Difference between revisions of "Recurrent Genomic Alterations in Pediatric and Adult Central Nervous System Tumors Detected by Chromosomal Microarray"
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'''Loss:''' NF1 in optic pathway PA | '''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 | |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 | ||
| − | |<ref>{{Cite journal|last=Sievert|first=Angela J.|last2=Jackson|first2=Eric M.|last3=Gai|first3=Xiaowu|last4=Hakonarson|first4=Hakon|last5=Judkins|first5=Alexander R.|last6=Resnick|first6=Adam C.|last7=Sutton|first7=Leslie N.|last8=Storm|first8=Phillip B.|last9=Shaikh|first9=Tamim H.|date=2009-07|title=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|url=https://pubmed.ncbi.nlm.nih.gov/19016743|journal=Brain Pathology (Zurich, Switzerland)|volume=19|issue=3|pages=449–458|doi=10.1111/j.1750-3639.2008.00225.x|issn=1750-3639|pmc=2850204|pmid=19016743}}</ref>PMID:19016743; <ref>{{Cite journal|last=Jones|first=David T. W.|last2=Ichimura|first2=Koichi|last3=Liu|first3=Lu|last4=Pearson|first4=Danita M.|last5=Plant|first5=Karen|last6=Collins|first6=V. Peter|date=2006-11|title=Genomic Analysis of Pilocytic Astrocytomas at 0.97 Mb Resolution Shows an Increasing Tendency Toward Chromosomal Copy Number Change With Age|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2761618/|journal=Journal of neuropathology and experimental neurology|volume=65|issue=11|pages=1049–1058|doi=10.1097/01.jnen.0000240465.33628.87|issn=0022-3069|pmc=2761618|pmid=17086101}}</ref>PMCID:2761618; <ref>{{Cite journal|last=Bar|first=Eli E.|last2=Lin|first2=Alex|last3=Tihan|first3=Tarik|last4=Burger|first4=Peter C.|last5=Eberhart|first5=Charles G.|date=2008-09|title=Frequent gains at chromosome 7q34 involving BRAF in pilocytic astrocytoma|url=https://pubmed.ncbi.nlm.nih.gov/18716556|journal=Journal of Neuropathology and Experimental Neurology|volume=67|issue=9|pages=878–887|doi=10.1097/NEN.0b013e3181845622|issn=0022-3069|pmid=18716556}}</ref>PMID:18716556 <ref name=":0">{{Cite journal|last=Appin|first=Christina L.|last2=Brat|first2=Daniel J.|date=2015-01|title=Molecular pathways in gliomagenesis and their relevance to neuropathologic diagnosis|url=https://pubmed.ncbi.nlm.nih.gov/25461780|journal=Advances in Anatomic Pathology|volume=22|issue=1|pages=50–58|doi=10.1097/PAP.0000000000000048|issn=1533-4031|pmid=25461780}}</ref>PMID:25461780 PMID:25664944; PMID:26378811 PMCID:3429698; PMID:23817572; PMID:23583981 PMID:18974108; PMID:23278243; PMID:21274720 | + | |<ref>{{Cite journal|last=Sievert|first=Angela J.|last2=Jackson|first2=Eric M.|last3=Gai|first3=Xiaowu|last4=Hakonarson|first4=Hakon|last5=Judkins|first5=Alexander R.|last6=Resnick|first6=Adam C.|last7=Sutton|first7=Leslie N.|last8=Storm|first8=Phillip B.|last9=Shaikh|first9=Tamim H.|date=2009-07|title=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|url=https://pubmed.ncbi.nlm.nih.gov/19016743|journal=Brain Pathology (Zurich, Switzerland)|volume=19|issue=3|pages=449–458|doi=10.1111/j.1750-3639.2008.00225.x|issn=1750-3639|pmc=2850204|pmid=19016743}}</ref>PMID:19016743; <ref>{{Cite journal|last=Jones|first=David T. 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Peter|date=2006-11|title=Genomic Analysis of Pilocytic Astrocytomas at 0.97 Mb Resolution Shows an Increasing Tendency Toward Chromosomal Copy Number Change With Age|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2761618/|journal=Journal of neuropathology and experimental neurology|volume=65|issue=11|pages=1049–1058|doi=10.1097/01.jnen.0000240465.33628.87|issn=0022-3069|pmc=2761618|pmid=17086101}}</ref>PMCID:2761618; <ref>{{Cite journal|last=Bar|first=Eli E.|last2=Lin|first2=Alex|last3=Tihan|first3=Tarik|last4=Burger|first4=Peter C.|last5=Eberhart|first5=Charles G.