Recurrent Genomic Alterations in Pediatric and Adult Central Nervous System Tumors Detected by Chromosomal Microarray

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Recurrent Genomic Alterations in Pediatric and Adult Central Nervous System Tumors Detected by Chromosomal Microarray

Table 1: Pediatric CNS Tumors. Table derived from CGC CNS Workgroup 2015-2018.

TUMOR SUBTYPES BROAD ABERRATIONS (>10Mb) FOCAL ABERRATIONS (<10Mb) CLINICAL FEATURES REFERENCES
GLIOMAS WHO CNS Tumors (2016)
Low grade glioma, WHO grade I Pilocytic astrocytoma/pilomyxoid astrocytoma Some tumors show polysomy 7; other polysomies more common in adult PA Fusions: KIAA1549-BRAF fusion (via 3'BRAF duplication), other BRAF partners reported; NTRK fusions (rare); FGFR1 fusions (rare)

Mutations: BRAF V600E (particularly extra-cerebellar tumors); FGFR1 (midline PA); NF1 (esp. germline), other MAPK pathway mutations
Loss: NF1 in optic pathway PA

Classic PA are cerebellar (most commonly associated with BRAF duplication); PA in patients with germline NF1 alterations often develop as optic gliomas;Surgical resection can be curative; PMA generally more aggressive than PA; BRAF fusions and BRAF mutations generally are mutually exclusive [1]PMID:19016743; [2]PMCID:2761618; [3]PMID:18716556 [4]PMID:25461780 [5]PMID:25664944; [6]PMID:26378811 [7]PMCID:3429698; [8]PMID:23817572; [9]PMID:23583981 [10]PMID:18974108; [11]PMID:23278243; [12]PMID:21274720
Angiocentric glioma Aberrations involving 6q24-q25 Fusions: MYB-QKI rearrangement/deletion (classic histology)

Rearrangement: MYB alone (atypical histology)
Amplification: MYB (atypical histology)

Generally indolent tumors; surgical resection can be curative [13]PMID:26829751; [14]PMID:23633565; [15]PMID:26778052 [9]PMID:23583981
Ganglioglioma Only 30% are abnormal by karyotype

Gain: polysomy 7

Mutations: BRAF V600E in 20-60% of cases (can be concurrent with CDKN2A homozygous deletion)

Fusions: KIAA1549-BRAF

Generally indolent tumors for which surgical resection can be curative [4]PMID:25461780; [9]PMID:23583981; [16]PMID:11996800 [17]PMID:23609006; [18]PMID:29880043
Low grade glioma, WHO grade II Diffuse astrocytoma No diagnostic aberrations Rearrangement: MYBL1 truncating rearrangements and tandem duplication, FGFR1 rearrangements

Mutation: FGFR1

Anaplastic features associated with decreased progression free survival [5]PMID:25664944; [14]PMID:23633565; [19]PMID:26061751 [20]PMID:26824661; [21]PMID:26004297; [4]PMID:25461780 [9]PMID:23583981
Pleomorphic xanthoastrocytoma (PXA) Polysomy 3, polysomy 7 observed

Loss: monosomy 9 / 9p deletion

Mutations: BRAF V600E in ~60%; TP53 (5%)

Loss: CDKN2A/CDKN2B

[4]PMID:25461780; [9]PMID:23583981; [22]PMID:16909113; [23]PMID:12484572
Anaplastic astrocytoma, WHO grade III IDH-mutant or IDH-wild type Gain: 1q, 7/7q, 8q, 10p

Loss: 6q, 9p, 10q, -11/11p, 12q, 13q, 14q, 17p, 19q, -22/22q

IDH-wild type astrocytomas can be more clinically aggressive than those that are IDH-mutant [24]PMCID:1891902; [21]PMID:26004297; [4]PMID:25461780; [25]PMID:24140581; [26]PMCID:5323185; [27]PMID:27230974 [28]PMID:27196377; [19]PMID:26061751; [29]PMID:25962792; [30]PMID:29687258
Other Anaplastic PXA, WHO grade III / Ganglioglioma, WHO Grade III Loss: monosomy 9 / 9p deletion, but no diagnostic findings Mutation: BRAF V600E less common here than in PXA, grade II

Loss: CDKN2A/CDKN2B

CDKN2A/CDKN2B loss may correlate with anaplastic histology WHO CNS Tumors (2016)

[31]PMID:25318587; [32]PMID:23096133; [12]PMID:21274720

Glioblastoma, WHO grade IV IDH-mutant Gain: 1q, 2q, 3q, 7, 16p, 17q, 21q

Loss: 6q, 8q, 9p, 9q, 10q, 13q, 17p, 22q
Chromothripsis: observed

Loss: PTEN, RB1, TP53, CDKN2A/B/C

Fusions: FGFR-TACC; NTRK fusions
Amplification: PDGFRA, MYCN, MET, CDK4, CDK6 (EGFR, MDM2 amp rare)
Mutations: IDH1/2 (rare in pediatric GBM), KRAS, RAS pathway, RB1 pathway, TP53 pathway, FGFR1, H3.3/H3.1-K27M (exclusively in diffuse midline tumors), PDGFRA, NF1, SETD2, ATRX, DAXX

Overall poor prognosis [33]PMID:25752754; [34]PMID:25727226; [35]PMID:26328271; [36]PMID:22837387; [37]PMID:25754088; [4]PMID:25461780; [24]PMCID:1891902; [38]PMID:23417712; [26]PMCID:5323185; [30]PMID:29687258; [39]PMID:20479398; [40]PMID:24959384
Diffuse midline glioma, H3 K27M mutant Gain: 1q, 2, 7, 8

