Mechanism of paediatric medulloblastoma

Paediatric Medulloblastoma, while rare, is a cancer that affects hundreds of children each year between the ages 0-14 years. Prognosis is typically poor and dependent on variant signalling pathways underlying pathogenesis of tumours. The following discussion will briefly describe four molecular pathways and tumour histology of paediatric medulloblastoma, as well as the methods to identify and treat each variant. *Correspondence to: Andrea LO Hebb, Department of Psychology, Saint Mary’s University, Halifax, Nova Scotia, Canada, E-mail: andrea.hebb@dal.ca Received: January 13, 2020; Accepted: January 23, 2020; Published: January 27, 2020 Introduction Medulloblastoma is a malignant, stage IV brain tumour which occurs more commonly in children than adults. Medulloblastoma is the most common form of high-grade embryonal neuroepithelial central nervous system (CNS) tumour in children and the leading cause of death in paediatric cancer patients [1,2]. The incidence of medulloblastoma has been estimated as 4.82 per 1,000,000 persons, with a male predominance and mean age of diagnosis at 5.8 years [1]. The 5-year and progression-free survival rates of children diagnosed with medulloblastoma between 1990 and 2009 has been reported as approximately 70% with children over the age of 14 having a greater survival rate [3,4]. Poor prognosis as indicated by a 5-year survival rate of approximately 13 % is associated with medulloblastoma recurrence. Genomic studies have identified 4 types of medulloblastoma, Wnt and Shh (Sonic Hedgehog), group 3 and group 4, each associated with different prognostic factors. Wnt and Shh were named after the signalling pathways underlying pathogenesis of tumours, while less is known of the biology of the generic group 3 and group 4. Metastases is rare in Wnt and Shh while frequent in group 3 and group 4 contributing to poor prognosis [5,6]. Tumour pathology and location Tumours with different histology arise from the brain matter near the posterior fossa, commonly affecting the cerebellar vermis and hemispheres, and metastasize through the CNS [5]. Five types of tumours found in children with medulloblastoma have been described. Classic type tumours are found in 70% of cases and are characterized by sheets of round cells with excess cytoplasm [5]. Desmoplastic tumours are composed of undifferentiated cells which form a casing of connective tissue around the neoplasm and originate from the cerebellar hemispheres as well as cells from the external granular layer [5]. Such tumours can also be nodular, forming aggregates of differentiated cells that can be either localized or metastatic [5]. Lastly, large cell and anaplastic tumours are frequently found together and have a mix of round cells with expanded nuclei and cells whose nuclei change shape [5]. Molecular subgroups The subgroups of medulloblastoma arise from faulty cell signalling pathways within neuroectodermal cells responsible for the formation of parts of the skull, brain, and surrounding structures [5,6]. The Wnt signalling pathway is vital for structural development in children as it triggers mitotic stem cell division and differentiation [5,6]. Normally within a cell, a β-catenin degradation complex composed of multiple proteins keeps intracellular β-catenin levels low [5,8]. When a Wnt protein binds to a Frizzled membrane receptor, it activates a Disheveled protein that inactivates the degradation complex, allowing β-catenin to enter the nucleus to trigger transcription [5,6-8]. Common mutations involve germline missense mutations of the Apc gene that codes for the protein adenomatous polyposis coli (Apc) which is a part of the β-catenin degradation complex, as well as somatic mutations to the Ctnnb1 gene which produces stabilized β-catenin [5-7]. As a result, β-catenin cannot be broken down and keeps the pathway activated resulting in excess cell proliferation and tumours [5-7]. The Sonic Hedgehog (Shh) pathway also plays a role in the development of stem cells, the central nervous system, and other tissues [5,9]. The Shh protein must bind to a patched protein located on a brain cell to cause a shape change [5]. In response, a Smoothened (Smo) protein also located on the cell membrane is activated which in turn activates a Gli protein [5]. The Gli protein can then move into the nucleus where it triggers gene transcription and results in cell proliferation [5,9]. Additionally, SUFU proteins play a role in inhibiting Gli to turn off the pathway [5]. Somatic cell mutations are common on the Smo gene that encodes the Smo protein, as well as on the Ptch1 and Sufu genes that encode the Patched and SUFU proteins which makes them unable to inactivate Gli [5,8,9]. Furthermore, additional abnormalities have been observed which result in the amplification of Gli proteins [5,8]. As a result, the pathway stays activated and causes excess cell division and tumours [5]. Zinck MJ (2020) Mechanism of paediatric medulloblastoma Neuro Neurosurg, 2020 doi: 10.15761/NNS.1000127 Volume 3: 2-3 The cause for group 3 and group 4 subgroups are less clear and are thought to arise from interactions between multiple cell signalling pathways [5]. What is known pertains to the OTX2 gene which aids in brain development and is overexpressed in both groups [5]. Additionally, the Myc gene is mutated in group 3 and causes issues with many genes whose functions include promoting stem cell proliferation [11]. When mutated, the gene amplifies these pathways and results in the formation of tumours [5]. One of the few mechanisms identified in group 4 is that one X-chromosome is commonly missing, but the origin of the tumours is unknown [5].