jueves, 31 de octubre de 2019

Childhood Cancer Genomics (PDQ®) 4/8 –Health Professional Version - National Cancer Institute

Childhood Cancer Genomics (PDQ®)–Health Professional Version - National Cancer Institute

National Cancer Institute

Childhood Cancer Genomics (PDQ®)–Health Professional Version


Central Nervous System Tumors

Central nervous system (CNS) tumors include pilocytic astrocytomas and other astrocytic tumors, diffuse astrocytic tumors, brain stem gliomas, CNS atypical teratoid/rhabdoid tumors, medulloblastomas, nonmedulloblastoma embryonal tumors, and ependymomas.
The terminology of the 2016 World Health Organization (WHO) Classification of Tumors of the Central Nervous System is used below. The 2016 WHO CNS classification incorporates genomic features in addition to histology, and it includes multiple changes from the previous 2007 WHO classification.[1] Of particular relevance for childhood brain cancers is the new entity diffuse midline glioma, H3 K27M-mutant, which includes diffuse intrinsic pontine glioma (DIPG) with the H3 K27M mutation and other high-grade gliomas of the midline with the H3 K27M mutation. Other examples of molecularly defined entities discussed below are RELA-fusion–positive ependymoma, WNT-activated and SHH-activated medulloblastoma, and embryonal tumor with multilayered rosettes, C19MC-altered.

Pilocytic Astrocytomas and Other Astrocytic Tumors

Genomic alterations involving activation of BRAF and the ERK/MAPK pathway are very common in sporadic cases of pilocytic astrocytoma, a type of low-grade glioma.
BRAF activation in pilocytic astrocytoma occurs most commonly through a BRAF-KIAA1549 gene fusion, producing a fusion protein that lacks the BRAF regulatory domain.[2-6] This fusion is seen in most infratentorial and midline pilocytic astrocytomas, but is present at lower frequency in supratentorial (hemispheric) tumors.[2,3,7-12] Other genomic alterations in pilocytic astrocytomas that can activate the ERK/MAPK pathway (e.g., alternative BRAF gene fusions, RAF1 rearrangements, RAS mutations, and BRAF V600E point mutations) are less commonly observed.[3,5,6,13]
Presence of the BRAF-KIAA1549 fusion predicted a better clinical outcome (progression-free survival [PFS] and overall survival [OS]) in one report that described children with incompletely resected low-grade gliomas.[11] However, other factors such as CDKN2A deletion, whole chromosome 7 gain, and tumor location may modify the impact of the BRAF mutation on outcome.[14]; [15][Level of evidence: 3iiiDiii] Progression to high-grade glioma is rare for pediatric low-grade glioma with the BRAF-KIAA1549 fusion.[16]
BRAF activation through the BRAF-KIAA1549 fusion has also been described in other pediatric low-grade gliomas (e.g., pilomyxoid astrocytoma).[10,11]
BRAF V600E point mutations are occasionally observed in pilocytic astrocytoma; the mutations are also observed in nonpilocytic pediatric low-grade gliomas, including ganglioglioma, desmoplastic infantile ganglioglioma, and approximately two-thirds of pleomorphic xanthoastrocytomas.[17-19] Studies have observed the following:
  • In a retrospective series of over 400 children with low-grade gliomas, 17% of tumors were BRAF V600E mutant. Ten-year PFS was 27% for BRAF V600E–mutant cases, compared with 60% for cases whose tumors did not harbor that mutation. Additional factors associated with this poor prognosis included subtotal resection and CDKN2A deletion.[20] Even in patients who underwent a gross-total resection, recurrence was noted in one-third of these cases, suggesting that BRAF V600E tumors have a more invasive phenotype than do other low-grade glioma variants.
  • In a similar analysis, children with diencephalic low-grade astrocytomas with a BRAF V600E mutation had a 5-year PFS of 22%, compared with a PFS of 52% in children who were BRAF wildtype.[21][Level of evidence: 3iiiDiii]
  • The frequency of the BRAF V600E mutation was significantly higher in pediatric low-grade glioma that transformed to high-grade glioma (8 of 18 cases) than was the frequency of the mutation in cases that did not transform to high-grade glioma (10 of 167 cases).[16]
Angiocentric gliomas have been noted to largely harbor MYB-QKI fusions, a putative driver mutation for this relatively rare class of gliomas.[22]
As with neurofibromatosis type 1 (NF1) deficiency in activating the ERK/MAPK pathway, activating BRAF genomic alterations are uncommon in pilocytic astrocytoma associated with NF1.[9]
Activating mutations in FGFR1, PTPN11, and in NTRK2 fusion genes have also been identified in noncerebellar pilocytic astrocytomas.[23] In pediatric grade II diffuse astrocytomas, the most common alterations reported (up to 53% of tumors) are rearrangements in the MYB family of transcription factors.[24,25]
Most children with tuberous sclerosis have a mutation in one of two tuberous sclerosis genes (TSC1/hamartin or TSC2/tuberin). Either of these mutations results in activation of the mammalian target of rapamycin (mTOR) complex 1. These children are at risk of developing subependymal giant cell astrocytomas, cortical tubers, and subependymal nodules. Because subependymal giant cell astrocytomas are driven by mTOR activation, mTOR inhibitors are active agents that can induce tumor regression in children with these tumors.[26]
(Refer to the PDQ summary on Childhood Astrocytomas Treatment for information about the treatment of low-grade childhood astrocytomas.)