|date=2008-09|title=Frequent gains at chromosome 7q34 involving BRAF in pilocytic astrocytoma|url=https://pubmed.ncbi.nlm.nih.gov/18716556|journal=Journal of Neuropathology and Experimental Neurology|volume=67|issue=9|pages=878–887|doi=10.1097/NEN.0b013e3181845622|issn=0022-3069|pmid=18716556}}</ref>PMID:18716556 <ref name=":0">{{Cite journal|last=Appin|first=Christina L.|last2=Brat|first2=Daniel J.|date=2015-01|title=Molecular pathways in gliomagenesis and their relevance to neuropathologic diagnosis|url=https://pubmed.ncbi.nlm.nih.gov/25461780|journal=Advances in Anatomic Pathology|volume=22|issue=1|pages=50–58|doi=10.1097/PAP.0000000000000048|issn=1533-4031|pmid=25461780}}</ref>PMID:25461780 <ref name=":1">{{Cite journal|last=Venneti|first=Sriram|last2=Huse|first2=Jason T.|date=2015-03|title=The evolving molecular genetics of low-grade glioma|url=https://pubmed.ncbi.nlm.nih.gov/25664944|journal=Advances in Anatomic Pathology|volume=22|issue=2|pages=94–101|doi=10.1097/PAP.0000000000000049|issn=1533-4031|pmc=4667550|pmid=25664944}}</ref>PMID:25664944; <ref name=":2">{{Cite journal|last=Fontebasso|first=Adam M.|last2=Shirinian|first2=Margret|last3=Khuong-Quang|first3=Dong-Anh|last4=Bechet|first4=Denise|last5=Gayden|first5=Tenzin|last6=Kool|first6=Marcel|last7=De Jay|first7=Nicolas|last8=Jacob|first8=Karine|last9=Gerges|first9=Noha|date=2015-10-13|title=Non-random aneuploidy specifies subgroups of pilocytic astrocytoma and correlates with older age|url=https://pubmed.ncbi.nlm.nih.gov/26378811|journal=Oncotarget|volume=6|issue=31|pages=31844–31856|doi=10.18632/oncotarget.5571|issn=1949-2553|pmc=4741644|pmid=26378811}}</ref>PMID:26378811 <ref>{{Cite journal|last=Rodriguez|first=Fausto J.|last2=Ligon|first2=Azra H.|last3=Horkayne-Szakaly|first3=Iren|last4=Rushing|first4=Elisabeth J.|last5=Ligon|first5=Keith L.|last6=Vena|first6=Natalie|last7=Garcia|first7=Denise I.|last8=Cameron|first8=J. 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'''Amplification:''' MYB (atypical histology) | '''Amplification:''' MYB (atypical histology) | ||
|Generally indolent tumors; surgical resection can be curative | |Generally indolent tumors; surgical resection can be curative | ||
| − | |PMID:26829751; PMID:23633565; PMID:26778052 PMID:23583981 | + | |<ref name=":5">{{Cite journal|last=Bandopadhayay|first=Pratiti|last2=Ramkissoon|first2=Lori A.|last3=Jain|first3=Payal|last4=Bergthold|first4=Guillaume|last5=Wala|first5=Jeremiah|last6=Zeid|first6=Rhamy|last7=Schumacher|first7=Steven E.|last8=Urbanski|first8=Laura|last9=O'Rourke|first9=Ryan|date=2016-03|title=MYB-QKI rearrangements in angiocentric glioma drive tumorigenicity through a tripartite mechanism|url=https://pubmed.ncbi.nlm.nih.gov/26829751|journal=Nature Genetics|volume=48|issue=3|pages=273–282|doi=10.1038/ng.3500|issn=1546-1718|pmc=4767685|pmid=26829751}}</ref>PMID:26829751; <ref name=":6">{{Cite journal|last=Ramkissoon|first=Lori A.|last2=Horowitz|first2=Peleg M.|last3=Craig|first3=Justin M.|last4=Ramkissoon|first4=Shakti H.|last5=Rich|first5=Benjamin E.|last6=Schumacher|first6=Steven E.|last7=McKenna|first7=Aaron|last8=Lawrence|first8=Michael S.|last9=Bergthold|first9=Guillaume|date=2013-05-14|title=Genomic analysis of diffuse pediatric low-grade gliomas identifies recurrent oncogenic truncating rearrangements in the transcription factor MYBL1|url=https://pubmed.ncbi.nlm.nih.gov/23633565|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=110|issue=20|pages=8188–8193|doi=10.1073/pnas.1300252110|issn=1091-6490|pmc=3657784|pmid=23633565}}</ref>PMID:23633565; <ref>{{Cite journal|last=Ampie|first=Leonel|last2=Choy|first2=Winward|last3=DiDomenico|first3=Joseph D.|last4=Lamano|first4=Jonathan B.|last5=Williams|first5=Christopher Kazu|last6=Kesavabhotla|first6=Kartik|last7=Mao|first7=Qinwen|last8=Bloch|first8=Orin|date=2016-06|title=Clinical attributes and surgical outcomes of angiocentric gliomas|url=https://pubmed.ncbi.nlm.nih.gov/26778052|journal=Journal of Clinical Neuroscience: Official Journal of the Neurosurgical Society of Australasia|volume=28|pages=117–122|doi=10.1016/j.jocn.2015.11.015|issn=1532-2653|pmid=26778052}}</ref>PMID:26778052 <ref name=":3" />PMID:23583981 |
