Medulloblastoma

A number sign (#) is used with this entry because medulloblastoma can be caused by germline mutations in the SUFU gene (607035) on chromosome 10q and the BRCA2 gene (600185) on chromosome 3p.

Somatic mutations in several genes have been found in sporadic cases of medulloblastoma. These genes include PTCH2 (603673) on chromosome 1p32, CTNNB1 (116806) on chromosome 3p, and APC (611731) on chromosome 5q.

Germline mutation in the SUFU gene (607035.0007) has been reported in a Finnish family with familial meningioma (607174).

Medulloblastoma is the most common brain tumor in children. It accounts for 16% of all pediatric brain tumors, and 40% of all cerebellar tumors in childhood are medulloblastoma. Medulloblastoma occurs bimodally, with peak incidences between 3 and 4 years and 8 and 9 years of age. Approximately 10 to 15% of medulloblastomas are diagnosed in infancy. Medulloblastoma accounts for less than 1% of central nervous system (CNS) tumors in adults, with highest incidence in adults 20 to 34 years of age. In 1 to 2% of patients, medulloblastoma is associated with Gorlin syndrome (109400), a nevoid basal carcinoma syndrome. Medulloblastoma also occurs in up to 40% of patients with Turcot syndrome (276300). Medulloblastoma is thought to arise from neural stem cell precursors in the granular cell layer of the cerebellum. Standard treatment includes surgery, chemotherapy, and, depending on the age of the patient, radiation therapy (Crawford et al., 2007).

Crawford et al. (2007) reviewed medulloblastoma, with a focus on clinical presentation, diagnosis, and treatment.

Cerebellar medulloblastoma is a feature of basal cell nevus syndrome (109400), von Hippel-Lindau syndrome (193300), and familial adenomatous polyposis (175100). In a formal risk analysis for brain tumors in familial adenomatous polyposis, Hamilton et al. (1995) found that the relative risk of cerebellar medulloblastoma in patients with familial adenomatous polyposis was 92 times that for the general population (95% confidence interval, 29 to 269; P less than 0.001).

Studying the molecular basis for metastasis in medulloblastoma, MacDonald et al. (2001) obtained expression profiles of 23 primary medulloblastomas clinically designated as either metastatic (M+) or nonmetastatic (M0) and identified 85 genes whose expression differed significantly between classes. They found that platelet-derived growth factor receptor-alpha (PDGFRA; 173490) and members of the downstream Ras/mitogen-activated protein kinase (MAPK) signal transduction pathway are upregulated in M+ tumors. Immunohistochemical validation on an independent set of tumors showed significant overexpression of PDGFRA in M+ tumors compared to M0 tumors. Using in vitro assays, they showed that platelet-derived growth factor-alpha (PDGFA; 173430) enhances medulloblastoma migration and increases phosphorylation of downstream MAP2K1 (176872), MAP2K2 (601263), MAPK1 (176948), and MAPK3 (601795) in a dose-dependent manner. MacDonald et al. (2001) suggested that inhibitors of PDGFRA and RAS proteins should be considered as possible novel therapeutic strategies against medulloblastoma.

Gilbertson and Clifford (2003) stated that the oligonucleotide probe used by MacDonald et al. (2001) to determine PDGFRA expression actually identified PDGFRB (173410), and therefore called into question whether PDGFRA or PDGFRB is regulated in invasive forms of medulloblastoma. Gilbertson and Clifford (2003) presented data confirming that PDGFRB is preferentially expressed in metastatic medulloblastoma and suggested that it may prove useful as a prognostic marker and as a therapeutic target for the disease.

Pomeroy et al. (2002) approached the problems of CNS tumor classification by developing a system based on DNA microarray gene expression data derived from 99 patient samples. They demonstrated that medulloblastomas are molecularly distinct from other brain tumors including primitive neuroectodermal tumors (PNETs), atypical teratoid/rhabdoid tumors (609322), and malignant gliomas. They also found evidence supporting the derivation of medulloblastomas from cerebellar granule cells through activation of the Sonic hedgehog pathway (see 600725). Pomeroy et al. (2002) further showed that the clinical outcome of children with medulloblastomas is highly predictable on the basis of the gene expression profiles of their tumors at diagnosis. Malignant gliomas were clearly separable from medulloblastomas in that they express genes typical of the astrocytic and oligodendrocytic lineage. Medulloblastomas express ZIC (600470) and NSCL1 (162360), encoding transcription factors that are specific for cerebellar granule cells. Pomeroy et al. (2002) suggested that medulloblastomas, but not PNETs, arise from cerebellar granule cells, or alternatively, have activated the transcriptional program of cerebellar granule cells.

