Yasin Mamatjan

Thompson Rivers University · Department of Engineering

Background We previously developed a DNA methylation-based risk predictor for meningioma, which has been used locally in a prospective fashion since its original publication. As a follow-up, we validate this model using a large prospective cohort and introduce a streamlined next-generation predictor compatible with newer methylation arrays. Method...

Brain metastases (BMs) are the most common and among the deadliest brain tumors. Currently, there are no reliable predictors of BM development from primary cancer, which limits early intervention. Lung adenocarcinoma (LUAD) is the most common BM source and here we obtained 402 tumor and plasma samples from a large cohort of patients with LUAD with...

Mutations in the pivotal metabolic isocitrate dehydrogenase (IDH) enzymes are recognized to drive the molecular footprint of diffuse gliomas, and patients with IDH mutant gliomas have overall favorable outcomes compared to patients with IDH wild-type tumors. However, survival still varies widely among patients with IDH mutated tumors. Here, we aime...

INTRODUCTION Mutations in isocitrate dehydrogenase (IDH) enzymes are recognised to drive the molecular footprint of diffuse gliomas through the accumulation of oncometabolite R-2-hydroxyglutarate which drives the widespread restructuring of the DNA methylome; however, beyond R-2-hydroxyglutarate, a comprehensive metabologenomic characterization of...

Background The clinical management of patients with incidental intracranial meningioma varies markedly and is often based on clinician choice and observational data. Heterogeneous outcome measurement has likely hampered knowledge progress by preventing comparative analysis of similar cohorts of patients. This systematic review aimed to summarize th...

BACKGROUND Diffuse gliomas represent over 80% of malignant brain tumors ranging from low-grade to aggressive high-grade lesions. Within IDH-mutant gliomas there is a high variability in survival and a need to more accurately predict outcome. METHODS To identify and characterize a predictive signature of outcome in gliomas, we utilized an integrati...

INTRODUCTION Mutations in isocitrate dehydrogenase (IDH) enzymes are recognised to drive the molecular footprint of diffuse gliomas through the accumulation of oncometabolite R-2-hydroxyglutarate which drives the widespread restructuring of the DNA methylome; however, beyond R-2-hydroxyglutarate , a comprehensive metabologenomic characterization of...

Hypoxia is a prominent characteristic of aggressive tumors, including glioblastoma (GB), and is linked to therapy resistance. Understanding the molecular mechanisms underlying hypoxia-induced changes in neoplastic and non-neoplastic cells is crucial for developing targeted therapies. In this study, we took a comprehensive approach to investigate th...

Background: Diffuse gliomas represent over 80% of malignant brain tumors ranging from low-grade to aggressive high-grade lesions. Within IDH-mutant gliomas there is a high variability in survival and a need to more accurately predict outcome. Methods: To identify and characterize a predictive signature of outcome in gliomas, we utilized an integ...

Mutations in isocitrate dehydrogenase (IDH) enzymes are recognised to drive the molecular footprint of diffuse gliomas, and patients with IDH-mutant gliomas have overall favorable outcomes compared to patients with IDH wildtype tumors. Nonetheless, survival can vary widely even amongst patients with IDH-mutant tumors. A comprehensive metabologenomi...

Malignant peripheral nerve sheath tumor (MPNST) is a highly aggressive sarcoma, and a lethal neurofibromatosis type 1-related malignancy, with little progress made on treatment strategies. Here, we apply a multiplatform integrated molecular analysis on 108 tumors spanning the spectrum of peripheral nerve sheath tumors to identify candidate drivers...

A child had been followed since infancy by our multi-disciplinary neuro-oncology clinic with annual magnetic resonance imaging (MRI) under the presumed diagnosis of encephalocraniocutaneous lipomatosis (ECCL), with clinical features including nevus psiloliparus, scalp lipoma, nodular skin tag on and coloboma of the eyelid, cortical atrophy and meni...

BACKGROUND: The pathophysiology of CNS germ cell tumors (GCTs) has yet to be fully unraveled, resulting in the paucity of treatment options. The biological comparison with its testicular counterpart has not been interrogated. METHODS: In total, 84 cases of CNS GCT were investigated for methylation and transcriptome analyses, and an integrative anal...

Background: Chordomas are rare malignant skull-base/spine cancers with devastating neurological morbidities and mortality. Unfortunately, no reliable prognostic factors exist to guide treatment decisions. This work identifies DNA methylation-based prognostic chordoma subtypes that are detectable non-invasively in plasma. Methods: Sixty-eight tissue...