Loss: 10q
Chromothripsis: 2p

Three molecular subgroups:

MYCN subgroup: no mutations but chromothripsis leading to amp of MYCN and ID2
Silent subgroup: no recurrent copy # changes, few mutations
H3-K27M subgroup: MYC, PDGFRA gains/amp; RB1, TP53 deletions
Mutation: ACVR1, H3F3A, HIST1H3B, TP53 Loss: CDKN2A, PTEN, RB1, TP53
Amplification: MYC, MYCN, ID2, PDGFRA

Overall poor prognosis regardless of subgroup [41]PMCID:3280796; [42]PMID:24705254; [43]PMID:24705252 [44]PMID:27048880; [45]PMID:26175967; [46]PMID:24705251; [47]PMID:28966033
EPENDYMOMA

(in order of increasing WHO grade)

DNA-based methylation classifies tumors across anatomical sites (posterior fossa, supratentorial, spinal), grades and age groups Fusion: YAP1 fusions (supratentorial tumors)

Mutation: NF2 (spinal tumors)
Loss: CDKN2A

Intracranial (in children, 90%) or spinal tumors; Histological distinction between WHO grade II and III is of questionable relevance; Prognostic differences among tumors suggested on the basis of methylation analysis WHO CNS Tumors (2016)

PMID:25965575; PMID:21627842; PMID:24939246; PMID:22516549

Classic ependymoma (no WHO grade assigned) Gain: 1q, 5, 7, 9, 11, 18, 20

Loss: 1p, 3, -6/6q, 9p, 13q, 17, 22

Usually intracranial, spinal tumors (myxopapillary) are rare; 80% of pediatric tumors develop in posterior fossa (PF); Supratentorial tumors preferentially show monosomy 9; 1q gain is unfavorable prognostic indicator in PF tumors; spinal tumors associated with NF2 (germline); children have worse outcomes than adults PMID:25965575; PMID:22338015; PMID:28371821
Subependymoma, WHO grade I Typically balanced genomes

Loss: -6/6q in spinal tumors

No diagnostic mutations Favorable prognosis WHO CNS Tumors (2016)

PMID:21959044; PMID:21840481

Myxopapillary ependymoma, WHO grade I Aneuploidy: multiple chromosomes lost and gained Mutation: NF2 (including germline) in spinal tumors Less common but more aggressive in children PMID:25965575; PMCID:3991130; PMID:20425037; PMID:25957288; PMID:25965575; PMID:22516549
Ependymoma, RELA fusion-positive, WHO grade II or III Gain: 1q

Aneuploidy: multiple chromosomes lost and gained
Chromothripsis: chromosome 11 (70% of supratentorial tumors)

Fusion: c11orf95-RELA (supratentorial tumors)

Loss: CDKN2A/B (may help distinguish from other supratentorial ependymomas)

Unfavorable prognosis; occur in infants or children PMID:25965575; PMID:24553141; PMID:28371821
Anaplastic ependymoma (no WHO grade assigned) Epigenetic studies suggest range of abnormalities: balanced or unbalanced genomes Mutation: NF2 (including germline) in spinal tumors

Fusion: RELA fusions, YAP1 fusions can correspond to anaplastic histology

Mostly intracranial tumors, rarely in spinal cord; YAP1 fusion tumors can occur in infants PMID: 25965575
EMBRYONAL TUMORS WHO CNS Tumors (2016)
Medulloblastoma WNT-activated Loss: monosomy 6/6q- as sole finding in 85% Mutation: CTNNB1, DDX3X, TP53, SMARCA4, KMT2D, APC (germline mutations in Turcot syndrome) Common in children > 3 years of age; typically show classic histology, rarely metastasize; overall favorable prognosis PMID:22832581, PMID:24493713; PMID:22134537 PMID:24894640; PMID:16258095; PMID:22832581 PMID:24493713; PMID:22358457; PMID:25043047 PMID:22820256; PMID:26976201; PMID:20823417 PMID:22265402; PMCID:3889646; PMID:16567768 PMID:20940197; PMID:23175120
SHH-activated Gain: 3q

Loss: 9q, 10q, 17p
Ploidy changes: Tetraploidy associated with chromothripsis and TP53 mutations
Chromothripsis: associated with TP53 mutation

Mutation:

TP53 wild-type tumors: PTCH1 (germline mutations in Gorlin syndrome), SMO, SUFU (can be germline), TERT promoter
TP53-mutant tumors: can be germline
Loss: PTCH1, PTEN
Amplification: GLI2 (TP53-mutant tumors), IGF1R, PPM1D, MYCN (TP53-mutant tumors), YAP1, MIR17/92, MDM4

Common in infants, rare in children, most common type of medulloblastoma in adults; Desmoplastic (or nodular) histology common; TP53 wild-type usually correlate with extensive nodularity or desmoplastic histology; TP53-mutant tumors correlate with metastatic disease PMID:24651015; PMID:21681522; PMID:22832581 PMID:24493713; PMID:24077351; PMID:22134537; PMID:22832581; PMID:24493713; PMID:22358457 PMID:25043047; PMID:22820256; PMID:26976201 PMID:20823417; PMID:22265402; PMCID:3889646 PMID:16567768; PMID:20940197; PMID:23175120
Group3 Gain: 1q, 7, 18q

Loss: 5q, 8, 10q, 11p, 16q
Rearrangement: idic(17)(p11.2)
Ploidy changes: tetraploidy in 40-50% of Group3/Group4 tumors

Mutation/Amplification: MYC (mainly in infants), OTX2, CDK6, SMARC4A, CTDNEP1, LRP1B, KMT2D

