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  • Genetic Study of Two Affected Siblings Provides Insight into the Pathogenesis of Subependymoma

    Final Number:

    Christopher Sungwoon Hong BA; Martin G Piazza BA; Prashant Chittiboina MD, MPH; John D. Heiss MD

    Study Design:
    Laboratory Investigation

    Subject Category:

    Meeting: Congress of Neurological Surgeons 2015 Annual Meeting

    Introduction: Subependymomas are rare, benign intracranial tumors with an incidence of 0.41/100,000. The predisposing and causative genetic alterations underlying its pathogenesis are unknown. We sought to identify pathogenic mutations through whole exome sequencing (WES) of two male siblings who underwent neurosurgical resection of fourth ventricle subependymomas.

    Methods: WES was performed in DNA from frozen tumor tissue of index patient 1 and blood from both index patients. Additionally, blood DNA from unaffected parents and a third male sibling was subjected to WES. WES analysis was performed utilizing Varsifter software.

    Results: A 34-year old male (index patient 1) underwent brain MRI at our institution as part of a research protocol, studying familial patterns in schizophrenia. His younger sibling had been diagnosed with schizophrenia and was receiving care at our institution. Brain MRI demonstrated a non-enhancing fourth ventricle mass, extending out to the foramens of Magendie and Luschka and causing mild obstructive hydrocephalus (Fig. 1). The patient underwent gross total resection of this lesion (Fig. 2), diagnosed upon histological review as a subependymoma (Fig. 3A). The patient’s older male sibling (index patient 2) had undergone resection of a fourth ventricle subependymoma at an outside hospital, years prior. Imaging of this tumor was unavailable, but H&E staining of the acquired surgical specimen confirmed subependymoma histology (Fig. 3B). WES results demonstrated somatic mutations, specific to the subependymoma of index patient 1 as outlined in Table 1. Previously, MUC4 was overexpressed in glioblastomas and contributed to tumor proliferation and invasive potential. We found tumors from both index patients stained prominently for MUC4, compared to normal brain tissue acquired from patients undergoing epilepsy surgery (Fig. 4).

    Conclusions: This study provides initial data, analyzing genetic alterations underlying the pathogenesis of subependymomas. Missense mutations in MUC4 affecting exon 2 may represent tumor-specific and potentially tumorigenic genetic alterations in subependymomas.

    Patient Care: Our findings provide important insight into the genetic alterations underlying subependymoma formation, an area with little to no data reported to date. Our data may contribute to future understanding of the natural history and potential treatment of these benign but often insidiously presenting tumors.

    Learning Objectives: 1. Recognize that the causative and/or pre-disposing genetic alterations underlying subependymomas are unknown. 2. Tumor-specific mutations outlined in table 1 provide preliminary evidence for further study of genetic mutations contributing to subependymoma formation. 3. MUC4 mutations may contribute to protein over-expression and be a unique tumorigenic feature of subependymomas.

    References: 1. Villano JL, Parker CK, Dolecek TA. Descriptive epidemiology of ependymal tumours in the United States. British journal of cancer 2013;108:2367-71. 2. Teer JK, Green ED, Mullikin JC, Biesecker LG. VarSifter: visualizing and analyzing exome-scale sequence variation data on a desktop computer. Bioinformatics 2012;28:599-600. 3. Li W, Wu C, Yao Y, Dong B, Wei Z, Lv X, et al. MUC4 modulates human glioblastoma cell proliferation and invasion by upregulating EGFR expression. Neuroscience letters 2014;566:82-7.

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