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.
背景/目的：颅内表皮样囊肿是一种罕见的颅内肿瘤，主要治疗手段为手术。囊肿与周围组织粘连导致完全切除困难，次全切除后肿瘤进展率高。目前对IEC的分子驱动机制尚不清楚，因此治疗进展有限。肿瘤基因谱分析已揭示药物开发的潜在靶点，包括FDA批准的方案及治疗策略的重塑。IEC的基因图谱尚未被探索。本研究应用全外显子组测序技术，旨在深入理解IEC的致癌机制并识别潜在治疗靶点。 方法：我们对肿瘤组织及可获取的匹配血液样本进行WES分析。遵循GATK最佳实践流程，完成测序数据读取处理、质量控制、体细胞变异检测及拷贝数变异推断。数据分析与可视化通过R语言实现。 结果：高频突变基因主要与免疫系统及肿瘤微环境相关，提示免疫逃逸机制的存在。基因与通路富集分析显示，细胞外基质相关基因及PI3K-AKT-mTOR信号通路存在高突变负荷。在队列中分别有50%和30%的样本检测到NOTCH2和USP8基因的反复性有害突变。去泛素化酶与β-防御素的频繁扩增进一步证实了免疫机制在癌变过程中的参与。 结论：高频突变基因与反复出现的基因突变可能参与塑造IEC微环境并调控免疫逃逸过程。USP8与NOTCH2或可作为IEC临床治疗的相关靶点。最后，本研究证实PI3K-Akt-mTOR与ECM信号通路间的交互作用可能在调控IEC免疫逃逸机制中发挥重要作用。
肿瘤(癌症)患者之家