This study, through a comprehensive analysis of the GBD 2021 database, provides a multi-dimensional perspective on the global burden of the CNS cancers in AYAs. The burden of CNS cancers among AYAs is increasing globally, and by 2040, the number of cases is projected to rise significantly. Despite this increase in total global cases, ASIR, ASMR, and ASDR are expected to decline, reflecting advancements in medical technology and improvements in cancer diagnosis and treatment. However, from an etiological standpoint, the trends observed are driven by a complex interplay of factors that vary significantly across different countries and regions.
The pathogenesis of the CNS cancers is multifaceted, involving genetic, environmental, lifestyle, and immunological factors. One of the critical drivers of CNS cancer is genetic susceptibility and gene mutations. Familial cancer syndromes, such as Li-Fraumeni syndrome, neurofibromatosis, and retinoblastoma, significantly increase the risk of CNS tumors10. These syndromes are often associated with mutations in tumor suppressor genes, including TP53, NF1, NF2, and RB1, which play crucial roles in cell cycle regulation and DNA repair11. High-income countries have advanced genetic screening and mutation detection capabilities, allowing them to identify high-risk individuals at earlier stages, which may partly explain the higher incidence rates observed in these regions12. In contrast, low-income countries, lacking the necessary infrastructure for genetic testing, may underestimate the actual incidence of CNS cancers due to undetected genetic susceptibility13. Additionally, the interaction between genetic predisposition and environmental factors likely plays a significant role in CNS cancer development, particularly in more industrialized nations where environmental pollution may accelerate the carcinogenic process14. While this study explores several potential contributors to CNS cancer burden, it is worth noting that the GBD 2021 dataset does not include CNS-specific risk factor modeling. Factors such as genetic predisposition, environmental exposures (e.g., ionizing radiation, air pollution), and lifestyle changes remain underrepresented in current global estimates4. Future iterations of the GBD framework should incorporate these data to provide a more comprehensive understanding of the global burden of CNS cancers and their geographical variations.
Environmental exposure is another key factor contributing to CNS cancer risk, particularly ionizing radiation. Research has consistently shown that ionizing radiation is a well-established risk factor for brain tumors, and cancer survivors who have undergone radiation therapy are at increased risk of developing secondary CNS malignancies15. While high-income countries are equipped with advanced medical technologies, radiation therapy remains a significant contributor to secondary brain tumors16. Moreover, long-term exposure to air pollution, particularly fine particulate matter (PM2.5) and chemical pollutants (e.g., formaldehyde and benzene), has been linked to an increased risk of CNS cancers. The carcinogenic mechanism of air pollution likely involves chronic inflammation and oxidative stress, which affect the nervous system and may promote tumor development17. The industrialization and urbanization of high-income countries exacerbate environmental pollution, which could explain the rising incidence of CNS cancers in these regions. Occupational exposure to harmful substances, such as organic solvents, pesticides, and petrochemicals, further increases the risk of CNS cancers, particularly in highly industrialized areas18.
Viral infections and immune suppression are also closely related to the development of CNS cancers. Epstein-Barr virus (EBV) has been implicated in primary CNS lymphomas, and individuals with compromised immune function, such as those with HIV, are at a significantly higher risk of developing CNS tumors19,20. This association is particularly pronounced in sub-Saharan Africa, where the HIV/AIDS epidemic has led to increased immune suppression and, consequently, a higher burden of CNS cancers. The immune system plays a crucial role in recognizing and eliminating abnormal cells, including cancer cells. When immune function is impaired—whether due to HIV infection, organ transplantation, or long-term immunosuppressive therapy—the body’s ability to clear cancerous cells diminishes, thereby increasing the risk of CNS cancer21. In low-income countries, where medical resources are limited and HIV prevalence is high, the burden of immune-related CNS cancers is likely underreported22.
Changes in lifestyle, particularly in high-income countries, may also act as driving factors in CNS cancer incidence23. Obesity and metabolic syndrome have been associated with various cancers, and while the direct link between obesity and CNS cancer remains unclear, obesity may indirectly increase cancer risk through chronic low-grade inflammation, insulin resistance, and oxidative stress. Dietary changes, particularly the increased consumption of high-fat and high-sugar foods, may further exacerbate these metabolic disruptions, contributing to the risk of CNS cancers24. Additionally, sedentary lifestyles have been identified as an independent risk factor for cancer. Lack of physical activity leads to metabolic dysregulation, fat accumulation, and an increased risk of chronic diseases, which may indirectly affect CNS cancer development. Residents of high-income countries are more exposed to these lifestyle risks, which could explain the rising cancer burden in these regions.
Socioeconomic and cultural differences also significantly influence the burden of CNS cancers. Residents of high-income countries typically have better access to healthcare services, including early screening, precise diagnostics, and advanced treatment options, resulting in higher incidence rates but lower mortality25. In contrast, low-income countries, with limited healthcare resources, often diagnose patients at later stages, leading to higher mortality rates26. In these regions, a lack of awareness about cancer further exacerbates the burden. For instance, in some cultural contexts, cancer may be perceived as an incurable disease, leading patients to delay seeking medical help or refuse treatment altogether27,28. Gender disparities also play a role in the burden of CNS cancers. In certain cultures, women may not receive adequate medical attention, which can result in delayed diagnosis and treatment, further increasing their disease burden29.
According to the BAPC model, although the total number of CNS cancer cases is expected to continue rising in the future, incidence rates, mortality, and disability rates are projected to decline. This trend reflects the progress in medical technology and the strengthening of preventive measures. In high-income countries, the widespread application of precision medicine, genetic testing, immunotherapy, and targeted treatments will likely further improve CNS cancer outcomes. Future prevention strategies should focus on reducing environmental exposure, promoting healthy lifestyles, and enhancing the control of viral infections, particularly in low-income countries where additional technological support and resource allocation are needed to address the growing health inequities associated with CNS cancers30,31,32.
Despite the significant advantages of this study, several limitations must be considered. First, the cancer registration systems in some low-income countries are incomplete, leading to underreporting or inaccuracies in the data, which may underestimate the true burden of CNS cancers in these regions33. Second, this study does not differentiate between the various types of CNS cancers, which have distinct etiologies, prognoses, and treatment responses. Additionally, while the BAPC model provides valuable predictions for future trends, it is based on historical data and may not fully account for future social, economic, and technological changes. For instance, the broad adoption of emerging therapies, such as gene therapy or more advanced immunotherapies, could significantly alter CNS cancer treatment outcomes34. This study also did not explicitly adjust for potential confounders such as healthcare access or population growth, which could influence the observed patterns of CNS cancer burden. However, the GBD framework inherently accounts for some of these factors through its modeling processes (e.g., SDI as a composite index and DALYs adjusted for age structure), and future studies could incorporate more granular adjustments, such as the HAQ Index, to refine these analyses35. Finally, this study lacks a detailed analysis of individual risk factors, such as genetic predisposition, lifestyle, and environmental exposure. Future research should adopt a multidisciplinary approach, incorporating genetics, environmental science, and epidemiology to further explore the causes of CNS cancers, particularly the interaction between genetic susceptibility and environmental exposure.
In conclusion, this study fills a significant gap in the literature by offering a global, multi-dimensional analysis of the burden of CNS cancers and predicting future trends. However, the limitations related to data quality, lack of differentiation between CNS cancer types, and uncertainties in predictive modeling remain challenges. Further research should focus on improving data collection, refining the classification of CNS cancers, and enhancing etiological studies to better understand the global burden of CNS cancers and support the development of more targeted public health policies.
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