Non-small cell lung cancer (NSCLC) is the leading cause of cancer deaths worldwide. Only a fraction of NSCLC harbor actionable driver mutations and there is an urgent need for patient-derived model systems that will enable the development of new targeted therapies. NSCLC and other cancers display profound proteome remodeling compared to normal tiss...

Background: CNS germ cell tumors (GCTs) predominantly develop in pediatric and young adult patients with variable responses to surgery, radiation, and chemotherapy. This study aimed to examine the complex and largely unknown pathogenesis of CNS GCTs. Methods: We used a combined transcriptomic and methylomic approach in 84 cases and conducted an...

BACKGROUND Chordomas are malignant bone cancers arising from the skull-base and spine that are rare but cause devastating central nervous system morbidities. Survival is highly variable despite surgery and radiotherapy as 10% live under 1 year and 30-35% survive over 20 years. There are currently no reliable prognostic factors and this limits our a...

IntroductionChoroid Plexus Tumours (CPTs) account for 1–4% of all brain tumours in children. Atypical choroid plexus papillomas (aCPPs) are a subset of these tumours, defined over a decade ago, yet no consensus exists on the optimal approach to their management.Methods We conducted a retrospective analysis of all patients treated for CPTs at the Ho...

Background: Chordomas are rare malignant bone cancers of the skull-base and spine. Patient survival is variable and not reliably predicted using clinical factors or molecular features. This study identifies prognostic epigenetic chordoma subtypes that are detected non-invasively using plasma methylomes. Methods: Methylation profiles of 68 chordo...

Background Accurate CNS tumor diagnosis can be challenging, and methylation profiling can serve as an adjunct to classify diagnostically difficult cases. Methods An integrated diagnostic approach was employed for a consecutive series of 1,258 surgical neuropathology samples obtained primarily in a consultation practice over 2-year period. DNA meth...

Meningiomas are the most common primary intracranial tumour in adults¹. Patients with symptoms are generally treated with surgery as there are no effective medical therapies. The World Health Organization histopathological grade of the tumour and the extent of resection at surgery (Simpson grade) are associated with the recurrence of disease; howev...

Diffuse gliomas represent over 80% of malignant brain tumors ranging from low-grade to aggressive high-grade lesions. Molecular characterization of these tumors led to the development of new classification system comprising specific glioma subtypes. While this provides novel molecular insight into gliomas it does not fully explain the variability i...

Introduction The development of brain metastases from primary cancer profoundly impacts patient prognosis. Up to one quarter of lung cancers develop brain metastases and subsequent median overall survival is one year. Although clinical factors do not reliably predict brain metastasis development, DNA methylation signatures have been recently shown...

Glioblastoma (GBM) is the deadliest and most vascularized brain tumor in adults; however, blood circulation is highly inefficient in these tumors, contributing to areas of cell death (necrosis) within the tumor, which is likely due to oxygen deprivation (hypoxia). Hypoxia plays a major role in tumor growth, invasion, and resistance to therapy. Hypo...

One of the most prominent features of glioblastoma (GBM) is hyper-vascularization. Bone marrow-derived macrophages are actively recruited to the tumor and referred to as glioma-associated macrophages (GAMs) which are thought to provide a critical role in tumor neo-vascularization. However, the mechanisms by which GAMs regulate endothelial cells (EC...

Rationale and purpose: Meningiomas are benign tumors, but significant number of meningiomas display risk of early tumor recurrence. The inter-observer variability among pathologists for grading and some indistinguishable features of meningioma under the microscope prevent accurate prediction of recurrence risk that critically limits appropriate tre...

Schwannomatosis (SWNTS) is a genetic cancer predisposition syndrome that manifests as multiple and often painful neuronal tumors called schwannomas (SWNs). While germline mutations in SMARCB1 or LZTR1, plus somatic mutations in NF2 and loss of heterozygosity in chromosome 22q have been identified in a subset of patients, little is known about the e...

In the original publication, corresponding author information missed indicating that Dr. Zadeh.

Background Recent international sequencing efforts have allowed for the molecular taxonomy of lower-grade gliomas (LGG). We sought to analyze The Cancer Genome Atlas (TCGA, 2015) gene expression datasets on molecularly defined oligodendrogliomas (IDH-mutated and 1p/19q-codeleted) patients treated with adjuvant radiation or those observed to discove...

