Abstract
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.
Highlights
Germ cell tumors (GCTs) are the most common solid malignancy in young adult men, with a peak incidence between the ages of 18 and 35 [1]
Of the 74 tumors we previously profiled by array comparative genomic hybridization (CGH), 53 were non-seminomatous GCTs (NSGCTs) that had been treated with cisplatin-based chemotherapy and had patient follow-up data, which were utilized for this study
We tested for associations between copy number alterations and outcome in a subset of 53 of NSGCT patients that were treated with cisplatin based chemotherapy and for whom we had clinical outcome information
Summary
Germ cell tumors (GCTs) are the most common solid malignancy in young adult men, with a peak incidence between the ages of 18 and 35 [1]. Patients are risk stratified using the International Germ Cell Cancer Collaborative Group (IGCCCG) prognostic classification, which is based on histology (seminoma [SEM] versus non-seminoma [NSGCT]), serum marker levels of alpha-fetoprotein (AFP), human chorionic gonadatropin (HCG), and lactate dehydrogenase (LDH), the presence of non-pulmonary visceral metastases, and the site of the primary tumor (gonadal versus mediastinal) [1]. Based on these parameters, patients are assigned to good, intermediate, and poor risk categories. The addition of prognostic molecular markers could improve patient outcome prediction, as well as identify patients who might benefit from more aggressive or alternative treatments that are traditionally reserved for second line or salvage therapies, such as high dose chemotherapy with stem cell rescue or ifosfamide based therapies [4]
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