 0.05 considered statistically significant.
"These findings could help refine treatment strategies for patients with germ cell tumors," said one of the lead researchers. "By identifying these genetic markers, we can better predict which patients are most likely to benefit from platinum-based chemotherapy and potentially avoid unnecessary toxicity in those who are resistant."
