Germ Cell Tumors (GCT) have a high cure rate, but we currently lack the ability to accurately identify the small subset of patients who will die from their disease. We used a combined genomic and expression profiling approach to identify genomic regions and underlying genes that are predictive of outcome in GCT patients. We performed array-based comparative genomic hybridization (CGH) on 53 non-seminomatous GCTs (NSGCTs) treated with cisplatin based chemotherapy and defined altered genomic regions using Circular Binary Segmentation. We identified 14 regions associated with two year disease-free survival (2yDFS) and 16 regions associated with five year disease-specific survival (5yDSS). From corresponding expression data, we identified 101 probe sets that showed significant changes in expression. We built several models based on these differentially expressed genes, then tested them in an independent validation set of 54 NSGCTs. These predictive models correctly classified outcome in 64-79.6% of patients in the validation set, depending on the endpoint utilized. Survival analysis demonstrated a significant separation of patients with good versus poor predicted outcome when using a combined gene set model. Multivariate analysis using clinical risk classification with the combined gene model indicated that they were independent prognostic markers. This novel set of predictive genes from altered genomic regions is almost entirely independent of our previously identified set of predictive genes for patients with NSGCTs. These genes may aid in the identification of the small subset of patients who are at high risk of poor outcome.

Background

Young adult testicular cancer survivors experience adverse impacts after treatment. We developed Goal-focused Emotion-regulation Therapy (GET) to improve distress symptoms, emotion regulation, and goal navigation skills.

Purpose

This pilot study examined GET versus an active control intervention in young adult survivors of testicular cancer.

Methods

Seventy-five eligible survivors treated with chemotherapy were randomized to receive GET or Individual Supportive Listening (ISL). Study acceptability, engagement, and tolerability were examined, and intervention fidelity and therapeutic alliance were compared between arms. Preliminary efficacy was evaluated by effect sizes for between-group changes in primary (anxiety and depressive symptoms) and secondary (career confusion, goal navigation, and emotion regulation) outcomes from baseline to immediately and 3-month post-intervention.

Results

Among the 38 men randomized to GET, 81.1% completed all study sessions compared with 82.4% of the 37 men assigned to ISL. Fidelity to the intervention was 87% in GET. Therapeutic alliance wassignificantly higher among those receiving GET versus ISL. Participants exhibited a medium group-by-time effect size with greater reductions in depressive (d = 0.45) and anxiety (d = 0.29) symptoms for those in GET versus ISL, with a similar pattern at 3 months for depressive (d = 0.46) and anxiety (d = 0.46) symptoms.

Conclusions

GET is a feasible and acceptable intervention for reducing adverse outcomes after testicular cancer for young adults. Observed effect sizes preliminarily suggest meaningful change, though should be interpreted with caution in small samples. GET may be a developmentally-matched behavioral approach to improve psychosocial function in this cancer group.

Clinical trial information

Clinicaltrials.gov, NCT04150848. Registered on October 28, 2019.

We studied 137 primary testicular germ cell tumors (TGCTs) using high-dimensional assays of genomic, epigenomic, transcriptomic, and proteomic features. These tumors exhibited high aneuploidy and a paucity of somatic mutations. Somatic mutation of only three genes achieved significance-KIT, KRAS, and NRAS-exclusively in samples with seminoma components. Integrated analyses identified distinct molecular patterns that characterized the major recognized histologic subtypes of TGCT: seminoma, embryonal carcinoma, yolk sac tumor, and teratoma. Striking differences in global DNA methylation and microRNA expression between histology subtypes highlight a likely role of epigenomic processes in determining histologic fates in TGCTs. We also identified a subset of pure seminomas defined by KIT mutations, increased immune infiltration, globally demethylated DNA, and decreased KRAS copy number. We report potential biomarkers for risk stratification, such as miRNA specifically expressed in teratoma, and others with molecular diagnostic potential, such as CpH (CpA/CpC/CpT) methylation identifying embryonal carcinomas.