Germ cell tumors (GCTs) are unique neoplasms in that they arise from the migrated cells which were supposed to be directed to gonads. They occur in the central nervous system (CNS), as well as gonadal organs such as testis and ovary. Our genomic analysis revealed that they are characterized by mutations in MAPK and PI3K pathways, chromosomal instab...

EGFR-mutant lung adenocarcinomas (EGFRm-LUAD) have a higher risk of developing brain metastases (BM) compared to non-EGFR-mutant tumors. BM development has significant prognostic impact and leads to poorer patient survival. MGMT promoter methylation is known to determine response to therapy in other cancer types including intracranial gliomas but h...

BACKGROUND One quarter of lung adenocarcinoma (LUAD) patients develop brain metastases (BM) and experience a poorer median survival of 12 months despite treatment. Clinical variables do not robustly predict who will develop BM and targeted preventative treatments are limited. Tumour DNA methylation signatures predict outcomes in other cancers and c...

Schwannomatosis (SWNTS) is a genetic cancer predisposition syndrome that manifests as multiple and often, painful neuronal tumors called schwannomas (SWNs). Very little is known about the epigenomic and genomic alterations in SWNTS related SWNs (SWNTS-SWNs) other than germline mutations in SMARCB1 and LZTR1 plus somatic mutations in NF2 and loss of...

Malignant peripheral nerve sheath tumors (MPNSTs) are highly aggressive Schwann-cell derived sarcomas. These tumors are resistant to all current therapies, with exception to gross total surgical resection, and unresectable or metastatic tumors are considered incurable. Our understanding of the molecular alterations driving malignant transformation...

Capicua (CIC) is a transcriptional repressor that counteracts activation of genes in response to receptor tyrosine kinase (RTK)/Ras/MEK/ERK signaling. Following activation of RTK, ERK enters the nucleus and serine-phosphorylates CIC, releasing it from its targets to permit gene expression. We recently showed that ERK triggers ubiquitin-mediated deg...

Glioblastoma (GBM) remains a universal fatal disease and improving survival remains a challenge. One of the most prominent features of GBM is hyper-vascularization, characterized by abnormally dilated, distorted, and leaky vessels. Bone marrow (BM)-derived macrophages are recognized to be an important host cell population that are actively recruite...

Management of clinically aggressive meningiomas is a considerable challenge. PD-L1 induced immune suppression has increasingly gained attention in clinical management of cancer; however, to date, the clinical significance and regulatory mechanisms of PD-L1 in meningioma is not yet fully characterized. We sought to characterize PD-L1 expression in m...

EGFR-mutant lung adenocarcinomas (EGFRm-LUAD) have a higher risk of brain metastasis (BM) development than non-mutant lesions regardless of cancer stage. BM development is a marker of tumor aggressiveness and has significant prognostic impact that leads to treatment failure. MGMT promoter methylation is known to determine response to therapy in oth...

Background: Both genetic and methylation analysis have been shown to provide insight into the diagnosis and prognosis of many brain tumors. However, the implication of methylation profiling and its interaction with genetic alterations in pediatric low-grade gliomas (PLGGs) are unclear. Methods: We performed a comprehensive analysis of PLGG with...

Schwannomas are benign nerve sheath tumors arising from peripheral, cranial, or autonomic nerves.1 Intracranial schwannomas represent 6–8% of all intracranial tumors, the majority located in the cerebellopontine angle. Intraventricular schwannomas are rare with only 31 cases reported.2 The wide differential of intraventricular lesions combined with...

Glioblastoma (GBM) contains a subpopulation of cells, GBM stem cells (GSCs), that maintain the bulk tumor and represent a key therapeutic target. Norrin is a Wnt ligand that binds the Frizzled4 (FZD4) receptor to activate canonical Wnt signaling. While Norrin, encoded by NDP, has a well- described role in vascular development, its function in human...

Capicua (CIC) is a transcriptional repressor that counteracts activation of genes in response to receptor tyrosine kinase (RTK)/Ras/ERK signaling. Following activation of RTK, ERK enters the nucleus and serine-phosphorylates CIC, releasing it from its targets to permit gene expression. We recently showed that ERK triggers ubiquitin-mediated degrada...

Background: Molecular signatures are being increasingly incorporated into cancer classification systems. DNA methylation-based central nervous system (CNS) tumor classification is being recognized as having the potential to aid in cases of difficult histopathological diagnoses. Here, we present our institutional clinical experience in integrating a...