Hallahan et al. (2003) established that retinoids cause extensive apoptosis of medulloblastoma cells. In a xenograft model, retinoids largely abrogated tumor growth. Using receptor-specific retinoid agonists, Hallahan et al. (2003) defined a subset of mRNAs that were induced by all active retinoids in retinoid-sensitive cell lines. They also identified BMP2 (112261) as a candidate mediator of retinoid activity. BMP2 protein induced medulloblastoma cell apoptosis, whereas the BMP2 antagonist Noggin (602991) blocked both retinoid and BMP2-induced apoptosis. BMP2 also induced p38 MAPK (600289), which is necessary for BMP2- and retinoid-induced apoptosis. Retinoid-resistant medulloblastoma cells underwent apoptosis when treated with BMP2 or when cultured with retinoid-sensitive medulloblastoma cells. Retinoid-induced expression of BMP2 is thus necessary and sufficient for apoptosis of retinoid-responsive cells, and expression of BMP2 by retinoid-sensitive cells is sufficient to induce apoptosis in surrounding retinoid-resistant cells.

Leung et al. (2004) demonstrated that BMI1 (164831) is strongly expressed in proliferating cerebellar precursor cells in mice and humans. Using Bmi1-null mice, Leung et al. (2004) demonstrated a crucial role for BMI1 in clonal expansion of granule cell precursors both in vivo and in vitro. Deregulated proliferation of these progenitor cells, by activation of the Shh pathway, leads to medulloblastoma development. Leung et al. (2004) also demonstrated linked overexpression of BMI1 and PTCH1 (601309), suggestive of SHH pathway activation, in a substantial fraction of primary human medulloblastomas. Together with the rapid induction of Bmi1 expression on addition of Shh or on overexpression of the Shh target Gli1 in cerebellar granule cell cultures, Leung et al. (2004) concluded that their findings implicate BMI1 overexpression as an alternative or additive mechanism in the pathogenesis of medulloblastomas, and highlight a role for BMI1-containing polycomb complexes in proliferation of cerebellar precursor cells.

Because Drosophila Cic (612082) had been shown to mediate c-erbB (EGFR; see 131550) signaling via transcriptional repression, Lee et al. (2005) studied the expression of human CIC in medulloblastoma, where high levels of ERBB2 (164870) and ERBB4 (600543) correlate with poor prognosis. In silico SAGE analysis of human normal and malignant brain demonstrated that medulloblastoma exhibited the highest level of CIC expression and that expression was most common in tumors of the central nervous system in general. RT-PCR and in situ hybridization verified the expression of CIC in tumor cells, although the level of expression varied between different medulloblastoma subtypes. In mouse postnatally developing cerebellum, in silico analysis and in situ hybridization indicated a strong correlation between Cic expression and the maturation profile of cerebellar granule cell precursors.

Northcott et al. (2009) used high-resolution SNP genotyping to identify regions of genomic gain and loss in 212 medulloblastoma tumors. There were focal amplifications of 15 known oncogenes and focal deletions of 20 known tumor suppressor genes, most not previously implicated in medulloblastoma. There were several amplifications and homozygous deletions, including highly focal genetic events, in genes targeting histone lysine methylation, particularly H3 histone (see 602810) lysine-9 (H3K9). In vitro studies showed that restoring expression of genes controlling H3K9 methylation greatly diminished proliferation of medulloblastoma cells. Northcott et al. (2009) postulated that defective control of the histone code may contribute to the pathogenesis of medulloblastoma.