|- | |- | ||
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'''Fusions:''' KIAA1549-BRAF | '''Fusions:''' KIAA1549-BRAF | ||
|Generally indolent tumors for which surgical resection can be curative | |Generally indolent tumors for which surgical resection can be curative | ||
| − | |<ref name=":0" />PMID:25461780; PMID:23583981; PMID:11996800 PMID:23609006; PMID:29880043 | + | |<ref name=":0" />PMID:25461780; <ref name=":3" />PMID:23583981; PMID:11996800 PMID:23609006; PMID:29880043 |
|- | |- | ||
|Low grade glioma, WHO grade II | |Low grade glioma, WHO grade II | ||
| Line 51: | Line 51: | ||
'''Mutation:''' FGFR1 | '''Mutation:''' FGFR1 | ||
|Anaplastic features associated with decreased progression free survival | |Anaplastic features associated with decreased progression free survival | ||
| − | |PMID:25664944; PMID:23633565; PMID:26061751 PMID:26824661; PMID:26004297; <ref name=":0" />PMID:25461780 PMID:23583981 | + | |<ref name=":1" />PMID:25664944; <ref name=":6" />PMID:23633565; PMID:26061751 PMID:26824661; PMID:26004297; <ref name=":0" />PMID:25461780 <ref name=":3" />PMID:23583981 |
|- | |- | ||
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'''Loss:''' CDKN2A/CDKN2B | '''Loss:''' CDKN2A/CDKN2B | ||
| | | | ||
| − | |<ref name=":0" />PMID:25461780; PMID:23583981; PMID:16909113; PMID:12484572 | + | |<ref name=":0" />PMID:25461780; <ref name=":3" />PMID:23583981; PMID:16909113; PMID:12484572 |
|- | |- | ||
|Anaplastic astrocytoma, WHO grade III | |Anaplastic astrocytoma, WHO grade III | ||
| Line 77: | Line 77: | ||
|CDKN2A/CDKN2B loss may correlate with anaplastic histology | |CDKN2A/CDKN2B loss may correlate with anaplastic histology | ||
|WHO CNS Tumors (2016)<br> | |WHO CNS Tumors (2016)<br> | ||
| − | PMID:25318587; PMID:23096133; PMID:21274720 | + | PMID:25318587; PMID:23096133; <ref name=":4" />PMID:21274720 |
|- | |- | ||
|Glioblastoma, WHO grade IV | |Glioblastoma, WHO grade IV | ||
| Line 289: | Line 289: | ||
'''Mutation:''' FGFR1 | '''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 | |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 | + | |PMID: 24470550; <ref name=":2" />PMID:26378811; <ref name=":1" />PMID: 25664944; PMID:26992069 |
|- | |- | ||
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| Line 316: | Line 316: | ||
'''Amplification:''' MYB (atypical histology) | '''Amplification:''' MYB (atypical histology) | ||
|Generally indolent tumors; surgical resection can be curative | |Generally indolent tumors; surgical resection can be curative | ||
| − | |PMID:26829751 | + | |<ref name=":5" />PMID:26829751 |
|- | |- | ||
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| Line 364: | Line 364: | ||
'''Mutation:''' FUBP1, CIC, IDH, TERT, NOTCH1, PIK3CA or PIK3R1 | '''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 | |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; PMID:25664944;PMID:26061753; PMID:26941959; PMID:26824661 PMID:26061751 | + | |PMID:27090007; PMID:26061753; PMID:25263767 PMID:26061754; PMID:24335697; <ref name=":1" />PMID:25664944;PMID:26061753; PMID:26941959; PMID:26824661 PMID:26061751 |
|- | |- | ||
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| Line 478: | Line 478: | ||
|PMID: 25965575; PMID:27022130 | |PMID: 25965575; PMID:27022130 | ||
|} | |} | ||
| + | <references /> | ||
Revision as of 12:51, 15 April 2021
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 |
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) |
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; 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 | [5]PMID:25664944; [14]PMID:23633565; PMID:26061751 PMID:26824661; 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; 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; [4]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; [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 |