INTRODUCTION The development of brain metastases from primary cancer profoundly impacts patient prognosis. Metastases are the most common adult brain tumor with up to one quarter of lung cancers developing metastases and median overall survival after metastasis being one year. Clinical factors do not reliably predict brain metastasis development an...

Brain metastasis (BM) in patients with EGFR-mutant lung adenocarcinoma is a major determinant of overall survival. Novel insight into the genetic and epigenetic underpinnings of BM development is lacking. The aim of this study is to compare the methylome of EGFR-mutant primary lung adenocarcinoma (EGFRM-PLA) and matched BM to identify important alt...

The update on the WHO classification of central nervous system (CNS) tumors incorporated molecular signatures for a more accurate diagnosis. Recently, DKFZ has demonstrated the utility of DNA methylation profiling(MP) for molecular classification of CNS tumors. We performed a prospective clinical study over the last three years to evaluate the clin...

We performed genome‐wide methylation analysis on 136 pediatric low grade gliomas, identifying a unique cluster consisting of 3 tumors with oligodendroglioma‐like histology, BRAF p.V600E mutations and recurrent whole chromosome gains of 7 and loss of 10. Morphologically, all showed similar features, including a diffusely infiltrative glioma composed...

The transmembrane protein ODZ1 has been associated with the invasive capacity of glioblastoma (GBM) cells through upregulation of RhoA/ROCK signaling, but the mechanisms triggering the ODZ1 pathway remain elusive. In addition, it is widely accepted that hypoxia is one of the main biological hallmarks of the GBM microenvironment and it is associated...

INTRODUCTION Malignant peripheral nerve sheath tumors (MPNSTs) are highly aggressive Schwann-cell derived sarcomas and the leading cause of mortality in neurofibromatosis Type 1. In many cases, MPNSTs develop through malignant transformation of an underlying neurofibroma (NF). The genomic alterations and molecular pathways driving malignant transfo...

BACKGROUND: Adenocarcinomas (ADC) are the most common lung tumours and EGFR-mutant lesions have a higher risk of brain metastasis development, which confers poorer survival. Genetic and epigenetic signatures of brain metastasis have not been comprehensively identified. The aim of this study is to compare the methylome of EGFR-mutant primary lung tu...

INTRODUCTION: Metastases are the most common adult brain tumor with half spreading from lung cancers and they reduce median overall survival from 26 to 12 months. There are no robust patient-specific predictors of brain metastasis. Epigenetic signatures predict disease recurrence in other cancers and identifying brain metastasis methylation-based s...

Norrin is an atypical WNT ligand that binds the Frizzled-4 (FZD4) and Low-density lipoprotein receptor-related protein (LRP5/6) receptor complex to activate canonical WNT/ β-catenin signaling. Norrin/FZD4 signaling is involved in the regulation of vasculature in several tissues including the retina and for blood-brain barrier function. The role of...

Background: Molecular signatures are being increasing used to classify central nervous system (CNS) tumors with incorporation into World Health Organization (WHO) classifications. A recently published genome-wide DNA methylation-based CNS tumor classifier assisted in diagnostically challenging cases. However its impact on patient care has not been...

Background: Challenges in predicting risk of recurrence for individual patients with meningioma limits appropriate selection of patients who may benefit from adjuvant radiation therapy to delay recurrence. Here, we aimed to develop and validate a combined clinicomolecular predictor of early recurrence for individual patients with meningiomas. Metho...

Background: Variability in standard-of-care classifications precludes accurate predictions of early tumor recurrence for individual patients with meningioma, limiting the appropriate selection of patients who would benefit from adjuvant radiotherapy to delay recurrence. We aimed to develop an individualized prediction model of early recurrence ris...

e20574 Background: EGFR-mutant lung cancer is a key molecular subtype of lung cancer. In recent years there is clear recognition in the value of using methylation signature of cancer for improving diagnosis and predicting outcome as well as understanding the biology of cancer progression. Methods: In this study we chose to characterize the methylom...

We performed genome-wide methylation analysis on 136 pediatric low grade gliomas, identifying a unique cluster consisting of BRAF V600E mutant tumors with chromosomal instability, including gain of Chromosome 7 and loss of Chromosome 10. The tumors were all located in the temporal lobe. Patients presented between 10 and 36 years of age, most with a...

Capicua (CIC) is a transcriptional repressor that counteracts activation of genes downstream of receptor tyrosine kinase (RTK)/Ras/ERK signaling. It is well-established that tumorigenesis, especially in glioblastoma (GBM), is attributed to hyperactive RTK/Ras/ERK signaling. While CIC is mutated in other tumors, here we show that CIC has a tumor sup...

