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
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

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