Diffuse Astrocytic Tumors

This category includes, among other diagnoses, diffuse astrocytomas (grade II) and pediatric high-grade gliomas (anaplastic astrocytoma [grade III], glioblastoma [grade IV], and diffuse midline glioma, H3 K27M-mutant (grade IV]).

Diffuse astrocytomas

For pediatric diffuse astrocytomas (grade II), rearrangements in the MYB family of transcription factors (MYB and MYBL1) are the most commonly reported genomic alteration.[24,25,27] Other alterations observed include FGFR1 alterations (primarily duplications involving the tyrosine kinase domain),[25,27] BRAF alterations, NF1 mutations, and RAS family mutations.[24,25] IDH1 mutations, which are the most common genomic alteration in adult diffuse astrocytomas, are uncommon in children with diffuse astrocytomas and, when present, are observed almost exclusively in older adolescents.[24,28]

Anaplastic astrocytomas and glioblastomas

Pediatric high-grade gliomas, especially glioblastoma multiforme, are biologically distinct from those arising in adults.[28-31]
Pediatric high-grade gliomas can be separated into distinct subgroups on the basis of epigenetic patterns (DNA methylation), and these subgroups show distinguishing chromosome copy number gains/losses and gene mutations.[32-34] Particularly distinctive subtypes of pediatric high-grade gliomas are those with recurring mutations at specific amino acids in histone genes, and together these account for approximately one-half of pediatric high-grade gliomas. The following pediatric high-grade glioma subgroups were identified on the basis of their DNA methylation patterns, and they show distinctive molecular and clinical characteristics:[34]
  1. H3.3 (H3F3A) and H3.1 (HIST1H3B and, rarely, HIST1H3C) mutation at K27: The Histone K27–mutated cases occur predominantly in midchildhood (median age, approximately 10 years), are almost exclusively midline (thalamus, brain stem, and spinal cord), and carry a very poor prognosis. The 2016 WHO classification groups these cancers into a single entity—diffuse midline glioma, H3 K27M–mutant—although there are clinical and biological distinctions between cases with H3.3 and H3.1 mutations, as described below.[1] These cases can be diagnosed using immunohistochemistry to identify the presence of K27M.
    • H3.3K27M cases occur throughout the midline and pons, account for approximately 60% of cases in these locations, and commonly present between the ages of 5 and 10 years.[34] The prognosis for H3.3K27M patients is especially poor, with a median survival of less than 1 year; the 2-year survival is less than 5%.[34]
    • H3.1K27M cases are approximately fivefold less common than H3.3K27M cases. They occur primarily in the pons and present at a younger age than other H3.3K27M cases (median age, 5 years vs. 6–10 years). These cases have a slightly more favorable prognosis than do H3.3K27M cases (median survival, 15 months vs. 11 months). Mutations in ACVR1, which is also the mutation observed in the genetic condition fibrodysplasia ossificans progressiva, are present in a high proportion of H3.1K27M cases.[34-36]
    • Rarely, K27M mutations are also identified in H3.2 (HIST2H3C) cases.[34]
  2. H3.3 (H3F3A) mutation at G34: The H3.3G34 subtype presents in older children and young adults (median age, 14–18 years) and arises exclusively in the cerebral cortex.[32,33] H3.3G34 cases commonly have mutations in TP53 and ATRX and show widespread hypomethylation across the whole genome. Patients with H3F3A mutations are at high risk of treatment failure, but the prognosis is not as poor as that of patients with Histone 3.1 or 3.3 K27M mutations.[33] O-6-methylguanine-DNA methyltransferase (MGMT) methylation is observed in approximately two-thirds of cases, and aside from the IDH1-mutated subtype (see below), the H3.3G34 subtype is the only pediatric high-grade glioma subtype that demonstrates MGMT methylation rates exceeding 20%.[34]
  3. IDH1 mutation: IDH1-mutated cases represent a small percentage of pediatric high-grade gliomas (approximately 5%), and pediatric high-grade glioma patients whose tumors have IDH1 mutations are almost exclusively older adolescents (median age in a pediatric population, 16 years) with hemispheric tumors.[34] IDH1-mutated cases often show TP53 mutations, MGMT promoter methylation, and a glioma-CpG island methylator phenotype (G-CIMP).[32,33] Pediatric patients with IDH1 mutations show a more favorable prognosis than do other pediatric glioblastoma multiforme patients; 5-year overall survival (OS) rates exceed 60% for pediatric patients with IDH1 mutations, compared with 5-year OS rates of less than 20% for patients with wild-type IDH1.[34]
  4. Pleomorphic xanthoastrocytoma (PXA)–like: Approximately 10% of pediatric high-grade gliomas have DNA methylation patterns that are PXA-like.[33] PXA-like cases commonly have BRAF V600E mutations and a relatively favorable outcome (approximately 50% survival at 5 years).[34]
  5. Low-grade glioma–like: A small subset of pediatric brain tumors with the histologic appearance of high-grade gliomas show DNA methylation patterns like those of low-grade gliomas.[33,34] These cases are primarily observed in young patients (median age, 4 years); 10 of 16 infants with a glioblastoma multiforme diagnosis were in the low-grade glioma–like group.[34] The prognosis for these patients is much more favorable than for other pediatric high-grade glioma subtypes. Refer below for additional discussion of glioblastoma multiforme in infants.
Pediatric glioblastoma multiforme high-grade glioma patients whose tumors lack both histone mutations and IDH1 mutations represent approximately 40% of pediatric glioblastoma multiforme cases.[34,37] This is a heterogeneous group, with higher rates of gene amplifications than other pediatric high-grade glioma subtypes. The most commonly amplified genes are PDGFRA, EGFR, CCND/CDK, and MYC/MYCN;[32,33] MGMT promoter methylation rates are low in this group.[37] One report divided this group into three subtypes. The subtype characterized by high rates of MYCN amplification showed the poorest prognosis, while the subtype characterized by TERT promoter mutations and EGFR amplification showed the most favorable prognosis. The third group was characterized by PDGFRA amplification.[37]
Infants and young children with a glioblastoma multiforme diagnosis appear to have tumors with distinctive molecular characteristics when compared with tumors of older children and adults. The application of DNA methylation analysis to pediatric glioblastoma multiforme tumors identified a group of patients (representing approximately 7% of pediatric patients with a histologic diagnosis of glioblastoma multiforme) whose tumors had molecular characteristics consistent with low-grade gliomas. The median age for this group of patients was 1 year, with eight of ten infants showing a low-grade glioma–like profile.[33] The low-grade glioma–like subtype had a favorable prognosis (3-year overall survival, approximately 90%).[33,34] BRAF V600E mutations were observed in 4 of 13 low-grade glioma–like tumors and in 3 of 15 tumors from patients aged 3 years and younger.[33] A second report investigated gene copy number gains and losses and mutation status of selected genes for glioblastoma multiforme tumors from children younger than 36 months.[38] Molecular alterations observed at appreciable rates in older children (e.g., K27M, CDKN2A loss, PDGFRA amplification, and TERT promoter mutations) were rare in the tumors of these young children, and novel abnormalities (e.g., loss of SNORD on chromosome 14q32) were observed in some cases.
Childhood secondary high-grade glioma (high-grade glioma that is preceded by a low-grade glioma) is uncommon (2.9% in a study of 886 patients). No pediatric low-grade gliomas with the BRAF-KIAA1549 fusion transformed to a high-grade glioma, whereas low-grade gliomas with the BRAF V600E mutations were associated with increased risk of transformation. Seven of 18 patients (approximately 40%) with secondary high-grade glioma had BRAF V600E mutations, with CDKN2A alterations present in 8 of 14 cases (57%).[16]
(Refer to the PDQ summary on Childhood Astrocytomas Treatment for information about the treatment of high-grade childhood astrocytomas.)