Fusions: PVT1-MYC, PVT1-NDRG1; GFI1/GFI1B structural variants

Usually classic histology, ~ 50% are metastatic at time of diagnosis, Not generally observed in adults PMID:22832581, PMID:25043047; PMID:24493713 PMID:23175120; PMID:22134537; PMID:22832581; PMID:24493713; PMID:22358457; PMID:25043047 PMID:22820256; PMID:26976201; PMID:20823417 PMID:22265402; PMCID:3889646; PMID:16567768 PMID:20940197; PMID:23175120
Group4 Gain: 7, 18q

Loss: X, 8, 11p
Rearrangement: idic(17)(p11.2) in >80%
Chromothripsis: rare, but associated with TP53 loss when observed

Mutation: TP53, KDM6A, KMT2C

Amplification: MYCN, CDK4, CDK6, OTX2
Rearrangement: SNCAIP tandem duplication; GFI1/GFI1B structural variants

Rarely seen in infants; usually classic histology PMID:22832581; PMID:25043047; PMID:24493713 PMID:23175120; PMID:22134537; PMID:22832581; PMID:24493713; PMID:22358457; PMID:25043047 PMID:22820256; PMID:26976201; PMID:20823417 PMID:22265402; PMCID:3889646; PMID:16567768 PMID:20940197 PMID:23175120
Atypical teratoid/rhabdoid tumor (AT/RT) Loss: 22/22q, though a subset of AT/RT-like tumors retain 22q Classic AT/RT: SMARCB1 mutation/deletion/exonic duplication in 98% of tumors

AT/RT-like tumors: SMARCB1 can be retained (with SMARCA4 mutations)
Three molecular classes:
TYR: ~ 75% show broad 22q loss that includes SMARCB1
SHH: ~ 50% lack any SMARCB1 mutation; ~ 25% have focal SMARCB1 aberrations
MYC: ~ 75% show focal SMARCB1 loss

Most cases occur before 3 yrs of age

TYR subclass: mostly infratentorial
SHH subclass: supra/infratentorial
MYC subclass: mostly supratentorial

Embryonal tumor with multilayered rosettes, C19MC-altered ETMR (incl. ETANTR): occasionally polysomy 2 ETANTR: miRNA cluster C19MC amplification Occurs mainly in children < 4 yrs old WHO CNS Tumors (2016)

PMID:24839957; PMID:24470553 PMID:24337497; PMID:22324795 PMID:20407781, PMID:19057917

Embryonal tumor, other CNS NB-FOXR2 group: 1q gain, 16q loss, polysomy 8

CNS EFT-CIC group: polysomy 8
CNS HGNET-MN1 group: 16q loss, polysomy 8
CNS HGNET-BCOR group: mostly balanced genomes

CNS NB-FOXR2 group: JMJD1C fusions, FOXR2 fusion or deletion

CNS EFT-CIC group: NUTM1 rearrangement/fusion, CIC rearrangement
CNS HGNET-MN1 group: MN1 rearrangement
CNS HGNET-BCOR group: BCOR intragenic tandem duplication

Most common in children, but may also occur in adolescents and adults WHO CNS Tumors (2016)

PMID:26919435; PMID:22691720; PMID:22772606

CHOROID PLEXUS TUMORS (CPT) Choroid plexus papilloma(CPP, WHO grade I) and atypical choroid plexus papilloma (WHO grade II) Hyperdiploidy

Loss: rare, no recurrent losses

No diagnostic mutations/events CPP and aCPP likely belong to same molecularly defined entity; CPP is a diagnostic feature of Aircardi syndrome WHO CNS Tumors (2016)

PMID:23172371; PMID:25575132; PMID:25336695 PMID:11891207

Choroid plexus carcinoma (CPC, WHO grade III) Aneuploidy (including both hypo- and hyperdiploidy types of CPC); copy neutral LOH is frequent, particularly involving chromosome 17

Gain: 1, 7, 12, 20 in > 80% of hyperdiploid CPCs
Loss: 3 (in all hypodiploid CPC), 6, 11, 12q, 16, 22

Mutation: TP53 in > 50%

Amplification: PDGFRB

80% occur in children; associated with Li-Fraumeni syndrome; Lack of SMARCB1/SMARCA4 aberrations can be used to distinguish CPC from AT/RT PMID:24478045; PMID:21990040; PMID:25575132; PMID:18157090; PMID:25336695

Table 2: Adult CNS Tumors. Table derived from CGC CNS Workgroup 2015-2018.

TUMOR SUBTYPES BROAD ABERRATIONS (>10Mb) FOCAL ABERRATIONS (<10Mb) CLINICAL FEATURES REFERENCES
GLIOMAS
Low grade gliomas, WHO grade I-II Pilocytic astrocytoma Gain: 5, 7, 6, 11

Loss: 1, 2, 3, 13, 14, 16, 17, 19

Fusion: KIAA1549-BRAF fusion (via 3'BRAF duplication), other BRAF partners reported; NTRK fusions (rare)

Mutation: FGFR1

Aneuploidy is more predominant in adult PA; Infratentorial tumors are more likely to have BRAF fusions/dup and be wildtype for BRAF mutations; Extra-cerebellar tumors are more likely to be BRAF V600E+, but negative for fusion; Surgical resection can be curative PMID: 24470550; [6]PMID:26378811; [5]PMID: 25664944; PMID:26992069
Pleomorphic xanthoastrocytoma (PXA) Gain: 7, 2, 5, 21, 20, 12, 15

Loss: monosomy 9 / 9p deletion most common, 22, 14, 13, 10
CN-LOH: 9p, 22

Loss: homozygous loss CDKN2A/B

Mutation: BRAF V600E

Adults and pediatric tumors show similar CNVs; CDKN2A/CDKN2B loss may correlate with anaplastic histology PMID:23442159; PMID:28181325
Ganglioglioma Gain: polysomy 5, polysomy 7, 10p

