Medulloblastoma – Molecular Genetics

Abstract

Medulloblastoma (MB) is an embryonal brain tumor of the cerebellum, it accounts for 4–6% of all primary intracranial tumors. It is the most common malignant brain tumor in children representing 15–30% of all pediatric brain tumors, with 85% of MB being diagnosed in patients younger than 18 years of age. MB is rare in adults and accounts for less than 1% of primary intracranial malignancies, thus most of the studies have been done on the MB of childhood. Histologically, MB is classified into five distinct subtypes: classic, desmoplastic, anaplastic, large cell and MB with extensive nodularity. These histological subtypes often are quite heterogeneous and exhibit highly variable clinical behavior, with anaplastic subtype typically associated with the worst prognosis, followed by classic and desmoplastic/nodular MB, which correlate with improved overall survival. Nowadays, there is a recognition that MB is a heterogeneous disease.Looking for characteristic genetic features for each MB subtypes have focused in the last 20 years, on the chromosomal and the molecular levels. Presently, two new approaches are under study in MB: the role of epigenomic and the role of microRNA (miR) in MB’s pathogenesis. The most common chromosomal finding in MB was i(17q) that appears in 30–50% of the pediatric MB. Consequently, a net loss of one 17p arm and a net gain of the 17q arm, can be seen. This aberration is in correlation with a poor clinical outcome. Other, less frequently found, aberrations are the gain of 1q7, 17q, 6q and loss of chromosomes 6, 6q, 8p, 9q, 10q 11, 16q, 17p and X chromosome in females. Loss of 6q mainly monosomy 6, is in correlation with improved outcome, while gain of 6q correlates with a considerably poor prognosis.Until recently, the molecular research strategy in most of the studies has been focused on genes that are already known to be involved in other different tumors or syndromes. In general two subtypes were clearly identified in MB: those involved Wnt pathways (Turcot syndrome) and those involved SHH pathways (Gorlin syndrome), other non Wnt/SHH subtypes were less defined. Wnt subtype is found to be associated with the best prognosis while SHH subtype is found to be associated with the worst prognosis. Mutated CTNNB1 gene has been found in 10–15% of the MB cases with an activated Wnt pathway, while in about 25–30% of the MB cases, components of the SHH pathway: about 10% carrying the germ line mutation in the PTCH1 gene will develop MB, also SUFU and SMOH rarely found to be mutated.Deregulation of the signaling cascade of p53 was also found to be implicated in pathogenesis of MB. P53 gene is the cause of Li-Fraumeni syndrome which occurs in 5–10% of the sporadic MB. In about 5–10% of the MB an amplification of the MYC family OTX2, PDGFRA, and CDK6 have been found. MYC1/MYCN amplification is in correlation with a poor outcome. The genes mentioned above are found in 5–30% of the MB, most probably point to the general pathway/s of tumors pathogenesis rather than MB specific pathway. However, recent advanced technologies enabled the finding of genes which are involved in chromatin modification particularly histone 3 lysine 9 (H3K9). Recurrent homozygous deletions of the H3K9 methyltransferase EHMT1; high level amplifications of JMJD2C, an H3K9 demethylase and a global reduction of H3K9 methylation levels have been found to be involved in MB.Recently, microRNAs have been implicated in MB pathogenesis, mir17/19 has been found to be over expressed, and its over expression has been associated with SHH pathways.The chapter will review the reported genetic alterations in MB and its correlation with the clinical and histopathological features.