Diffuse Midline Glioma, H3 K27M-Mutant (Including Diffuse Intrinsic Pontine Gliomas [DIPGs])

The diffuse midline glioma, H3 K27M-mutant, category includes tumors previously classified as DIPG; most of the data is derived from experience with DIPG. This category also includes gliomas with the H3 K27M mutation arising in midline structures such as the thalamus.
The genomic characteristics of DIPGs appear to differ from those of many other pediatric high-grade gliomas of the cerebrum and from those of adult high-grade gliomas.[39] The molecular and clinical characteristics of DIPGs align with those of other midline high-grade gliomas, with a specific H3 K27M mutation in histone H3.3 (H3F3A) or H3.1 (HIST1H3B and HIST1H3C), which led the World Health Organization to group these tumors together into a single entity, called diffuse midline glioma, H3 K27M-mutant.[1]
In one report of 64 children with thalamic tumors, 50% of high-grade gliomas (11 of 22) had an H3 K27M mutation, and approximately 10% of tumors with low-grade morphological characteristics (5 of 42) had an H3 K27M mutation. Five-year overall survival (OS) was only 6% (1 of 16).[40] In another study that included 202 children with glioblastoma, 68 of the tumors were midline (primarily thalamic) and had an H3 K27M mutation. Five-year OS for this group was only 5%, which was significantly inferior to the survival rates of the remaining patients in the study.[33]
A number of chromosomal and genomic abnormalities have been reported for DIPG, including the following:
  • Histone H3 genes: Approximately 80% of DIPG tumors have a mutation in a specific amino acid in the histone H3.3 (H3F3A) or H3.1 (HIST1H3B and HIST1H3C) genes.[35,36,41-43] This H3 K27M mutation is observed in pediatric high-grade gliomas at other midline locations but is uncommon in cerebral pediatric high-grade gliomas and in adult high-grade gliomas.[35,36,41-44]
    An autopsy study that examined multiple tumor sites (primary, contiguous, and metastatic) in seven DIPG patients found that the H3 K27M mutation was invariably present, supporting its role as a driver mutation for DIPG.[45]
    Patients with H3.1 K27M mutations have a longer median survival (15 months) than do patients with H3.3 K27M mutations (10.4 months).[46]
  • ACVR1 gene: Approximately 20% of DIPG cases have activating mutations in the ACVR1 gene, with most occurring concurrently with H3.3 mutations.[35,36,42,43]
  • Receptor tyrosine kinase amplification: PDGFRA amplification occurs in approximately 30% of cases, with lower rates of amplification observed for some other receptor tyrosine kinase genes (e.g., MET and IGF1R).[47,48]
    An autopsy study that examined multiple tumor sites (primary, contiguous, and metastatic) in seven DIPG patients found that PDGFRA amplification was variably present across these sites, suggesting that this change is a secondary genomic alteration in DIPG.[45]
  • TP53 deletion: DIPG tumors commonly show deletion of the TP53 gene on chromosome 17p.[48] Additionally, TP53 is commonly mutated in DIPG tumors, particularly those with histone H3 gene mutations.[35,36,42,43,49] Aneuploidy is commonly observed in cases with TP53 mutations.[35]
The gene expression profile of DIPG differs from that of non–brain stem pediatric high-grade gliomas, further supporting a distinctive biology for this subset of pediatric gliomas.[48] Pediatric H3 K27M-mutant tumors rarely show O-6-methylguanine-DNA methyltransferase (MGMT) promoter methylation,[33] which explains the lack of efficacy of temozolomide when it was tested in patients with DIPG.[50]
(Refer to the PDQ summary on Childhood Brain Stem Glioma Treatment for information about the treatment of childhood brain stem gliomas.)

