Difference between revisions of "Recurrent Genomic Alterations in Pediatric and Adult Central Nervous System Tumors Detected by Chromosomal Microarray"
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|Diffuse astrocytoma/anaplastic Astrocytoma, WHO grade II/III, IDH mutant | |Diffuse astrocytoma/anaplastic Astrocytoma, WHO grade II/III, IDH mutant | ||
|'''Gain:''' 4q, 7q, 8q24, 12q<br> | |'''Gain:''' 4q, 7q, 8q24, 12q<br> | ||
Revision as of 09:08, 17 November 2018
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 | 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) |
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 |
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; 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; PMID:26378811; 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 | 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; PMID:25664944;PMID:26061753; PMID:26941959; PMID:26824661 PMID:26061751 |