Molecular variants and mutations in medulloblastoma

Figures & data

Table 1 Pathologic subtypes of medulloblastoma

Pathologic subtype	Histologic appearance	Prognosis (% overall survival at 5 years)
Classic (71%)	Sheets of uniform small cells with high nuclear to cytoplasmic ratio and round hyperchromatic nuclei. Focal neural differentiation is present in a minority.	WNT subgroup (>95%) SHH subgroup (80%) Group 4 (70%)
Nodular/desmoplastic (5%) – Conventional (3%) – Paucinodular (1%) – DMEN (<1%)	Heterogeneous architecture with regions of dense intercellular reticulin and nodules containing tumor cells with a neuronal phenotype and decreased growth fraction.	Infants and children (80%) Adults (80%) p53 mutant tumors (45%)
Large cell/anaplastic (17%)	Anaplastic tumors have marked pleomorphism, nuclear molding, cell-cell wrapping, and high mitotic activity. Large cell type features spherical cells with round nuclei, open chromatin, and prominent central nucleoli. Large cell and anaplastic types coexist.	Group 3 (<50%)

Abbreviations: WNT, wingless; SHH, sonic hedgehog; DMEN, desmoplastic medulloblastoma with excessive nodularity.

Table 2 Clinical and molecular characteristics of subgroups of medulloblastoma

	WNT (~10%)	SHH (~30%)	Group 3 (~25%)	Group 4 (~35%)
Clinical
Sex ratio	1:1	1.5:1	2:1	3:1
Age distribution	Older children	Infants, children, adults	Mostly infants	Older children and young adults
Histology	Classic; very rarely LCA	Classic >nodular/desmoplastic >LCA >MBEN	Classic >LCA	Classic; rarely LCA
Metastasis at diagnosis	5%–10%	15%–20%	40%–45%	35%–40%
Overall survival	~95%	~75%	~50%	~75%
Proposed cell of origin	Lower rhombic lip progenitor cells	CGNP of the EGL and cochlear nucleus	Prominin-1+, lineage− neural stem cells; CGNPs of the EGL	Unknown
Genomic
Cytogenetic	6−	3q+ 9p+ 9q− 10q− 14q− 17p−	1q+ 7+ 17q+ 18+ 8− 10q− 11− 16q− 17p−	4+ 7+ 17q+ 18+ 8− 10− 11− 17p− X−
Driver genes	CTNNB1 (90.6%) DDX3X (50%) SMARCA4 (26.3%) MLL2 (12.5%) TP53 (12.5%)	PTCH1 (28%) TP53 (13.6%) MLL2 (12.9%) DDX3X (11.7%) MycN (8.2%) BCOR (8%) LDB1 (6.9%) TCF4 (5.5%) GLI2 (5.2%)	Myc (16.7%) PVT1 (11.9%) SMARCA4 (10.5%) OTX2 (7.7%) CTDNEP1 (4.6%) LRP1B (4.6%) MLL2 (4%)	KDM6A (13%) SNCAIP (10.4%) MycN (6.3%) MLL3 (5.3%) CDK6 (4.7%) ZMYM3 (3.7%)
Expression signature	WNT signaling	SHH signaling	Myc signature Retinal signature	Neuronal signature

Note: Adapted with permission from Macmillan Publishers Limited: Nat Rev Cancer. Northcott PA, Jones DT, Kool M, et al. Medulloblastomics: the end of the beginning. Nat Rev Cancer. 2012;12:818–834.²⁷ Copyright © 2012.

Abbreviations: WNT, wingless; SHH, Sonic Hedgehog; LCA, large cell/anaplastic; MBEN, medulloblastoma with excessive nodularity; CGNP, cerebellar granular neuron precursor; EGL, external granular layer.

Table 3 Clinical and biologic characteristics of infant and adult SHH medulloblastoma

	Infant SHH medulloblastoma	Adult SHH medulloblastoma
Sex	Males = females	Male predominance
Age	<4 years	>16 years
Tumor location	Vermis	Cerebellar hemispheres
Metastasis at diagnosis	Frequently metastatic	Frequently localized
Overall survival (5-year)	85%	80%
Survival by histology	Desmoplastic > classic	No difference
Survival by M0 versus M+	No difference	M0 >M+
Survival by 10q loss (+ or −)	No difference	10q loss+ < 10q loss−
Survival by GLi2 amp (+ or −)	No difference	GLI2 amp+ <GLI2 amp−
Gene enrichment	extracellular matrix	HOX, BARHL1, LHX2
Cytogenetics	CDK 6 amplification (3.6%) 6q loss (0%) 9q loss (56.4%) MycN amplification (12.7%) GLI2 amplification (7.3%) Chr 2 gain (27.3%) Chr 10q loss (54.5%)	CDK 6 amplification (2.1%) 6q loss (3.1%) 9q loss (37.5%) MycN amplification (1%) GLI2 amplification (6.2%) Chr 2 gain (15.6%) Chr 10q loss (19.8%)

Note: With kind permission from Springer Science+Business Media: Acta Neuropathol. Pediatric and adult sonic hedgehog medulloblastomas are clinically and molecularly distinct, volume 122, 2011, page 238, Northcott PA, Hielscher T, Dubuc A, et al, Table 3.⁴⁶ Copyright © 2011.

Abbreviation: SHH, Sonic Hedgehog.

NorthcottPAJonesDTKoolMMedulloblastomics: the end of the beginningNat Rev Cancer20121281883423175120

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NorthcottPAHielscherTDubucAPediatric and adult sonic hedgehog medulloblastomas are clinically and molecularly distinctActa Neuropathol201112223124021681522

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