Central Nervous System (CNS) Atypical Teratoid/Rhabdoid Tumors (AT/RT)

SMARCB1 gene

AT/RT was the first primary pediatric brain tumor in which a candidate tumor suppressor gene, SMARCB1 (previously known as INI1 and hSNF5), was identified.[51] SMARCB1 is genomically altered in most rhabdoid tumors, including CNS, renal, and extrarenal rhabdoid malignancies.[51] Loss of SMARCB1/SMARCA4 staining is a defining marker for AT/RT. Additional genomic alterations (mutations and gains/losses) in other genes are very uncommon in patients with SMARCB1-associated AT/RT. Less commonly, SMARCA4-negative (with retained SMARCB1) tumors have been described.[52] No other genes are recurrently mutated in AT/RT.[53-55]
SMARCB1 is a component of a switch (SWI) and sucrose non-fermenting (SNF) adenosine triphosphate–dependent chromatin-remodeling complex.[56] Rare familial cases of rhabdoid tumors expressing SMARCB1 and lacking SMARCB1 mutations have also been associated with germline mutations of SMARCA4/BRG1, another member of the SWI/SNF chromatin-remodeling complex.[57,58]
The 2016 WHO classification defines AT/RT by the presence of either SMARCB1 or SMARCA4 alterations. Tumors with histological features of AT/RT that lack these genomic alterations are termed CNS embryonal tumor with rhabdoid features.[1]
Despite the absence of recurring genomic alterations beyond SMARCB1 (and, more rarely, other SWI/SNF complex members), biologically distinctive subsets of AT/RT have been identified.[59,60] The following three distinctive subsets of AT/RT were identified through the use of DNA methylation arrays for 150 AT/RT tumors and gene expression arrays for 67 AT/RT tumors:[60]
  • AT/RT TYR: This subset represented approximately one-third of cases and was characterized by elevated expression of melanosomal markers such as TYR (the gene encoding tyrosinase). Cases in this subset were primarily infratentorial, with most presenting in children aged 0 to 1 year and showing chromosome 22q loss.[60] For patients with AT/RT TYR, the mean overall survival (OS) was 37 months in a clinically heterogeneous group (95% confidence interval [CI], 18–56 months).[61] Cribriform neuroepithelial tumor is a brain cancer that also presents in young children and has genomic and epigenomic characteristics that are very similar to AT/RT TYR.[61] (Refer to the Cribriform Neuroepithelial Tumor section of the PDQ summary on Childhood Central Nervous System Atypical Teratoid/Rhabdoid Tumor Treatment for more information.)
  • AT/RT SHH: This subset represented approximately 40% of cases and was characterized by elevated expression of genes in the sonic hedgehog (SHH) pathway (e.g., GLI2 and MYCN). Cases in this subset occurred with similar frequency in the supratentorium and infratentorium. While most presented before age 2 years, approximately one-third of cases presented between ages 2 and 5 years.[60] For patients with AT/RT SHH, the mean OS was 16 months (95% CI, 8–25 months).[61]
  • AT/RT MYC: This subset represented approximately one-fourth of cases and was characterized by elevated expression of MYC. AT/RT MYC cases tended to occur in the supratentorial compartment. While most AT/RT MYC cases occurred by age 5 years, AT/RT MYC represented the most common subset diagnosed at age 6 years and older. Focal deletions of SMARCB1 were the most common mechanism of SMARCB1 loss for this subset.[60] For patients with AT/RT MYC, the mean OS was 13 months (95% CI, 5–22 months).[61]
In addition to somatic mutations, germline mutations in SMARCB1 have been reported in a substantial subset of AT/RT patients.[51,62] A study of 65 children with rhabdoid tumors found that 23 (35%) had germline mutations and/or deletions of SMARCB1.[63] Children with germline alterations in SMARCB1 presented at an earlier age than did sporadic cases (median age, approximately 5 months vs. 18 months) and were more likely to present with synchronous, multifocal tumors.[63] One parent was found to be a carrier of the SMARCB1 germline abnormality in 7 of 22 evaluated cases showing germline alterations, with four of the carrier parents being unaffected by SMARCB1-associated cancers.[63] This indicates that AT/RT shows an autosomal dominant inheritance pattern with incomplete penetrance.
Gonadal mosaicism has also been observed, as evidenced by families in which multiple siblings are affected by AT/RT and have identical SMARCB1 alterations, but both parents lack a SMARCB1 mutation/deletion.[63,64] Screening for germline SMARCB1 mutations in children diagnosed with AT/RT may provide useful information for counseling families on the genetic implications of their child’s AT/RT diagnosis.[63]
Loss of SMARCB1 or SMARCA4 protein expression has therapeutic significance, because this loss creates a dependence of the cancer cells on EZH2 activity.[65] Preclinical studies have shown that some AT/RT xenograft lines with SMARCB1 loss respond to EZH2 inhibitors with tumor growth inhibition and occasional tumor regression.[66,67] In a study of the EZH2 inhibitor tazemetostat, objective responses were observed in adult patients whose tumors had either SMARCB1 or SMARCA4 loss (non-CNS malignant rhabdoid tumors and epithelioid sarcoma).[68] (Refer to the Treatment of Recurrent Childhood CNS Atypical Teratoid/Rhabdoid Tumor section of this summary for more information.)
(Refer to the PDQ summary on Childhood Central Nervous System Atypical Teratoid/Rhabdoid Tumors Treatment for information about the treatment of childhood CNS atypical teratoid/rhabdoid tumors.)