Loss: PTEN, RB1, TP53, CDKN2A/B/C
Fusions: FGFR-TACC; NTRK fusions |
Overall poor prognosis | PMID:25752754; PMID:25727226; PMID:26328271; PMID:22837387; PMID:25754088; [4]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 |
Three molecular subgroups: MYCN subgroup: no mutations but chromothripsis leading to amp of MYCN and ID2 |
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) |
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 |
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 |
Mutation: TP53 wild-type tumors: PTCH1 (germline mutations in Gorlin syndrome), SMO, SUFU (can be germline), TERT promoter |
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 |
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 |
Mutation: TP53, KDM6A, KMT2C Amplification: MYCN, CDK4, CDK6, OTX2 |
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) |
Most cases occur before 3 yrs of age TYR subclass: mostly infratentorial |
||
| 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 NB-FOXR2 group: JMJD1C fusions, FOXR2 fusion or deletion CNS EFT-CIC group: NUTM1 rearrangement/fusion, CIC rearrangement |
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 |
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 |
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; PMID:29880043 | |
| Angiocentric glioma | Loss: 6q24-q25 | Fusion: MYB-QKI rearrangement/deletion (classic histology) Rearrangement: MYB alone (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 |
Fusion: KIAA1549-BRAF fusion (via 3'BRAF duplication) Mutation: PIK3CA, FGFR1 |
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. | PMID:26824661; PMID:26061753; PMID:25263767 PMID:26061754; PMID:28535583; PMID:26091668 PMID: 25701198; PMID:26865861; PMID:29687258 |
| Diffuse astrocytoma/anaplastic astrocytoma, WHO grade II/III, IDH wild-type | Gain: 7, 19 Loss: 4, 9p 10 |
Loss: homozygous CDKN2A/B Mutation: EGFR, NF1, PTEN |
Poor prognosis with similar abnormalities to glioblastoma | PMID:26061754; 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 |
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; PMID:26824661 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) |
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; PMID:25754088; PMID:28535583 PMID:25931051; PMID:26091668; [4]PMID:25461780; PMID:27157931; PMID:25727226; PMID:26323991 PMID:26061751; 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) |
Loss: homozygous CDKN2A/B, PTEN, RB1 Mutation: TERT, EGFR, PTEN, NF1, RB1, PIK3CA or PIK3R1, TP53 |
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; PMID:25754088; PMID:28535583 PMID:25931051; PMID:26091668; [4]PMID:25461780; PMID:27157931; PMID:25727226; PMID:26061751 | |
| MENINGIOMA | |||||
| Grade 1 | No copy number changes in 44% Gain: multiple polysomies, 5 |
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 |
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) |
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 |
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 |
- ↑ 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) - ↑ 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) - ↑ 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) - ↑ 4.0 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) - ↑ 5.0 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) - ↑ 6.0 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.
- ↑ 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) - ↑ 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) - ↑ 9.0 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) - ↑ 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.
- ↑ 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) - ↑ 12.0 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) - ↑ 13.0 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) - ↑ 14.0 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.
- ↑ 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)