Loss: 1p loss, monosomy (with focal CDKN2A loss)

Mutation: BRAF V600E , TSC1, TSC2, FGFR1, FGFR2, KRAS Generally indolent tumors; surgical resection can be curative PMID:23442159; PMID:25764012; [18]PMID:29880043
Angiocentric glioma Loss: 6q24-q25 Fusion: MYB-QKI rearrangement/deletion (classic histology)

Rearrangement: MYB alone (atypical histology)
Amplification: MYB (atypical histology)

Generally indolent tumors; surgical resection can be curative [13]PMID:26829751
Dysembryoplastic neuroepithelial tumor (DNET) No specific changes Mutation: intragenic duplication or mutation FGFR1; BRAF V600E Rare in adults; Benign with excellent prognosis even with subtotal resection PMID:26920151; PMID:23442159; PMID:21937911
Rosette forming glioneuronal tumor Gain:1q , 7, 9, 16

Loss: 1p
Amplification: 9q34.2, 19p13.3

Fusion: KIAA1549-BRAF fusion (via 3'BRAF duplication)

Mutation: PIK3CA, FGFR1
Amplification: SBNO2

Generally indolent tumors; surgical resection can be curative PMID:27893178; PMID:26371886
Infiltrating Gliomas Diffuse astrocytoma/anaplastic Astrocytoma, WHO grade II/III, IDH mutant Gain: 4q, 7q, 8q24, 12q

Loss: 9p, 19q (without 1p)

Gain: MYC

Loss: CDKN2A/B, PML15q22

Better prognosis than IDH wildtype astrocytoma; Progression to grade IV will often involves loss of 10q, gain of CDK4, CDK6, and cyclin E2, and an increase in copy number alterations. [20]PMID:26824661; PMID:26061753; PMID:25263767 PMID:26061754; PMID:28535583; PMID:26091668 PMID: 25701198; PMID:26865861; [30]PMID:29687258
Diffuse astrocytoma/anaplastic astrocytoma, WHO grade II/III, IDH wild-type Gain: 7, 19

Loss: 4, 9p 10
Amplification: EGFR, MDM4, CDK4

Loss: homozygous CDKN2A/B

Mutation: EGFR, NF1, PTEN
Amplification: EGFR, MDM4, CDK4

Poor prognosis with similar abnormalities to glioblastoma PMID:26061754; [20]PMID:26824661;PMID:28535583 PMID:26091668; PMID:26810070
Oligodendroglioma/anaplastic oligodendroglioma, WHO grade II/III, IDH mutant Rearrangement: der(1;19)(q10;p10) leads to 1p/19q co-deletion

Loss: 1p/19q, 9p, 14q, less frequent 4, 18q

Gain: MYC

Loss: MAX (14q), FBXW7, CDN2KA/B
Mutation: FUBP1, CIC, IDH, TERT, NOTCH1, PIK3CA or PIK3R1

Activation of MYC pathway is often seen with loss of 9p (CDKN2A/B), and 14q (MAX gene) and is reported to have a worse prognosis PMID:27090007; PMID:26061753; PMID:25263767 PMID:26061754; PMID:24335697; [5]PMID:25664944;PMID:26061753; PMID:26941959; [20]PMID:26824661 [19]PMID:26061751
Glioblastoma , grade IV, IDH mutant Gain: 1/1q, 6p

Loss: 3p, 10, 13, 14, 15, 22 (3, 4q, 19q, 16p, 21q, 5p seen in age <40)
Amplification: CDK6, cyclin E2, CDK4, MET
Chromothripsis

Gain or Amplification: CDK4, CDK6, cyclin E2

Loss: PTEN

About 10% of glioblastomas; correspond closely to secondary glioblastoma with history of prior glioma. These cases often involve loss of 10q , gain of CDK4, CDK6, cyclin E2, and increase in copy number alterations. PMID:26061754; [37]PMID:25754088; PMID:28535583 PMID:25931051; PMID:26091668; [4]PMID:25461780; PMID:27157931; [34]PMID:25727226; PMID:26323991 [19]PMID:26061751; [30]PMID:29687258
Glioblastoma , grade IV, IDH wildtype Loss: 4, 9p, 10, 13, 14, 15, 22 , (3, 4q, 19q, 16p, 21q, 5p loss in age <40)

Gain: 7, 19, 20 (1q, 12p, 11q, 9q, 4, 10p gain in age <40)
Amplification: EGFR, MDM4, CDK4, MET

Loss: homozygous CDKN2A/B, PTEN, RB1

Mutation: TERT, EGFR, PTEN, NF1, RB1, PIK3CA or PIK3R1, TP53
Amplification: EGFR, MDM4, MDM2, CDK4, PDGFRA, MET

Overall poor prognosis. Gain of 19q, amplification of EGFR, and homozygous loss of CDKN2A are seen primarily in patients over age 40. Co-gain of 19 and 20 may be associated with longer survival. PMID:26061754; [37]PMID:25754088; PMID:28535583 PMID:25931051; PMID:26091668; [4]PMID:25461780; PMID:27157931; [34]PMID:25727226; [19]PMID:26061751
MENINGIOMA
Grade 1 No copy number changes in 44%

Gain: multiple polysomies, 5
Loss: 22/22q- common as sole aberration
CN-LOH: 1p, 14q

