Brain Tumors

We are also exploiting the power of bioinformatics to identify novel mutations that drive the initiation and progression of brain tumors. Based on the CBTRUS 2006-2010 report, the overall average annual incidence rate for primary brain and CNS tumors was 21.04/100,000, 7.27/100,000 for malignant tumors. 68,184 individuals deceased between 2006-2010 due to malignant brain and central nervous system tumors. The same report estimated new cases for 2014 to be 66,240.

Our lab focuses on the identification of genetic and epigenetic causes of brain and central nervous system tumors with various histologies and pathological grades. Identification of molecular make-up of brain tumors will guide the development personalized targeted therapies. With well-established collaborations with scientists across the world, the Brain tumor database at Gunel-lab currently contains more than 5,000 brain tumors, from various centers in US, Germany and Turkey. The tumor types in the database include ependymomas, gliomas, medulloblastomas, meningiomas, pituitary adenomas, schwannomas, etc. Using a wide spectrum of approaches, we then elucidate the functional relevance of these mutations.

Our lab utilizes multilevel data including whole exome and whole genome sequencing, molecular inversion probe sequencing (MIPS), whole genome genotyping, array based gene expression, RNA sequencing, whole genome methylation and chromatin immunoprecipitation sequencing (ChIP-seq). We perform analysis and integration of these data across various cancer types followed by downstream biological analysis of candidates in cell culture systems and animal models.

Meningiomas: We conducted genomic analyses of 300 meningiomas and identified new molecular subgroups of meningiomas with: (i) NF2 mutations or loss of NF2 by copy number alterations, (ii) TRAF7 mutations co-occuring with AKT1 or KLF4 mutations and (iv) SMO mutations. The molecular subgroups also correlated with locations of tumors and also the likelihood of becoming malignant. These findings with better classification of meningiomas promised potential targeted therapies for the most common primary brain tumor type. (Clark, Erson-Omay et al. 2013).

Gliomas: Capitalizing on our large tumor collection, we have undertaken two streams of investigation using WES, exome sequencing, gene expression and methylation analysis – to identify novel mutations that (i) drive tumor initiation, and (ii) drive tumor progression.

Recently, analysis of more than 700 gliomas, revealed a new rare subtype of primary GBMs, with improved time to recurrence. We identified 6 primary GBM with somatic POLE mutations leading to ultramutated phenotype, carrying a distinct histology and presenting improved prognosis. These findings help to better characterize the genomic profiles of GBMs, which will improve the targeted personalized therapy studies. (Erson-Omay, Çağlayan et al. 2015).

Vestibular Schwannoma: or acoustic neuromas are benign tumors arising from the vestibular 8th cranial nerve of the peripheral nervous system. They represent 6 to 8% of the total intracranial tumors. Over 90% of the cases of sporadic vestibular schwannoma present an inactivation of both NF2 alleles. To better understand the disease, we have applied genomics technologies including Whole Exome Sequencing and gene expression profiles of a set of vestibular schwannoma. We are now investigating and confirming the role of the identified mutations using in vitro and in vivo approaches.

Using genomics tools and sequence analysis, we identified TRAF7, KLF4, AKT and SMO as novel drivers of non-NF2 meningiomas. We are now further characterizing these driver mutations using molecular and biochemical approaches and also using next-generation sequencing techniques to discover new genetic alterations.

For gliomas, we are employing in vitro cell culture systems using primary cell cultures and established glioma lines along with biochemical and cell biological approaches to tease out the mechanistic effects of the mutations we have identified. In addition, we are employing animal models (both Mouse and Drosophila) to elucidate the molecular mechanisms of these tumor-causing mutations. We are now also using in vivo intracranial xenograft mouse models to determine, as well as to target, aberrant genetic and epigenetic status of tumor cells and/or tumor initiating cells that contribute to cancer development and its progression. Drosophila has proven to be a powerful and fast system to study tumor initiation and metastasis, we are now exploiting this model to study the ability of candidate mutations to serve as drivers for glioma initiation.

For schwannomas, we are using similar cell biological and biochemical approaches to test the ability of novel candidate genes in schwannoma formation.