PATH-57. WHOLE EXOME SEQUENCING OF INTRACRANIAL EPIDERMOID CYSTS (IECS) REVEALS POTENTIAL SOMATIC DRIVERS

Abstract

Abstract Intracranial Epidermoid Cysts (IECs) are benign, slow-growing, asymptomatic tumors with an incidence rate of 1% of all intracranial tumors. They are significantly enlarged when discovered and can cause seizures. IECs are suspected to form due to disruptions in neural tube closure. Given their rarity, formation of IECs is under-investigated and surgery is the only treatment option. However, because the cyst lining can be adherent to important brain structures, resection is challenging and can result in post-operative complications, highlighting the need to investigate the pathogenesis of IECs to develop drug therapeutic options. We performed paired-end Whole Exome Sequencing (WES) on DNA from six sporadic IECs. Data processing of raw unmapped reads was performed in tumor-normal and tumor-only mode as appropriate, following GATK best practices for variant calling. We identified 2,850 SNPs and 2,102 indels in this cohort. We identified two common variants, NKX2.5 (p.P214del) and STIM-1 (p.T576del, p.T502del) across all samples, which is a novel finding. We also identified 27 genes and variants shared variably across the samples. Gene enrichment analysis revealed that the Sonic Hedgehog (SHH) pathway is implicated in these gene sets due to activating mutations in the SMO gene (p.L23del). We are using an immunohistochemical stain to validate this finding. The mutant NKX2.5, a transcription factor (TF) responsible for stem-cell differentiation in embryogenesis, strongly indicates that the tumor microenvironment (TME) is disrupted. Deletions in the STIM-1 gene indicate loss of interaction with Orai1 calcium channels, disrupting store operated Ca2+ entry (SOCE) and preventing typical cell migration, resulting in trapped fibroblasts. Digital droplet PCR (ddPCR) of these samples is underway to validate the low tumor allele frequencies (< 4%). The discovery of activating mutations in SMO is significant because it potentiates FDA-approved SMO-inhibitors like Vismodegib and Sonidegib as viable treatment options for patients with IECs.