Loss: NF2, CDKN2A, PTEN

Mutation: NF2, PI3K, SMO, AKT1, KLF4, TRAF7, TERT, ARID1A

Array findings characteristic of higher grade tumors when histology supports lower grade may suggest increased likelihood of recurrence. Polysomy, particularly involving chromosome 5, are seen in angiomatous meningiomas. LOH 1p and/or LOH 1p/14q correlated with anaplastic transformation. PMID:23528542; PMID:27575681; PMID:20015288 PMID:21988727; PMID19918127; PMID:25347344 PMID:23334667; PMID:25963524; PMID:26826201 PMID:28195122; PMID:26323607;

PMID:11958368; PMID:25965831; PMID:24536048; PMID:24722350 PMID:12568317; PMID:26771848; PMID:27012381; PMID:27480481; PMID:27624470; PMID:27624470 PMID:27458586; PMID:25347344; PMID:17225936

Grade 2 atypical Gain: 1q, 9q, 12q, 15q, 17q, 20q

Loss: 1p, 3p, 6q, 7p, 14/14q, 9p, 10, 11p, 18/18q, 19q, 22/loss 22q

Loss: NF2, CDKN2A, PTEN

Mutation: NF2, CDKN2A/C, SMARCE1, SMARCB1, TERT

Gain of 1q is assocociated with a shorter PFS; Loss of 1p, 9p and 10 appear with greater frequency as tumor grade increases. PMID:23528542; PMID:27575681; PMID:20015288 PMID:21988727; PMID19918127; PMID:25347344 PMID:23334667; PMID:25963524; PMID:26826201 PMID:28195122; PMID:26323607; PMID:11958368; PMID:25965831; PMID:24536048; PMID:24722350 PMID:12568317; PMID:26771848; PMID:27012381; PMID:27480481; PMID:27624470; PMID:27624470 PMID:27458586; PMID:25347344; PMID:17225936
Grade 3 anaplastic Gain: 1q, 9q, 12q, 15q, 17q23, 20q

Loss: 1p, 3p, 6q, 7p, 14/14q, 9p, 10, 11p,18/18q,19q,22/loss 22q

Loss: NF2, CDKN2A, PTEN

Mutation: NF2, CDKN2A/C, TERT
Amplification: RPS6K in higher grades, 17q23

Loss of 9p and amplification or gain of 17q23 are more frequent than other abnormalities. Gain of 1q is assocociated with a shorter PFS; Loss of 1p, 9p and 10 appear with greater frequency as tumor grade increases. PMID:23528542; PMID:27575681; PMID:20015288 PMID:21988727; PMID19918127; PMID:25347344 PMID:23334667; PMID:25963524; PMID:26826201 PMID:28195122; PMID:26323607; PMID:11958368; PMID:25965831; PMID:24536048; PMID:24722350 PMID:12568317; PMID:26771848; PMID:27012381; PMID:27480481; PMID:27624470; PMID:27624470 PMID:27458586; PMID:25347344; PMID:17225936
EPENDYMOMA

(in order of increasing WHO grade)

DNA-based methylation classifies tumors across anatomical sites --- intracranial (posterior fossa or supratentorial) or spinal --- and across tumor grades and age groups Fusion: YAP1 fusions (supratentorial tumors)

Mutation: NF2 (spinal tumors)
Loss: CDKN2A

Intracranial (in children, 90%) or spinal tumors; Histological distinction between WHO grade II and III is not reliable; Prognostic differences among tumors suggested on the basis of methylation analysis WHO CNS Tumors (2016)

PMID:25965575; PMID:21627842; PMID:24939246; PMID:22516549

Classic ependymoma (no WHO grade assigned) Gain: 1q, 5, 7, 9, 11, 18, 20

Loss: 1p, 3, -6/6q, 9p, 13q, 17, 22

Loss: CDKN2A/CDKN2B (rare); NF2

Mutation: NF2 (esp. in spinal tumors)

Usually intracranial, spinal tumors (myxopapillary) are rare; 80% of pediatric tumors develop in posterior fossa (PF); Supratentorial tumors preferentially show monosomy 9; 1q gain is unfavorable prognostic indicator in PF tumors; spinal tumors associated with NF2 mutation (germline) PMID:25965575; PMID:22338015; PMID:28371821
Subependymoma, WHO grade I

(intracranial or spinal)

Typically balanced genomes

Loss: -6/6q in spinal tumors

No diagnostic mutations Favorable prognosis WHO CNS Tumors (2016)

PMID:21959044; PMID:21840481

Myxopapillary ependymoma, WHO grade I (spinal) Aneuploidy: multiple chromosomes lost and gained Mutation: NF2 (including germline) in spinal tumors More common in adults PMID:25965575; PMCID:3991130; PMID:20425037 PMID:25957288; PMID:25965575; PMID:22516549
Ependymoma, RELA fusion-positive, WHO grade II or III

(intracranial)

Gain: 1q

Aneuploidy: multiple chromosomes lost and gained
Chromothripsis: chromosome 11 (70% of supratentorial tumors)

Fusion: c11orf95-RELA (supratentorial tumors)

Loss: CDKN2A/B (may help distinguish from other supratentorial ependymomas)

Unfavorable prognosis PMID:25965575; PMID:24553141; PMID:28371821
Anaplastic ependymoma (no WHO grade assigned; intracranial or spinal) Epigenetic studies suggest range of abnormalities: balanced or unbalanced genomes Mutation: NF2 (including germline) in spinal tumors

