Nada Amer1, Hala Taha2,3, Dina Hesham1, Nouran Al-Shehaby1, Amal Mosaab1, Mohamed Soudy4, Aya Osama4, Noura Mahmoud5, Moatasem Elayadi5,6, Ayda Youssef7,8, Mohamed Elbeltagy9,10, Mohamed Saad Zaghloul11,12, Sameh Magdeldin4,13, Ahmed A Sayed14,15, Shahenda El-Naggar16. 1. Tumor Biology Research Program, Basic Research Unit, Research Department, Children's Cancer Hospital Egypt, 1 Sekket El Emam, El Madbah El Kadeem Yard, Sayeda Zeinab, Cairo, 57357, Egypt. 2. Department of Pathology, Children's Cancer Hospital Egypt, Cairo, 57357, Egypt. 3. Department of Pathology, National Cancer Institute, Cairo University, Cairo, Egypt. 4. Proteomics and Metabolomics Research Program, Basic Research Unit, Research Department, Children's Cancer Hospital Egypt, Cairo, 57357, Egypt. 5. Department of Pediatric Oncology, Children's Cancer Hospital Egypt, Cairo, 57357, Egypt. 6. Department of Pediatric Oncology, National Cancer Institute, Cairo University, Cairo, Egypt. 7. Department of Radiology, Children's Cancer Hospital Egypt, Cairo, 57357, Egypt. 8. Department of Radiology, National Cancer Institute, Cairo University, Cairo, Egypt. 9. Department of Neurosurgery, Children's Cancer Hospital Egypt, Cairo, 57357, Egypt. 10. Department of Neurosurgery, Faculty of Medicine, Cairo University, Cairo, Egypt. 11. Department of Radiotherapy, National Cancer Institute, Cairo University, Cairo, Egypt. 12. Department of Radiotherapy, Children's Cancer Hospital Egypt, Cairo, 57357, Egypt. 13. Department of Physiology, Faculty of Veterinary Medicine, Suez Canal University, Ismailia, Egypt. 14. Genomics Research Program, Basic Research Unit, Research Department, Children's Cancer Hospital Egypt, Cairo, 57357, Egypt. 15. Department of Biochemistry, Faculty of Science, Ain Shams University, Cairo, Egypt. 16. Tumor Biology Research Program, Basic Research Unit, Research Department, Children's Cancer Hospital Egypt, 1 Sekket El Emam, El Madbah El Kadeem Yard, Sayeda Zeinab, Cairo, 57357, Egypt. shahenda.elnaggar@57357.org.
Abstract
PURPOSE: Protein misfolding and aggregation result in proteotoxic stress and underlie the pathogenesis of many diseases. To overcome proteotoxicity, cells compartmentalize misfolded and aggregated proteins in different inclusion bodies. The aggresome is a paranuclear inclusion body that functions as a storage compartment for misfolded proteins. Choroid plexus tumors (CPTs) are rare neoplasms comprised of three pathological subgroups. The underlying mechanisms of their pathogenesis remain unclear. This study aims to elucidate the prognostic role and the biological effects of aggresomes in pediatric CPTs. METHODS: We examined the presence of aggresomes in 42 patient-derived tumor tissues by immunohistochemistry and we identified their impact on patients' outcomes. We then investigated the proteogenomics signature associated with aggresomes using whole-genome DNA methylation and proteomic analysis to define their role in the pathogenesis of pediatric CPTs. RESULTS: Aggresomes were detected in 64.2% of samples and were distributed among different pathological and molecular subgroups. The presence of aggresomes with different percentages was correlated with patients' outcomes. The ≥ 25% cutoff had the most significant impact on overall and event-free survival (p-value < 0.001) compared to the pathological and the molecular stratifications. CONCLUSIONS: These results support the role of aggresome as a novel prognostic molecular marker for pediatric CPTs that was comparable to the molecular classification in segregating samples into two distinct subgroups, and to the pathological stratification in the prediction of patients' outcomes. Moreover, the proteogenomic signature of CPTs displayed altered protein homeostasis, manifested by enrichment in processes related to protein quality control.
PURPOSE: Protein misfolding and aggregation result in proteotoxic stress and underlie the pathogenesis of many diseases. To overcome proteotoxicity, cells compartmentalize misfolded and aggregated proteins in different inclusion bodies. The aggresome is a paranuclear inclusion body that functions as a storage compartment for misfolded proteins. Choroid plexus tumors (CPTs) are rare neoplasms comprised of three pathological subgroups. The underlying mechanisms of their pathogenesis remain unclear. This study aims to elucidate the prognostic role and the biological effects of aggresomes in pediatric CPTs. METHODS: We examined the presence of aggresomes in 42 patient-derived tumor tissues by immunohistochemistry and we identified their impact on patients' outcomes. We then investigated the proteogenomics signature associated with aggresomes using whole-genome DNA methylation and proteomic analysis to define their role in the pathogenesis of pediatric CPTs. RESULTS: Aggresomes were detected in 64.2% of samples and were distributed among different pathological and molecular subgroups. The presence of aggresomes with different percentages was correlated with patients' outcomes. The ≥ 25% cutoff had the most significant impact on overall and event-free survival (p-value < 0.001) compared to the pathological and the molecular stratifications. CONCLUSIONS: These results support the role of aggresome as a novel prognostic molecular marker for pediatric CPTs that was comparable to the molecular classification in segregating samples into two distinct subgroups, and to the pathological stratification in the prediction of patients' outcomes. Moreover, the proteogenomic signature of CPTs displayed altered protein homeostasis, manifested by enrichment in processes related to protein quality control.
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