Medulloblastomas

Multiple medulloblastoma subtypes have been identified by integrative molecular analysis.[69-84] Since 2012, the general consensus is that medulloblastoma can be molecularly separated into at least four core subtypes, including WNT-activated, sonic hedgehog (SHH)–activated, group 3, and group 4 medulloblastoma. However, different regions of the same tumor are likely to have other disparate genetic mutations, adding to the complexity of devising effective molecularly targeted therapy.[85] These subtypes remain stable across primary and metastatic components.[86,87]
The 2016 World Health Organization (WHO) classification has endorsed this consensus by adding the following categories for genetically defined medulloblastoma:[1]
  • Medulloblastoma, WNT-activated.
  • Medulloblastoma, SHH-activated and TP53-mutant.
  • Medulloblastoma, SHH-activated and TP53–wild-type.
  • Medulloblastoma, non-WNT/non-SHH.
Further subclassification within these subgroups is possible, which will provide even more prognostic information.[87-89]
Medulloblastoma, WNT-activated
WNT tumors are medulloblastomas with aberrations in the WNT signaling pathway and represent approximately 10% of all medulloblastomas.[88] WNT medulloblastomas show a WNT signaling gene expression signature and beta-catenin nuclear staining by immunohistochemistry.[90] They are usually histologically classified as classic medulloblastoma tumors and rarely have a large cell/anaplastic appearance. WNT medulloblastomas generally occur in older patients (median age, 10 years) and are infrequently metastasized at diagnosis.
CTNNB1 mutations are observed in 85% to 90% of WNT medulloblastoma cases, with APC mutations detected in many of the cases that lack CTNNB1 mutations. Patients with WNT medulloblastoma whose tumors have APC mutations often have Turcot syndrome (i.e., germline APC mutations).[89] In addition to CTNNB1 mutations, WNT medulloblastoma tumors show 6q loss (monosomy 6) in 80% to 90% of cases. While monosomy 6 is observed in most medulloblastoma patients younger than 18 years at diagnosis, it appears to be much less common (approximately 25% of cases) in patients older than 18 years.[88,90]
The WNT subset is primarily observed in older children, adolescents, and adults and does not show a male predominance. The subset is believed to have brain stem origin, from the embryonal rhombic lip region.[91] WNT medulloblastomas are associated with a very good outcome in children, especially in individuals whose tumors have beta-catenin nuclear staining and proven 6q loss and/or CTNNB1 mutations.[84,92,93]
Medulloblastoma, SHH-activated and TP53-mutant and medulloblastoma, SHH-activated and TP53-wildtype
SHH tumors are medulloblastomas with aberrations in the SHH pathway and represent approximately 25% of medulloblastoma cases.[88] SHH medulloblastomas are characterized by chromosome 9q deletions; desmoplastic/nodular histology; and mutations in SHH pathway genes, including PTCH1, PTCH2, SMO, SUFU, and GLI2.[90]
SHH medulloblastomas show a bimodal age distribution and are observed primarily in children younger than 3 years and in older adolescence/adulthood. The tumors are believed to emanate from the external granular layer of the cerebellum. The heterogeneity in age at presentation maps to distinctive subsets identified by further molecular characterization, as follows:
  • The subset of medulloblastoma most common in children aged 3 to 16 years is enriched for MYCN and GLI2 amplifications, with TP53 mutations commonly co-occurring with one of these amplifications.[87,88] PTCH1 mutations occur in this subtype and are mutually exclusive with TP53 mutations (often germline), while SMO and SUFU mutations are rare.[87,94]
  • Two SHH subtypes that occur primarily in children younger than 3 years have been described.[88] One of these subtypes is more frequently metastatic, with more frequent focal amplifications.[95] The second of these subtypes is enriched for the medulloblastoma with extensive nodularity (MBEN) histology. SHH pathway mutations in children younger than 3 years with medulloblastoma include PTCH1 and SUFU mutations.[87] SUFU mutations are rarely observed in older children and adults, and they are commonly germline events.[94]
    A second report that used DNA methylation arrays also identified two subtypes of SHH medulloblastoma in young children.[95] One of the subtypes contained all of the cases with SMO mutations, and it was associated with a favorable prognosis. The other subtype had most of the SUFU mutations, and it was associated with a much lower progression-free survival (PFS) rate. PTCH1 mutations were present in both subtypes.
  • A fourth SHH subtype includes most of the adult cases of SHH medulloblastoma.[88] This subtype is enriched for TERT promoter mutations, which are observed in approximately 90% of cases. PTCH1 and SMO mutations are observed in adults with SHH medulloblastoma, with the latter being virtually restricted to the adult subtype.
The outcome for patients with nonmetastatic SHH medulloblastoma is relatively favorable for children younger than 3 years and for adults.[88] Young children with the MBEN histology have a particularly favorable prognosis.[96-100] Patients with SHH medulloblastoma at greatest risk of treatment failure are children older than 3 years whose tumors have TP53 mutations, often with co-occurring GLI2 or MYCN amplification and large cell/anaplastic histology.[88,94,101]
Patients with unfavorable molecular findings have an unfavorable prognosis, with fewer than 50% of patients surviving after conventional treatment.[94,101-104]
