View source for 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.
{| class="wikitable"
|-
! 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) <br>
'''Mutations:''' BRAF V600E (particularly extra-cerebellar tumors); FGFR1 (midline PA); NF1 (esp. germline), other MAPK pathway mutations <br>
'''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)<br>
'''Rearrangement:''' MYB alone (atypical histology)<br>
'''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 <br>
'''Gain:''' polysomy 7
| '''Mutations:''' BRAF V600E in 20-60% of cases (can be concurrent with CDKN2A homozygous deletion)<br>
'''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<br>
'''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<br>
'''Loss:''' monosomy 9 / 9p deletion
| '''Mutations:''' BRAF V600E in ~60%; TP53 (5%)<br>
'''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<br>
'''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<br>
'''Loss:''' CDKN2A/CDKN2B
| CDKN2A/CDKN2B loss may correlate with anaplastic histology
| WHO CNS Tumors (2016)<br>
PMID:25318587; PMID:23096133; PMID:21274720
|-
|Glioblastoma, WHO grade IV
|IDH-mutant 
|'''Gain:''' 1q, 2q, 3q, 7, 16p, 17q, 21q<br>
'''Loss:''' 6q, 8q, 9p, 9q, 10q, 13q, 17p, 22q<br>
''' Chromothripsis:''' observed
|'''Loss:''' PTEN, RB1, TP53, CDKN2A/B/C 
'''Fusions:''' FGFR-TACC; NTRK fusions 
'''Amplification:''' PDGFRA, MYCN, MET, CDK4, CDK6 (EGFR, MDM2 amp rare)<br>
'''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<br>
'''Loss:''' 10q<br>
'''Chromothripsis:''' 2p
|'''Three molecular subgroups:''' <br>
'''MYCN subgroup:''' no mutations but chromothripsis leading to amp of MYCN and ID2<br>
'''Silent subgroup:''' no recurrent copy # changes, few mutations<br>
'''H3-K27M subgroup:''' MYC, PDGFRA gains/amp; RB1, TP53 deletions<br>
'''Mutation:''' ACVR1, H3F3A, HIST1H3B, TP53 '''Loss:''' CDKN2A, PTEN, RB1, TP53<br>
'''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'''<br>
(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)<br>
'''Mutation:''' NF2 (spinal tumors)<br>
'''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)<br>
PMID:25965575; PMID:21627842; PMID:24939246; PMID:22516549 
|-
|
|Classic ependymoma (no WHO grade assigned)
|'''Gain:''' 1q, 5, 7, 9, 11, 18, 20<br>
'''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'''<br>
'''Loss:''' -6/6q in spinal tumors
|No diagnostic mutations
|Favorable prognosis
|WHO CNS Tumors (2016) <br>
PMID:21959044; PMID:21840481<br>
|-
|
|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<br>
'''Aneuploidy:''' multiple chromosomes lost and gained<br>
'''Chromothripsis:''' chromosome 11 (70% of supratentorial tumors)
|'''Fusion:''' c11orf95-RELA (supratentorial tumors)<br>
'''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<br>
'''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'''
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|
|
|
|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<br>
'''Loss:''' 9q, 10q, 17p<br>
'''Ploidy changes:''' Tetraploidy associated with chromothripsis and TP53 mutations<br>
'''Chromothripsis:''' associated with TP53 mutation   
|'''Mutation:'''<br>
'''TP53 wild-type tumors:''' PTCH1 (germline mutations in Gorlin syndrome), SMO, SUFU (can be germline), TERT promoter<br>
'''TP53-mutant tumors:''' can be germline<br>
'''Loss:''' PTCH1, PTEN<br>
'''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<br>
'''Loss:''' 5q, 8, 10q, 11p, 16q<br>
'''Rearrangement:''' idic(17)(p11.2)<br>
'''Ploidy changes:''' tetraploidy in 40-50% of Group3/Group4 tumors
|'''Mutation/Amplification:''' MYC (mainly in infants), OTX2, CDK6, SMARC4A, CTDNEP1, LRP1B, KMT2D<br>
'''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<br>
'''Loss:''' X, 8, 11p<br>
'''Rearrangement:''' idic(17)(p11.2) in >80%<br>
'''Chromothripsis:''' rare, but associated with TP53 loss when observed 
|'''Mutation:''' TP53, KDM6A, KMT2C <br>
'''Amplification:''' MYCN, CDK4, CDK6, OTX2<br>
'''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<br>
AT/RT-like tumors: SMARCB1 can be retained (with SMARCA4 mutations)<br>
'''Three molecular classes:'''<br>
'''TYR:''' ~ 75% show broad 22q loss that includes SMARCB1<br>
'''SHH:''' ~ 50% lack any SMARCB1 mutation; ~ 25% have focal SMARCB1 aberrations<br>
'''MYC:''' ~ 75% show focal SMARCB1 loss
|Most cases occur before 3 yrs of age<br>
TYR subclass: mostly infratentorial<br>
SHH subclass: supra/infratentorial<br>
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)<br>
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<br>
'''CNS EFT-CIC group:''' polysomy 8<br>
'''CNS HGNET-MN1 group:''' 16q loss, polysomy 8<br>
'''CNS HGNET-BCOR group:''' mostly balanced genomes
|'''CNS NB-FOXR2 group:''' JMJD1C fusions, FOXR2 fusion or deletion<br>
'''CNS EFT-CIC group:''' NUTM1 rearrangement/fusion, CIC rearrangement<br>
'''CNS HGNET-MN1 group:''' MN1 rearrangement <br>
'''CNS HGNET-BCOR group:''' BCOR intragenic tandem duplication
|Most common in children, but may also occur in adolescents and adults
|WHO CNS Tumors (2016)<br>
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'''<br>
'''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)<br>
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<br>
'''Gain:''' 1, 7, 12, 20 in > 80% of hyperdiploid CPCs<br>
'''Loss:''' 3 (in all hypodiploid CPC), 6, 11, 12q, 16, 22
|'''Mutation:''' TP53 in > 50%<br>
'''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.
{| class="wikitable"
|-
! ADULT 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<br>
'''Loss:''' 1, 2, 3, 13, 14, 16, 17, 19
|'''Fusion:''' KIAA1549-BRAF fusion (via 3'BRAF duplication), other BRAF partners reported; NTRK fusions (rare)<br>
'''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; PMID:26378811; PMID: 25664944; PMID:26992069
|-
|
|Pleomorphic xanthoastrocytoma (PXA)
|'''Gain:''' 7, 2, 5, 21, 20, 12, 15<br>
'''Loss:''' monosomy 9 / 9p deletion most common, 22, 14, 13, 10<br>
'''CN-LOH:''' 9p, 22
|'''Loss:''' homozygous loss CDKN2A/B<br>
Mutation: BRAF V600E
|Adults and pediatric tumors show similar CNVs; CDKN2A/CDKN2B loss may correlate with anaplastic histology 
|PMID:23442159; PMID:28181325