Parsons et al. (2011) searched for copy number alterations using high-density microarrays and sequenced all known protein-coding genes and microRNA genes using Sanger sequencing in a set of 22 medulloblastomas. Parsons et al. (2011) found that, on average, each tumor had 11 gene alterations, fewer by a factor of 5 to 10 than in the adult solid tumors that had been sequenced to that time. In addition to alterations in the Hedgehog (see 600725) and Wnt pathways (see 164820), their analysis led to the discovery of genes not known to be altered in medulloblastomas. Most notably, inactivating mutations of the histone-lysine N-methyltransferase genes MLL2 (602113) or MLL3 (606833) were identified in 16% of medulloblastoma patients. Parsons et al. (2011) concluded that their results demonstrated key differences between the genetic landscapes of adult and childhood cancers, highlighted dysregulation of developmental pathways as an important mechanism underlying medulloblastomas, and identified a role for a specific type of histone methylation in human tumorigenesis.

Gibson et al. (2010) provided evidence that a discrete subtype of medulloblastoma that contains activating mutations in the WNT pathway effector CTNNB1 (116806) arises outside the cerebellum from cells of the dorsal brainstem. They found that genes marking human WNT-subtype medulloblastomas are more frequently expressed in the lower rhombic lip and embryonic dorsal brainstem than in the upper rhombic lip and developing cerebellum. MRI and intraoperative reports showed that human WNT-subtype tumors infiltrate the dorsal brainstem, whereas SHH-subtype tumors are located within the cerebellar hemispheres. Activating mutations in Ctnnb1 had little impact on progenitor cell populations in the cerebellum, but caused the abnormal accumulation of cells on the embryonic dorsal brainstem which included aberrantly proliferating Zic1+ precursor cells. These lesions persisted in all mutant adult mice; moreover, in 15% of cases in which Tp53 (191170) was concurrently deleted, they progressed to form medulloblastomas that recapitulated the anatomy and gene expression profiles of human WNT-subtype medulloblastoma. The data of Gibson et al. (2010) provided the first evidence that subtypes of medulloblastoma have distinct cellular origins, and provided an explanation for the marked molecular and clinical differences between SHH- and WNT-subtype medulloblastomas.

Reviews

In their review, Crawford et al. (2007) provided an overview of the molecular biology of medulloblastoma.

Guessous et al. (2008) reviewed the involvement multiple signaling pathways in medulloblastoma malignancy, with a focus on their modes of deregulation, prognostic value, functional effects, cellular and molecular mechanisms of action, and implications for therapy.

Berman et al. (2002) investigated therapeutic efficacy of the hedgehog pathway antagonist cyclopamine in preclinical models of medulloblastoma, the most common malignant brain tumor in children. Cyclopamine treatment of murine medulloblastoma cells blocked proliferation in vitro and induced changes in gene expression consistent with initiation of neuronal differentiation and loss of neuronal stem cell-like character. The compound also caused regression of murine tumor allografts in vivo and induced rapid death of cells from freshly resected human medulloblastomas, but not from other brain tumors, and thus established a specific role for hedgehog pathway activity in medulloblastoma growth.

Rudin et al. (2009) described a 26-year-old man with metastatic medulloblastoma that was refractory to multiple therapies. Molecular analysis of the tumor specimens demonstrated activation of the hedgehog pathway, with loss of heterozygosity and somatic mutation of the gene encoding patched-1 (PTCH1; 601309), a key negative regulator of hedgehog signaling. The patient was treated with a novel hedgehog pathway inhibitor, GDC-0449, and treatment resulted in a rapid, although transient, regression of the tumor and reduction of symptoms.

Medulloblastoma Locus on Chromosome 17

A locus for medulloblastoma may map to chromosome 17p. Isochromosome 17q has been observed in high frequency in cytogenetic studies of medulloblastoma. By studies using restriction fragment length polymorphisms, Cogen et al. (1990) showed loss of heterozygosity for 17p sequences in 45% of medulloblastomas. The finding was predictive of a poor clinical response to treatment. Furthermore, a deletion could be mapped to 17p13.1-p12, the same chromosomal region for which loss of alleles has been shown in tumor specimens from patients with colon cancer, and the same region to which the p53 gene (191170) has been mapped. However, using denaturing gradient gel electrophoresis and direct sequencing, Cogen et al. (1992) detected p53 mutations in only 2 of 20 medulloblastoma specimens. Moreover, additional RFLP studies of these 20 specimens showed loss of heterozygosity at a more distal and distinct site, 17p13.3.