The 2016 WHO classification identifies SHH medulloblastoma with a TP53 mutation as a distinctive entity (medulloblastoma, SHH-activated and TP53-mutant).[1] Approximately 25% of SHH-activated medulloblastoma cases have TP53 mutations, with a high percentage of these cases also showing a TP53 germline mutation (9 of 20 in one study). These patients are commonly between the ages of 5 years and 18 years and have a worse outcome (overall survival at 5 years, <50%).[104] The tumors often show large cell anaplastic histology.[104]
Medulloblastoma, non–WNT/non–SHH-activated
The WHO classification combines group 3 and group 4 medulloblastoma cases into a single entity, partly on the basis of the absence of immediate clinical impact for this distinction. Group 3 medulloblastoma represents approximately 25% of medulloblastoma cases, while group 4 medulloblastoma represents approximately 40% of medulloblastoma cases.[88,90] Both group 3 and group 4 medulloblastoma patients are predominantly male.[78,87] Group 3 and group 4 medulloblastomas can be further subdivided on the basis of characteristics such as gene expression and DNA methylation profiles, but the optimal approach to their subdivision is not established.[88,89]
Various genomic alterations are observed in group 3 and group 4 medulloblastomas; however, no single alteration occurs in more than 10% to 20% of cases. Genomic alterations include the following:
  • MYC amplification was the most common distinctive alteration reported for group 3 medulloblastoma, occurring in approximately 15% of cases.[83,89]
  • The most common distinctive genomic alteration described for group 4 medulloblastoma (observed in approximately 15% of cases) was activation of PRDM6 by enhancer hijacking, resulting from the tandem duplication of the adjacent SNCAIP gene.[89]
  • Other genomic alterations were observed in both group 3 and group 4 cases, including MYCN amplification and structural variants leading to GFI1 or GFI1B overexpression through enhancer hijacking.
  • Isochromosome 17q (i17q) is the most common cytogenetic abnormality and is observed in a high percentage of group 4 cases as well as in group 3 cases, but it is rarely observed in WNT and SHH medulloblastoma.[83,89] Prognosis for group 3 and group 4 patients does not appear to be affected by the presence of i17q.[105]
Group 3 patients with MYC amplification or MYC overexpression have a poor prognosis,[87] with fewer than 50% of these patients surviving 5 years after diagnosis.[88] This poor prognosis is especially true in children younger than 4 years at diagnosis.[102] However, patients with group 3 medulloblastoma without MYC amplification who are older than 3 years have a prognosis similar to that of most patients with non-WNT medulloblastoma, with a 5-year PFS rate higher than 70%.[103,105]
Group 4 medulloblastomas occur throughout infancy and childhood and into adulthood. The prognosis for group 4 medulloblastoma patients is similar to that for patients with other non-WNT medulloblastomas and may be affected by additional factors such as the presence of metastatic disease, chromosome 11q loss, and chromosome 17p loss.[82,83,88,101] One study found that group 4 patients with either chromosome 11 loss or gain of chromosome 17 were low risk, regardless of metastases. In cases lacking both of these cytogenetic features, metastasis at presentation differentiated between high and intermediate risk.[101]
For group 3 and group 4 standard-risk patients (i.e., without MYC amplification or metastatic disease), the gain or loss of whole chromosomes appears to connote a favorable prognosis. This finding was derived from the data of 91 patients with non-WNT/non-SHH medulloblastoma enrolled in the SIOP-PNET-4 (NCT01351870) clinical trial and was confirmed in an independent group of 70 children with non-WNT/non-SHH medulloblastoma treated between 1990 and 2014.[105] Chromosomal abnormalities include the following:
  • The gain/loss of one or more whole chromosomes was associated with a 5-year event-free survival (EFS) of 93%, compared with an EFS of 64% for no whole chromosome gains/losses.
  • The most common chromosomal gains/losses are gain of chromosome 7 and loss of chromosomes 8 and 11.
  • The optimally performing prognosis discriminator was determined to be the occurrence of two or more of the following aberrations: chromosome 7 gain, chromosome 8 loss, and chromosome 11 loss. Approximately 40% of group 3 and group 4 standard-risk patients had two or more of these chromosomal aberrations and had a 5-year EFS of 100%, compared with an EFS of 68% for patients with fewer than two aberrations.
  • In an independent cohort, the prognostic significance of two or more gains/losses versus zero or one gain/loss of chromosomes 7, 8, and 11 was confirmed (5-year EFS, 95% for patients with two or more vs. 59% for patients with one or fewer).
The classification of medulloblastoma into the four major subtypes will likely be altered in the future.[88,89,106,107] Further subdivision within subgroups based on molecular characteristics is likely as each of the subgroups is further molecularly dissected, although there is no consensus regarding an alternative classification.[82,90,94]
Whether the classification for adults with medulloblastoma has a predictive ability similar to that for children is unknown.[83,102] In one study of adult medulloblastoma, MYC oncogene amplifications were rarely observed, and tumors with 6q deletion and WNT activation (as identified by nuclear beta-catenin staining) did not share the excellent prognosis seen in pediatric medulloblastomas, although another study did confirm an excellent prognosis for WNT-activated tumors in adults.[83,102]
(Refer to the PDQ summary on Childhood Medulloblastoma and Other Central Nervous System Embryonal Tumors Treatment for information about the treatment of childhood medulloblastoma.)