Fusion: RELA fusions, YAP1 fusions can correspond to anaplastic histology

Mostly intracranial tumors, rarely in spinal cord PMID: 25965575; PMID:27022130
  1. ↑ Sievert, Angela J.; et al. (2009-07). "Duplication of 7q34 in pediatric low-grade astrocytomas detected by high-density single-nucleotide polymorphism-based genotype arrays results in a novel BRAF fusion gene". Brain Pathology (Zurich, Switzerland). 19 (3): 449–458. doi:10.1111/j.1750-3639.2008.00225.x. ISSN 1750-3639. PMC 2850204. PMID 19016743. Check date values in: |date= (help)
  2. ↑ Jones, David T. W.; et al. (2006-11). "Genomic Analysis of Pilocytic Astrocytomas at 0.97 Mb Resolution Shows an Increasing Tendency Toward Chromosomal Copy Number Change With Age". Journal of neuropathology and experimental neurology. 65 (11): 1049–1058. doi:10.1097/01.jnen.0000240465.33628.87. ISSN 0022-3069. PMC 2761618. PMID 17086101. Check date values in: |date= (help)
  3. ↑ Bar, Eli E.; et al. (2008-09). "Frequent gains at chromosome 7q34 involving BRAF in pilocytic astrocytoma". Journal of Neuropathology and Experimental Neurology. 67 (9): 878–887. doi:10.1097/NEN.0b013e3181845622. ISSN 0022-3069. PMID 18716556. Check date values in: |date= (help)
  4. ↑ 4.0 4.1 4.2 4.3 4.4 4.5 4.6 4.7 Appin, Christina L.; et al. (2015-01). "Molecular pathways in gliomagenesis and their relevance to neuropathologic diagnosis". Advances in Anatomic Pathology. 22 (1): 50–58. doi:10.1097/PAP.0000000000000048. ISSN 1533-4031. PMID 25461780. Check date values in: |date= (help)
  5. ↑ 5.0 5.1 5.2 5.3 Venneti, Sriram; et al. (2015-03). "The evolving molecular genetics of low-grade glioma". Advances in Anatomic Pathology. 22 (2): 94–101. doi:10.1097/PAP.0000000000000049. ISSN 1533-4031. PMC 4667550. PMID 25664944. Check date values in: |date= (help)
  6. ↑ 6.0 6.1 Fontebasso, Adam M.; et al. (2015-10-13). "Non-random aneuploidy specifies subgroups of pilocytic astrocytoma and correlates with older age". Oncotarget. 6 (31): 31844–31856. doi:10.18632/oncotarget.5571. ISSN 1949-2553. PMC 4741644. PMID 26378811.
  7. ↑ Rodriguez, Fausto J.; et al. (2012-9). "BRAF Duplications and MAPK Pathway Activation Are Frequent in Gliomas of the Optic Nerve Proper". Journal of neuropathology and experimental neurology. 71 (9): 789–794. doi:10.1097/NEN.0b013e3182656ef8. ISSN 0022-3069. PMC 3429698. PMID 22892521. Check date values in: |date= (help)
  8. ↑ Jones, David T. W.; et al. (2013-08). "Recurrent somatic alterations of FGFR1 and NTRK2 in pilocytic astrocytoma". Nature Genetics. 45 (8): 927–932. doi:10.1038/ng.2682. ISSN 1546-1718. PMC 3951336. PMID 23817572. Check date values in: |date= (help)
  9. ↑ 9.0 9.1 9.2 9.3 9.4 Zhang, Jinghui; et al. (2013-06). "Whole-genome sequencing identifies genetic alterations in pediatric low-grade gliomas". Nature Genetics. 45 (6): 602–612. doi:10.1038/ng.2611. ISSN 1546-1718. PMC 3727232. PMID 23583981. Check date values in: |date= (help)
  10. ↑ Jones, David T. W.; et al. (2008-11-01). "Tandem duplication producing a novel oncogenic BRAF fusion gene defines the majority of pilocytic astrocytomas". Cancer Research. 68 (21): 8673–8677. doi:10.1158/0008-5472.CAN-08-2097. ISSN 1538-7445. PMC 2577184. PMID 18974108.
  11. ↑ Colin, C.; et al. (2013-10). "Outcome analysis of childhood pilocytic astrocytomas: a retrospective study of 148 cases at a single institution". Neuropathology and Applied Neurobiology. 39 (6): 693–705. doi:10.1111/nan.12013. ISSN 1365-2990. PMID 23278243. Check date values in: |date= (help)
  12. ↑ 12.0 12.1 Schindler, Genevieve; et al. (2011-03). "Analysis of BRAF V600E mutation in 1,320 nervous system tumors reveals high mutation frequencies in pleomorphic xanthoastrocytoma, ganglioglioma and extra-cerebellar pilocytic astrocytoma". Acta Neuropathologica. 121 (3): 397–405. doi:10.1007/s00401-011-0802-6. ISSN 1432-0533. PMID 21274720. Check date values in: |date= (help)
  13. ↑ 13.0 13.1 Bandopadhayay, Pratiti; et al. (2016-03). "MYB-QKI rearrangements in angiocentric glioma drive tumorigenicity through a tripartite mechanism". Nature Genetics. 48 (3): 273–282. doi:10.1038/ng.3500. ISSN 1546-1718. PMC 4767685. PMID 26829751. Check date values in: |date= (help)
  14. ↑ 14.0 14.1 Ramkissoon, Lori A.; et al. (2013-05-14). "Genomic analysis of diffuse pediatric low-grade gliomas identifies recurrent oncogenic truncating rearrangements in the transcription factor MYBL1". Proceedings of the National Academy of Sciences of the United States of America. 110 (20): 8188–8193. doi:10.1073/pnas.1300252110. ISSN 1091-6490. PMC 3657784. PMID 23633565.
