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

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