Whole Exome Sequencing of Intracranial Epidermoid Cysts Reveals Immune-Associated Mechanistic and Potential Targets.

Simple Summary: Intracranial Epidermoid Cysts (IECs) are rare tumors. Despite their benign course, IECs can adhere to critical brain structures resulting in impairment and morbidity. The primary treatment is surgery; however, cyst adherence often complicates complete removal, resulting in notably high progression rates after subtotal resection. Due to the rarity of IECs, there has been limited research focused on understanding the mechanisms of the disease and advancing therapeutic options. As a result, there are currently no effective drug therapies available for treating patients with IECs. Targeted therapy is an effective form of treatment for tumors. It focuses on mutations that turn healthy cells into tumor cells. The mutation profile of IECs has not been investigated. We aimed to investigate the somatic landscape of IECs to gain insights into tumor biology and identify mutations that could potentially serve as targets for additional therapies. Surgery is still the most effective treatment for these patients. Background/Objectives: Intracranial Epidermoid Cysts (IECs) are rare intracranial tumors primarily treated through surgery. Cyst adherence complicates complete removal, leading to high rates of tumor progression after subtotal resection. The molecular drivers of IEC remain unknown. Consequently, advances in treatment have fallen short. Tumor genetic profiling has revealed potential targets for drug development, including FDA-approved options and reshaping treatment. The genetic landscape of IECs has not been explored. We applied Whole Exome Sequencing (WES) to IECs to gain insights into the mechanisms of oncogenesis and identify potential therapeutic targets. Methods: We performed WES on tumor tissue and matched blood samples, when available. Following GATK best practices, we conducted read processing, quality control, somatic variant calling, and copy-number inference. Data analyses and visualization were conducted in R. Results: Top altered genes are associated with the immune system and tumor microenvironment, suggesting a mechanism of immune evasion. Gene and pathway enrichment revealed a high mutation burden in genes associated with Extracellular Matrix (ECM) and PI3K-AKT-mTOR cascades. Recurrent and deleterious alterations in NOTCH2 and USP8 were identified in 50% and 30% of the cohort, respectively. Frequent amplifications in deubiquitinases and beta-defensins strengthened the involvement of immune mechanisms for oncogenic transformation. Conclusions: Top altered genes and recurrent mutations may play a role in shaping the microenvironment and modulating immune evasion in IECs. USP8 and NOTCH2 may serve as clinically relevant target for IECs. Finally, we present evidence that the crosstalk between the PI3K-Akt-mTOR and ECM signaling pathways may play a role in modulating the immune escape mechanism in IECs. [ABSTRACT FROM AUTHOR]