  15. ↑ Ampie, Leonel; et al. (2016-06). "Clinical attributes and surgical outcomes of angiocentric gliomas". Journal of Clinical Neuroscience: Official Journal of the Neurosurgical Society of Australasia. 28: 117–122. doi:10.1016/j.jocn.2015.11.015. ISSN 1532-2653. PMID 26778052. Check date values in: |date= (help)
  16. ↑ Yin, Xiao Lu; et al. (2002-04-01). "Genome-wide survey for chromosomal imbalances in ganglioglioma using comparative genomic hybridization". Cancer Genetics and Cytogenetics. 134 (1): 71–76. doi:10.1016/s0165-4608(01)00611-2. ISSN 0165-4608. PMID 11996800.
  17. ↑ Dahiya, Sonika; et al. (2013-06). "BRAF(V600E) mutation is a negative prognosticator in pediatric ganglioglioma". Acta Neuropathologica. 125 (6): 901–910. doi:10.1007/s00401-013-1120-y. ISSN 1432-0533. PMID 23609006. Check date values in: |date= (help)
  18. ↑ 18.0 18.1 Pekmezci, Melike; et al. (2018-06-07). "The genetic landscape of ganglioglioma". Acta Neuropathologica Communications. 6 (1): 47. doi:10.1186/s40478-018-0551-z. ISSN 2051-5960. PMC 5992851. PMID 29880043.
  19. ↑ 19.0 19.1 19.2 19.3 19.4 Cancer Genome Atlas Research Network; et al. (2015-06-25). "Comprehensive, Integrative Genomic Analysis of Diffuse Lower-Grade Gliomas". The New England Journal of Medicine. 372 (26): 2481–2498. doi:10.1056/NEJMoa1402121. ISSN 1533-4406. PMC 4530011. PMID 26061751.
  20. ↑ 20.0 20.1 20.2 20.3 Ceccarelli, Michele; et al. (2016-01-28). "Molecular Profiling Reveals Biologically Discrete Subsets and Pathways of Progression in Diffuse Glioma". Cell. 164 (3): 550–563. doi:10.1016/j.cell.2015.12.028. ISSN 1097-4172. PMC 4754110. PMID 26824661.
  21. ↑ 21.0 21.1 Appin, Christina L.; et al. (2015-11). "Biomarker-driven diagnosis of diffuse gliomas". Molecular Aspects of Medicine. 45: 87–96. doi:10.1016/j.mam.2015.05.002. ISSN 1872-9452. PMID 26004297. Check date values in: |date= (help)
  22. ↑ Weber, R. G.; et al. (2007-02-15). "Frequent loss of chromosome 9, homozygous CDKN2A/p14(ARF)/CDKN2B deletion and low TSC1 mRNA expression in pleomorphic xanthoastrocytomas". Oncogene. 26 (7): 1088–1097. doi:10.1038/sj.onc.1209851. ISSN 0950-9232. PMID 16909113.
  23. ↑ Kaulich, Kerstin; et al. (2002-12). "Genetic alterations commonly found in diffusely infiltrating cerebral gliomas are rare or absent in pleomorphic xanthoastrocytomas". Journal of Neuropathology and Experimental Neurology. 61 (12): 1092–1099. doi:10.1093/jnen/61.12.1092. ISSN 0022-3069. PMID 12484572. Check date values in: |date= (help)
  24. ↑ 24.0 24.1 Rickert, Christian H.; et al. (2001-4). "Pediatric High-Grade Astrocytomas Show Chromosomal Imbalances Distinct from Adult Cases". The American Journal of Pathology. 158 (4): 1525–1532. doi:10.1016/S0002-9440(10)64103-X. ISSN 0002-9440. PMC 1891902. PMID 11290570. Check date values in: |date= (help)
  25. ↑ Killela, Patrick J.; et al. (2014-03-30). "The genetic landscape of anaplastic astrocytoma". Oncotarget. 5 (6): 1452–1457. doi:10.18632/oncotarget.1505. ISSN 1949-2553. PMC 4039223. PMID 24140581.
  26. ↑ 26.0 26.1 Koschmann, Carl; et al. (2016-08-25). "Characterizing and targeting PDGFRA alterations in pediatric high-grade glioma". Oncotarget. 7 (40): 65696–65706. doi:10.18632/oncotarget.11602. ISSN 1949-2553. PMC 5323185. PMID 27582545.
  27. ↑ Grimm, Sean A.; et al. (2016-07). "Anaplastic astrocytoma". CNS oncology. 5 (3): 145–157. doi:10.2217/cns-2016-0002. ISSN 2045-0915. PMC 6042632. PMID 27230974. Check date values in: |date= (help)
  28. ↑ Hattori, Natsuki; et al. (2016-08). "World Health Organization grade II-III astrocytomas consist of genetically distinct tumor lineages". Cancer Science. 107 (8): 1159–1164. doi:10.1111/cas.12969. ISSN 1349-7006. PMC 4982592. PMID 27196377. Check date values in: |date= (help)
  29. ↑ Reuss, David E.; et al. (2015-06). "IDH mutant diffuse and anaplastic astrocytomas have similar age at presentation and little difference in survival: a grading problem for WHO". Acta Neuropathologica. 129 (6): 867–873. doi:10.1007/s00401-015-1438-8. ISSN 1432-0533. PMC 4500039. PMID 25962792. Check date values in: |date= (help)
  30. ↑ 30.0 30.1 30.2 30.3 Shirahata, Mitsuaki; et al. (2018-07). "Novel, improved grading system(s) for IDH-mutant astrocytic gliomas". Acta Neuropathologica. 136 (1): 153–166. doi:10.1007/s00401-018-1849-4. ISSN 1432-0533. PMID 29687258. Check date values in: |date= (help)
  31. ↑ Ida, Cristiane M.; et al. (2015-09). "Pleomorphic Xanthoastrocytoma: Natural History and Long-Term Follow-Up". Brain Pathology (Zurich, Switzerland). 25 (5): 575–586. doi:10.1111/bpa.12217. ISSN 1750-3639. PMC 4400218. PMID 25318587. Check date values in: |date= (help)