Nonmedulloblastoma Embryonal Tumors

This section describes the genomic characteristics of embryonal tumors other than medulloblastoma and atypical teratoid/rhabdoid tumor. The 2016 WHO classification removed the term primitive neuroectodermal tumors (PNET) from the diagnostic lexicon.[1] This change resulted from the recognition that many tumors previously classified as CNS PNETs have the common finding of amplification of the C19MC region on chromosome 19. These entities included ependymoblastoma, embryonal tumors with abundant neuropil and true rosettes (ETANTR), and some cases of medulloepithelioma. The 2016 WHO classification now categorizes tumors with C19MC amplification as embryonal tumor with multilayered rosettes (ETMR), C19MC-altered. Tumors previously classified as CNS PNETs are now termed CNS embryonal tumor, NOS, with the recognition that tumors in this category will likely be classified by their defining genomic lesions in future editions of the WHO classification.
A study applying unsupervised clustering of DNA methylation patterns for 323 nonmedulloblastoma embryonal tumors found that approximately one-half of these tumors diagnosed as nonmedulloblastoma embryonal tumors showed molecular profiles characteristic of other known pediatric brain tumors (e.g., high-grade glioma, atypical teratoid/rhabdoid tumor [AT/RT]).[108] This observation highlights the utility of molecular characterization to assign this class of tumors to their appropriate biology-based diagnosis.
Among the same collection of 323 tumors diagnosed as nonmedulloblastoma embryonal tumors, molecular characterization identified genomically and biologically distinctive subtypes, including the following:
  • Embryonal tumor with multilayered rosettes (ETMR): Representing 11% of the 323 cases, this subtype combines embryonal rosette-forming neuroepithelial brain tumors that were previously categorized as either embryonal tumor with abundant neuropil and true rosettes (ETANTR), ependymoblastoma, or medulloepithelioma.[108,109] ETMRs arise in young children (median age at diagnosis, 2–3 years) and show a highly aggressive clinical course, with a median progression-free survival (PFS) of less than 1 year and few long-term survivors.[109-111]
    ETMRs are defined at the molecular level by high-level amplification of the microRNA cluster C19MC and by a gene fusion between TTYH1 and C19MC.[109,112,113] This gene fusion puts expression of C19MC under control of the TTYH1 promoter, leading to high-level aberrant expression of the microRNAs within the cluster. The World Health Organization (WHO) allows histologically similar tumors without C19MC alteration to be classified as ETMR, not otherwise specified (NOS).
  • Central nervous system (CNS) neuroblastoma with FOXR2 activation (CNS NB-FOXR2): Representing 14% of the 323 cases, this subtype is characterized by genomic alterations that lead to increased expression of the transcription factor FOXR2.[108] CNS NB-FOXR2 is primarily observed in children younger than 10 years, and the histology of these tumors is typically that of CNS neuroblastoma or CNS ganglioneuroblastoma.[108] There is no single genomic alteration among CNS NB-FOXR2 tumors leading to FOXR2 overexpression, with gene fusions involving multiple FOXR2 partners identified.[108] This subtype has not been added to the WHO diagnostic lexicon.
  • CNS Ewing sarcoma family tumor with CIC alteration (CNS EFT-CIC): Representing 4% of the 323 cases, this subtype is characterized by genomic alterations affecting CIC (located on chromosome 19q13.2), with fusion to NUTM1 being identified in several cases tested.[108] CIC gene fusions are also identified in extra-CNS Ewing-like sarcomas, and the gene expression signature of CNS EFT-CIC tumors is similar to that of these sarcomas.[108] CNS EFT-CIC tumors generally occur in children younger than 10 years and are characterized by a small cell phenotype but with variable histology.[108] This subtype has not been added to the WHO diagnostic lexicon.
  • CNS high-grade neuroepithelial tumor with MN1 alteration (CNS HGNET-MN1): Representing 3% of the 323 cases, this subtype is characterized by gene fusions involving MN1 (located on chromosome 22q12.3), with fusion partners including BEND2 and CXXC5.[108] The CNS HGNET-MN1 subtype shows a striking female predominance and tends to occur in the second decade of life.[108] This subtype contained most cases carrying a diagnosis of astroblastoma as per the 2007 WHO classification scheme.[108] This subtype has not been added to the WHO diagnostic lexicon.
  • CNS high-grade neuroepithelial tumor with BCOR alteration (CNS HGNET-BCOR): Representing 3% of the 323 cases, this subtype is characterized by internal tandem duplications of BCOR,[108] a genomic alteration that is also found in clear cell sarcoma of the kidney.[114,115] While the median age at diagnosis is younger than 10 years, cases arising in the second decade of life and beyond do occur.[108] This subtype has not been added to the WHO diagnostic lexicon.
The contribution of DNA methylation profiling to correctly diagnose supratentorial embryonal tumors was demonstrated in a clinical trial of patients with supratentorial primitive neuroectodermal tumors of the CNS (CNS-PNET) and pineoblastoma.[116] For the pineoblastoma cases, there was high concordance between the diagnosis made by methylation profiling and the diagnosis made by central pathology review diagnosis (26 of 29). However, for the remaining 31 patients, the diagnosis made by methylation profiling was high-grade glioma in 18 patients, AT/RT in 2 patients, and RELA-fusion–positive ependymoma in 2 patients. Adjudication of discrepancies between the diagnosis made by central review pathology and the diagnosis made by methylation profiling was in favor of methylation profiling in the ten cases that were re-examined.
Medulloepithelioma
Medulloepithelioma with the classic C19MC amplification is considered an ETMR, C19MC-altered (refer to the ETMR information above). However, when a tumor has the histological features of medulloepithelioma, but without a C19MC amplification, it is identified as a histologically discrete tumor within the WHO classification system and called medulloepithelioma.[117,118] Medulloepithelioma tumors are rare and tend to arise most commonly in infants and young children. Medulloepitheliomas, which histologically recapitulate the embryonal neural tube, tend to arise supratentorially, primarily intraventricularly, but may arise infratentorially, in the cauda, and even extraneurally, along nerve roots.[117,118]
Intraocular medulloepithelioma is biologically distinct from intra-axial medulloepithelioma.[119,120]
(Refer to the PDQ summary on Childhood Medulloblastoma and Other Central Nervous System Embryonal Tumors Treatment for information about the treatment of childhood PNETs.)

