Abstract
Recent genomic studies have shed light on the biology and inter-tumoral heterogeneity underlying pineal parenchymal tumors, in particular pineoblastomas (PBs) and pineal parenchymal tumors of intermediate differentiation (PPTIDs). Previous reports, however, had modest sample sizes and lacked the power to integrate molecular and clinical findings. The different proposed molecular group structures also highlighted a need to reach consensus on a robust and relevant classification system. We performed a meta-analysis on 221 patients with molecularly characterized PBs and PPTIDs. DNA methylation profiles were analyzed through complementary bioinformatic approaches and molecular subgrouping was harmonized. Demographic, clinical, and genomic features of patients and samples from these pineal tumor groups were annotated. Four clinically and biologically relevant consensus PB groups were defined: PB-miRNA1 (n = 96), PB-miRNA2 (n = 23), PB-MYC/FOXR2 (n = 34), and PB-RB1 (n = 25). A final molecularly distinct group, designated PPTID (n = 43), comprised histological PPTID and PBs. Genomic and transcriptomic profiling allowed the characterization of oncogenic drivers for individual tumor groups, specifically, alterations in the microRNA processing pathway in PB-miRNA1/2, MYC amplification and FOXR2 overexpression in PB-MYC/FOXR2, RB1 alteration in PB-RB1, and KBTBD4 insertion in PPTID. Age at diagnosis, sex predilection, and metastatic status varied significantly among tumor groups. While patients with PB-miRNA2 and PPTID had superior outcome, survival was intermediate for patients with PB-miRNA1, and dismal for those with PB-MYC/FOXR2 or PB-RB1. Reduced-dose CSI was adequate for patients with average-risk, PB-miRNA1/2 disease. We systematically interrogated the clinical and molecular heterogeneity within pineal parenchymal tumors and proposed a consensus nomenclature for disease groups, laying the groundwork for future studies as well as routine use in tumor diagnostic classification and clinical trial stratification.
Overview
- The study aims to provide a comprehensive analysis of pineal parenchymal tumors (PPTs) and their molecular and clinical heterogeneity. The authors performed a meta-analysis on 221 patients with molecularly characterized PPTs, including pineoblastomas (PBs) and pineal parenchymal tumors of intermediate differentiation (PPTIDs).
- The study used DNA methylation profiles and complementary bioinformatic approaches to identify molecular subgroups within PPTs. The authors harmonized the molecular subgrouping and annotated demographic, clinical, and genomic features of patients and samples from these pineal tumor groups. Four clinically and biologically relevant consensus PB groups were defined: PB-miRNA1, PB-miRNA2, PB-MYC/FOXR2, and PB-RB1. A final molecularly distinct group, designated PPTID, comprised histological PPTID and PBs. Genomic and transcriptomic profiling allowed the characterization of oncogenic drivers for individual tumor groups. Age at diagnosis, sex predilection, and metastatic status varied significantly among tumor groups. While patients with PB-miRNA2 and PPTID had superior outcome, survival was intermediate for patients with PB-miRNA1, and dismal for those with PB-MYC/FOXR2 or PB-RB1. Reduced-dose CSI was adequate for patients with average-risk, PB-miRNA1/2 disease. The study aims to provide a robust and relevant classification system for PPTs, laying the groundwork for future studies and clinical trial stratification.
Comparative Analysis & Findings
- The study compared the outcomes observed under different experimental conditions or interventions detailed in the study. The authors identified significant differences in the results between the four clinically and biologically relevant consensus PB groups defined: PB-miRNA1, PB-miRNA2, PB-MYC/FOXR2, and PB-RB1. Patients with PB-miRNA2 and PPTID had superior outcome, while survival was intermediate for patients with PB-miRNA1, and dismal for those with PB-MYC/FOXR2 or PB-RB1. Reduced-dose CSI was adequate for patients with average-risk, PB-miRNA1/2 disease. The study also identified oncogenic drivers for individual tumor groups, specifically, alterations in the microRNA processing pathway in PB-miRNA1/2, MYC amplification and FOXR2 overexpression in PB-MYC/FOXR2, RB1 alteration in PB-RB1, and KBTBD4 insertion in PPTID. The study found that age at diagnosis, sex predilection, and metastatic status varied significantly among tumor groups. The key findings of the study suggest that the proposed consensus nomenclature for disease groups can be used to stratify patients for clinical trials and improve diagnostic accuracy. The study also highlights the importance of identifying oncogenic drivers for individual tumor groups to inform personalized treatment strategies.
Implications and Future Directions
- The study's findings have significant implications for the field of research and clinical practice. The proposed consensus nomenclature for disease groups can be used to stratify patients for clinical trials and improve diagnostic accuracy. The study also highlights the importance of identifying oncogenic drivers for individual tumor groups to inform personalized treatment strategies. The study's limitations include the modest sample size and the need for further validation of the proposed molecular subgroups. Future research should focus on validating the proposed molecular subgroups and identifying additional oncogenic drivers for individual tumor groups. The study also suggests that the proposed consensus nomenclature for disease groups can be used to inform personalized treatment strategies and improve patient outcomes.