  32. ↑ Schmidt, Yao; et al. (2013-01). "Anaplastic PXA in adults: case series with clinicopathologic and molecular features". Journal of Neuro-Oncology. 111 (1): 59–69. doi:10.1007/s11060-012-0991-4. ISSN 1573-7373. PMC 4617340. PMID 23096133. Check date values in: |date= (help)
  33. ↑ Korshunov, Andrey; et al. (2015-05). "Integrated analysis of pediatric glioblastoma reveals a subset of biologically favorable tumors with associated molecular prognostic markers". Acta Neuropathologica. 129 (5): 669–678. doi:10.1007/s00401-015-1405-4. ISSN 1432-0533. PMID 25752754. Check date values in: |date= (help)
  34. ↑ 34.0 34.1 34.2 Karsy, Michael; et al. (2015-03). "A practical review of prognostic correlations of molecular biomarkers in glioblastoma". Neurosurgical Focus. 38 (3): E4. doi:10.3171/2015.1.FOCUS14755. ISSN 1092-0684. PMID 25727226. Check date values in: |date= (help)
  35. ↑ Furgason, John M.; et al. (2015). "Whole genome sequence analysis links chromothripsis to EGFR, MDM2, MDM4, and CDK4 amplification in glioblastoma". Oncoscience. 2 (7): 618–628. doi:10.18632/oncoscience.178. ISSN 2331-4737. PMC 4549359. PMID 26328271.
  36. ↑ Singh, Devendra; et al. (2012-09-07). "Transforming fusions of FGFR and TACC genes in human glioblastoma". Science (New York, N.Y.). 337 (6099): 1231–1235. doi:10.1126/science.1220834. ISSN 1095-9203. PMC 3677224. PMID 22837387.
  37. ↑ 37.0 37.1 37.2 Ramkissoon, Shakti H.; et al. (2015-10). "Clinical implementation of integrated whole-genome copy number and mutation profiling for glioblastoma". Neuro-Oncology. 17 (10): 1344–1355. doi:10.1093/neuonc/nov015. ISSN 1523-5866. PMC 4578577. PMID 25754088. Check date values in: |date= (help)
  38. ↑ Fontebasso, Adam M.; et al. (2013-05). "Mutations in SETD2 and genes affecting histone H3K36 methylation target hemispheric high-grade gliomas". Acta Neuropathologica. 125 (5): 659–669. doi:10.1007/s00401-013-1095-8. ISSN 1432-0533. PMC 3631313. PMID 23417712. Check date values in: |date= (help)
  39. ↑ Paugh, Barbara S.; et al. (2010-06-20). "Integrated molecular genetic profiling of pediatric high-grade gliomas reveals key differences with the adult disease". Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology. 28 (18): 3061–3068. doi:10.1200/JCO.2009.26.7252. ISSN 1527-7755. PMC 2903336. PMID 20479398.
  40. ↑ Giunti, Laura; et al. (2014). "Genome-wide copy number analysis in pediatric glioblastoma multiforme". American Journal of Cancer Research. 4 (3): 293–303. ISSN 2156-6976. PMC 4065410. PMID 24959384.
  41. ↑ Warren, Katherine E.; et al. (2012-3). "Genomic aberrations in pediatric diffuse intrinsic pontine gliomas". Neuro-Oncology. 14 (3): 326–332. doi:10.1093/neuonc/nor190. ISSN 1522-8517. PMC 3280796. PMID 22064882. Check date values in: |date= (help)
  42. ↑ Buczkowicz, Pawel; et al. (2014-05). "Genomic analysis of diffuse intrinsic pontine gliomas identifies three molecular subgroups and recurrent activating ACVR1 mutations". Nature Genetics. 46 (5): 451–456. doi:10.1038/ng.2936. ISSN 1546-1718. PMC 3997489. PMID 24705254. Check date values in: |date= (help)
  43. ↑ Taylor, Kathryn R.; et al. (2014-05). "Recurrent activating ACVR1 mutations in diffuse intrinsic pontine glioma". Nature Genetics. 46 (5): 457–461. doi:10.1038/ng.2925. ISSN 1546-1718. PMC 4018681. PMID 24705252. Check date values in: |date= (help)
  44. ↑ Nikbakht, Hamid; et al. (2016-04-06). "Spatial and temporal homogeneity of driver mutations in diffuse intrinsic pontine glioma". Nature Communications. 7: 11185. doi:10.1038/ncomms11185. ISSN 2041-1723. PMC 4823825. PMID 27048880.
  45. ↑ Buczkowicz, Pawel; et al. (2015). "Pathology, Molecular Genetics, and Epigenetics of Diffuse Intrinsic Pontine Glioma". Frontiers in Oncology. 5: 147. doi:10.3389/fonc.2015.00147. ISSN 2234-943X. PMC 4485076. PMID 26175967.
  46. ↑ Wu, Gang; et al. (2014-05). "The genomic landscape of diffuse intrinsic pontine glioma and pediatric non-brainstem high-grade glioma". Nature Genetics. 46 (5): 444–450. doi:10.1038/ng.2938. ISSN 1546-1718. PMC 4056452. PMID 24705251. Check date values in: |date= (help)
  47. ↑ Mackay, Alan; et al. (2017-10-09). "Integrated Molecular Meta-Analysis of 1,000 Pediatric High-Grade and Diffuse Intrinsic Pontine Glioma". Cancer Cell. 32 (4): 520–537.e5. doi:10.1016/j.ccell.2017.08.017. ISSN 1878-3686. PMC 5637314. PMID 28966033.
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