BRCA2 Mutations in Medulloblastomas

In 2 brothers who developed Wilms tumor (194070) and brain tumors, Reid et al. (2005) identified 2 truncating BRCA2 mutations (600185.0027 and 600185.0031). One boy had recurrent medulloblastoma.

SUFU Mutations in Desmoplastic Medulloblastomas and Medulloblastomas with Extensive Nodularity (MBEN)

Bayani et al. (2000) showed that loss of heterozygosity (LOH) on 10q24 is frequent in medulloblastomas, suggesting that this region contains 1 or more tumor suppressor genes. Taylor et al. (2002) reported children with medulloblastoma who carried germline and somatic mutations in the SUFU gene (607035) accompanied by LOH of the wildtype allele. Several of these mutations encoded truncated proteins that were unable to export the GLI transcription factor (165220) from nucleus to cytoplasm, resulting in activation of SHH signaling. Thus, SUFU is a tumor suppressor gene that predisposes individuals to medulloblastoma by modulating the SHH signaling pathway. Taylor et al. (2002) noted that all 4 medulloblastomas with SUFU truncating mutations were of the desmoplastic subtype. Desmoplastic tumors make up about 20 to 30% of medulloblastomas, have a more nodular architecture than 'classical' medulloblastoma, and may have a better prognosis. Activation of the SHH pathway is particularly high in desmoplastic medulloblastomas, as shown by increased expression of the SHH target genes GLI, SMOH (601500), and PTCH.

Brugieres et al. (2010) identified germline truncating SUFU mutations in 2 unrelated families with several children under 3 years of age diagnosed with medulloblastoma (607035.0005 and 607035.0006, respectively). Among the 25 mutation carriers in the 2 families, 7 developed medulloblastomas; of the 5 tumors for which histology was reviewed, 3 were classified as medulloblastoma with extensive nodularity (MBEN) and 2 were typical desmoplastic/nodular medulloblastoma. No obvious physical stigmata of nevoid basal cell carcinoma syndrome was found among 21 mutation carriers from both families who were examined, including 11 patients who underwent brain MRI. SUFU sequence analysis of 1 tumor from each family confirmed that only the mutant allele was detected in the tumor DNA, thus demonstrating the loss of the wildtype allele and supporting a tumor-suppressor role for SUFU.

Somatic Mutations in Medulloblastomas

Among 46 medulloblastomas derived from patients with sporadic disease, Huang et al. (2000) identified 2 with somatic mutations in the APC gene and 4 with somatic mutations in the beta-catenin gene. This study provided the first evidence that APC mutations are operative in a subset of sporadic medulloblastomas.

To identify mutations that drive medulloblastoma, Robinson et al. (2012) sequenced the entire genomes of 37 tumors and matched normal blood. One-hundred and thirty-six genes harboring somatic mutations in this discovery set were sequenced in an additional 56 medulloblastomas. Recurrent mutations were detected in 41 genes not theretofore implicated in medulloblastoma; several targeted distinct components of the epigenetic machinery in different disease subgroups, such as regulators of histone-3 lys27 (H3K27) and H3K4 trimethylation in subgroups 3 and 4 (e.g., KDM6A, 300128 and ZMYM3, 300061), and beta-catenin-1 (CTNNB1; 116806)-associated chromatin remodelers in WNT-subgroup tumors (e.g., SMARCA4, 603254 and CREBBP, 600140). Modeling of mutations in mouse lower rhombic lip progenitors that generate WNT-subgroup tumors identified genes that maintain this cell lineage (DDX3X; 300160), as well as mutated genes that initiate (CDH1; 192090) or cooperate (PIK3CA; 171834) in tumorigenesis. Robinson et al. (2012) concluded that their data provided important new insights into the pathogenesis of medulloblastoma subgroups and highlighted targets for therapeutic development.

Northcott et al. (2012) reported somatic copy number aberrations in 1,087 unique medulloblastomas. These copy number variations are common in medulloblastoma, and are predominantly subgroup-enriched. The most common region of focal copy number gain is a tandem duplication of SNCAIP (603779), a gene associated with Parkinson disease (168600), which is exquisitely restricted to Group 4-alpha. Recurrent translocations of PVT1 (165140), including PVT1-MYC (190080) and PVT1-NDRG1 (605262), that arise through chromothripsis are restricted to Group 3. Numerous targetable somatic copy number aberrations, including recurrent events targeting TGF-beta (190180) signaling in Group 3, and NF-kappa-B (see 164011) signaling in Group 4, suggested future avenues for rational, targeted therapy.