Meningiomas are the most common primary intracranial neoplasm. The current World Health Organization (WHO) classification categorizes meningiomas based on histopathological features, but emerging molecular data demonstrate the importance of genomic and epigenomic factors in the clinical behavior of these tumors. Treatment options for symptomatic me...

Background: Few studies have evaluated the health-related quality of life (HRQoL) of patients with meningiomas. Here, we report the largest prospective, longitudinal cross-sectional cohort study of HRQoL in meningiomas to date, in order to identify possible actionable determinants of global HRQoL. Methods: Adults who had undergone resection of a...

Surgery has long been established as the first-line treatment for the majority of symptomatic and enlarging meningiomas, and evidence for its success is derived from retrospective case series. Despite surgical resection, a subset of meningiomas display aggressive behavior with early recurrences that are difficult to treat. The decision to radically...

The archetypal imaging characteristics of meningiomas are among the most stereotypic of all central nervous system (CNS) tumors. In the era of plain film and ventriculography, imaging was only performed if a mass was suspected, and their results were more suggestive than definitive. Following more than a century of technological development, we can...

INTRODUCTION Radiation-induced meningiomas (RIMS) are more clinically aggressive than their sporadic counterparts, with higher rates of tumor recurrence, multiplicity and neurological impairment. Our laboratory has previously demonstrated that RIMs have a distinct genomic profile with a subset of tumors harboring NF2 inactivation through genomic re...

Diffuse gliomas are separated based on IDH mutation (mut) status. However, IDH-mut gliomas manifest wide range of clinical outcome that are not explained by the current genomic classification. We aim to identify clinically and biologically relevant subgroups within IDH-mut low grade gliomas to gain a deeper insight and improve classification. We us...

Differentiation of GBM stem-like cells activates an ODZ1-associated pathway, involving activation of the RhoA-ROCK cascade, leading to cytoskeletal remodelling and invasion into the surrounding environment. Clinically, ODZ1 is associated with decreased survival rates. Nevertheless, the association of the ODZ1-mediated invasion pathway with hypoxia,...

High cellularity and poorly organized tumour vasculature in high-grade gliomas leads to insufficient blood supply, hypoxic areas, and ultimately to the formation of necrosis. Thus, hypoxia is a hallmark of malignant glioma microenvironment and it is associated with aggressive tumor behavior such as growth, progression, and resistance to chemo-radia...

Schwannomas are characteristic manifestations of NF2 and schwannomatosis syndromes. However, the majority of schwannomas are solitary and sporadic. It is unclear whether and to what extent sporadic and syndrome-associated schwannomas or their histologic subtypes represent distinct biological groups. Clinically, although schwannomatosis schwannomas...

Multicentre sequencing efforts have allowed for the molecular characterization of low-grade gliomas (LGG)(The Cancer Genome Atlas (TCGA), 2015). We sought to analyze TCGA gene expression datasets on oligodendrogliomas patients treated with adjuvant radiation (RT) or those observed to discover prognostic markers and pathways. METHODS mRNA expressio...

BACKGROUND Glioma patients continue to carry a very poor prognosis despite maximal therapy, urging for the development of novel therapies. Previous studies have identified mutations of metabolic enzymes directly regulating cellular metabolism, specifically, isocitrate dehydrogenase (IDH1/2) mutation. IDH1/2 mutations occur early in glioma pathogene...

The greatest clinical challenge faced in meningioma is the inability to predict recurrence for individual patients, limiting the ability to select patients who would benefit from adjuvant radiation therapy to prevent recurrence. Therefore, in this multi-center cohort study, we utilized global epigenome DNA methylation profiles from human meningioma...

Tumor recurrence is one of the most important clinical challenges in the management of meningioma patients. Prognostic significance of PD-L1 as a driver for immunosuppressive response and predictor for tumor growth has been demonstrated in several malignancies. We studied the prognostic role of PD-L1 expression for tumor recurrence in meningioma an...

INTRODUCTION Neurofibromas, a peripheral nerve sheath tumor commonly associated with Neurofibromatosis Type 1, are broadly categorized as cutaneous or peripheral nerve neurofibromas (localized or plexiform lesions). More recently, atypical neurofibromatous neoplasm of unknown biological potential (ANNUBP) has been described and believed to be a pre...