Kondaboina Shruthi, Parrish Oscar, Parada Carolina Angelica, Ferreira Manuel
Department of Neurological Surgery, University of Washington Medical Center 1, Seattle, WA 98195, USA.
Cancers (Basel). 2024 Oct 15;16(20):3487. doi: 10.3390/cancers16203487.
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. 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. 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. 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.
颅内表皮样囊肿（IECs）是罕见的颅内肿瘤，主要通过手术治疗。囊肿粘连使完全切除变得复杂，导致次全切除术后肿瘤进展率很高。IEC的分子驱动因素仍然未知。因此，治疗进展有限。肿瘤基因谱分析揭示了药物开发的潜在靶点，包括FDA批准的药物和重塑治疗方案。IEC的基因图谱尚未得到探索。我们对IECs应用全外显子测序（WES），以深入了解肿瘤发生机制并确定潜在的治疗靶点。如有可用的肿瘤组织和匹配的血液样本，我们对其进行了WES。遵循GATK最佳实践，我们进行了 reads 处理、质量控制、体细胞变异检测和拷贝数推断。数据分析和可视化在R中进行。 top改变的基因与免疫系统和肿瘤微环境相关，提示免疫逃逸机制。基因和通路富集显示与细胞外基质（ECM）和PI3K-AKT-mTOR级联相关的基因中存在高突变负担。在队列的50%和30%中分别鉴定出NOTCH2和USP8的复发性和有害改变。去泛素酶和β-防御素的频繁扩增加强了免疫机制在致癌转化中的作用。 top改变的基因和复发性突变可能在塑造IECs的微环境和调节免疫逃逸中起作用。USP8和NOTCH2可能作为IECs的临床相关靶点。最后，我们提供证据表明PI3K-Akt-mTOR和ECM信号通路之间的串扰可能在调节IECs的免疫逃逸机制中起作用。