Jones et al. (2012) described an integrative deep-sequencing analysis of 125 tumor-normal pairs, conducted as part of the International Cancer Genome Consortium (ICGC) PedBrain Tumor Project. Tetraploidy was identified as a frequent early event in Group 3 and 4 medulloblastomas, and a positive correlation between patient age and mutation rate was observed. Several recurrent mutations were identified, both in known medulloblastoma-related genes (CTNNB1; PTCH1, 601309; MLL2, 602113; SMARCA4) and in genes not previously linked to this tumor (DDX3X; CTDNEP1, 610684; KDM6A, TBR1; 604616), often in subgroup-specific patterns. RNA sequencing confirmed these alterations, and revealed the expression of, to their knowledge, the first medulloblastoma fusion genes identified. Chromatin modifiers were frequently altered across all subgroups.

Using whole-exome sequencing of 92 primary medulloblastoma/normal pairs, Pugh et al. (2012) observed that overall, medulloblastomas have low mutation rates consistent with other pediatric tumors, with a median of 0.35 non-silent mutations per megabase. Pugh et al. (2012) identified 12 genes mutated at statistically significant frequencies, including previously known mutated genes in medulloblastoma such as CTNNB1, PTCH1, MLL2, SMARCA4, and TP53 (191170). Recurrent somatic mutations were newly identified in an RNA helicase gene, DDX3X, often concurrent with CTNNB1 mutations, and in the nuclear co-repressor (N-CoR) complex genes GPS2 (601935), BCOR (300485), and LDB1 (603451). Pugh et al. (2012) showed that mutant DDX3X potentiates transactivation of a transcription factor (TCF4; 602272) promoter and enhanced cell viability in combination with mutant, but not wildtype, beta-catenin. Pugh et al. (2012) concluded that their study revealed the alteration of WNT, hedgehog, histone methyltransferase, and N-CoR pathways across medulloblastomas and within specific subtypes of this disease, and nominated the RNA helicase DDX3X as a component of pathogenic beta-catenin signaling in medulloblastoma.

Northcott et al. (2017) analyzed the somatic landscape across 491 sequenced medulloblastoma samples and the molecular heterogeneity among 1,256 epigenetically analyzed cases, and identified subgroup-specific driver alterations that included novel actionable targets. Patients with Group 3 medulloblastomas were characterized by MYC (190080) amplifications. New molecular subtypes were differentially enriched for specific driver events, including hotspot in-frame insertions that target KBTBD4 (617645) and 'enhancer hijacking' events that activate PRDM6 in patients with highly recurrent, stereotypical tandem duplications in the SNCAIP gene (603779), restricted to Group 4. Northcott et al. (2017) concluded that the application of integrative genomics to an extensive cohort of clinical samples derived from a single childhood cancer entity revealed a series of cancer genes and biologically relevant subtype diversity that represent attractive therapeutic targets for the treatment of patients with medulloblastoma.

Deletions in DMBT1 in Medulloblastoma

Mollenhauer et al. (1997) identified the DMBT1 gene (601969) as the site of homozygous intragenic deletions at chromosome 10q25.3-q26.1 in medulloblastoma and glioblastoma multiforme tumor tissue, as well as in brain tumor cell lines.

Marino et al. (2000) generated a mouse model for medulloblastoma by Cre-LoxP-mediated inactivation of Rb (RB1; 614041) and p53 tumor suppressor genes in the cerebellar external granular layer (EGL) cells. Recombination mediated by Gfap (137780) promoter-driven Cre was found both in astrocytes and in immature precursor cells of the EGL in the developing cerebellum. Gfap-Cre-mediated inactivation of Rb in a p53-null background produced mice that developed highly aggressive embryonal tumors of the cerebellum with typical features of medulloblastoma. These tumors were identified as early as 7 weeks of age on the outer surface of the molecular layer, corresponding to the location of the EGL cells during development. Marino et al. (2000) concluded that loss of function of Rb is essential for medulloblastoma development in the mouse and stated that their results strongly support the hypothesis that medulloblastomas arise from multipotent precursor cells located in the EGL.