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 ... 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 ... 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).
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.
- ... - 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. - 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.