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 PMID:19016743; PMCID:2761618; PMID:18716556 PMID:25461780 PMID:25664944; PMID:26378811 PMCID:3429698; PMID:23817572; PMID:23583981 PMID:18974108; PMID:23278243; 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 PMID:26829751; PMID:23633565; PMID:26778052 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 PMID:25461780; PMID:23583981; PMID:11996800 PMID:23609006; 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 PMID:25664944; PMID:23633565; PMID:26061751 PMID:26824661; PMID:26004297; PMID:25461780 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

PMID:25461780; PMID:23583981; PMID:16909113; 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 PMCID:1891902; PMID:26004297; PMID:25461780; PMID:24140581; PMCID:5323185; PMID:27230974 PMID:27196377; PMID:26061751; PMID:25962792; 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)

PMID:25318587; PMID:23096133; 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 PMID:25752754; PMID:25727226; PMID:26328271; PMID:22837387; PMID:25754088; PMID:25461780; PMCID:1891902; PMID:23417712; PMCID:5323185; PMID:29687258; PMID:20479398; 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 PMCID:3280796; PMID:24705254; PMID:24705252 PMID:27048880; PMID:26175967; PMID:24705251; 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.

ADULT TUMOR SUBTYPES BROAD ABERRATIONS (>10Mb) FOCAL ABERRATIONS (<10Mb) CLINICAL FEATURES REFERENCES
GLIOMAS
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