Pineoblastoma

Pineoblastoma, which was previously conventionally grouped with embryonal tumors, is now categorized by the World Health Organization (WHO) as a pineal parenchymal tumor. Given that therapies for pineoblastoma are quite similar to those utilized for embryonal tumors, the previous convention of including pineoblastoma with the central nervous system (CNS) embryonal tumors is followed here. Pineoblastoma is associated with germline mutations in both the RB1 gene and in DICER1, as described below:
  • Pineoblastoma is associated with germline mutations in RB1, with the term trilateral retinoblastoma used to refer to ocular retinoblastoma in combination with a histologically similar brain tumor generally arising in the pineal gland or other midline structures. Historically, intracranial tumors have been reported in 5% to 15% of children with heritable retinoblastoma.[121] Rates of pineoblastoma among children with heritable retinoblastoma who undergo current treatment programs may be lower than these historical estimates.[122-124]
  • Germline DICER1 mutations have also been reported in patients with pineoblastoma.[125] Among 18 patients with pineoblastoma, 3 patients with DICER1 germline mutations were identified, and an additional 3 patients known to be carriers of germline DICER1 mutations developed pineoblastoma.[125] The DICER1 mutations in patients with pineoblastoma are loss-of-function mutations that appear to be distinct from the mutations observed in DICER1 syndrome–related tumors such as pleuropulmonary blastoma.[125]
(Refer to the PDQ summary on Childhood Medulloblastoma and Other Central Nervous System Embryonal Tumors Treatment for information about the treatment of childhood pineoblastoma.)

Ependymomas

Molecular Subgroups of Ependymoma

Molecular characterization studies have identified nine molecular subgroups of ependymoma, six of which predominate in childhood. The subgroups are determined by their distinctive DNA methylation and gene expression profiles and by their distinctive spectrum of genomic alterations (refer to Figure 4).[126-129]
  • Infratentorial tumors.
    • Posterior fossa A (PF-EPN-A), loss of H3 K27 trimethylation mark.
    • Posterior fossa B (PF-EPN-B), retained H3 K27 trimethylation mark.
  • Supratentorial tumors.
    • C11orf95-RELA–positive ependymoma (ST-EPN-RELA).
    • YAP1 fusion–positive ependymoma (ST-EPN-YAP1).
  • Spinal tumors.
    • Myxopapillary ependymoma (SP-EPN-MPE).
    • Classic histology (SP-EPN).
Subependymoma—whether supratentorial, infratentorial, or spinal—accounts for the remaining three molecular variants, and it is rarely, if ever, seen in children.
ENLARGEGraph showing key molecular and clinical characteristics of ependymal tumor subgroups.
Figure 4. Graphical summary of key molecular and clinical characteristics of ependymal tumor subgroups. Schematic representation of key genetic and epigenetic findings in the nine molecular subgroups of ependymal tumors as identified by methylation profiling. CIN, Chromosomal instability. Reprinted from Cancer CellExit Disclaimer, Volume 27, Kristian W. Pajtler, Hendrik Witt, Martin Sill, David T.W. Jones, Volker Hovestadt, Fabian Kratochwil, Khalida Wani, Ruth Tatevossian, Chandanamali Punchihewa, Pascal Johann, Juri Reimand, Hans-Jorg Warnatz, Marina Ryzhova, Steve Mack, Vijay Ramaswamy, David Capper, Leonille Schweizer, Laura Sieber, Andrea Wittmann, Zhiqin Huang, Peter van Sluis, Richard Volckmann, Jan Koster, Rogier Versteeg, Daniel Fults, Helen Toledano, Smadar Avigad, Lindsey M. Hoffman, Andrew M. Donson, Nicholas Foreman, Ekkehard Hewer, Karel Zitterbart, Mark Gilbert, Terri S. Armstrong, Nalin Gupta, Jeffrey C. Allen, Matthias A. Karajannis, David Zagzag, Martin Hasselblatt, Andreas E. Kulozik, Olaf Witt, V. Peter Collins, Katja von Hoff, Stefan Rutkowski, Torsten Pietsch, Gary Bader, Marie-Laure Yaspo, Andreas von Deimling, Peter Lichter, Michael D. Taylor, Richard Gilbertson, David W. Ellison, Kenneth Aldape, Andrey Korshunov, Marcel Kool, and Stefan M. Pfister, Molecular Classification of Ependymal Tumors across All CNS Compartments, Histopathological Grades, and Age Groups, Pages 728–743, Copyright (2015), with permission from Elsevier.
Infratentorial tumors
Posterior fossa A ependymoma (PF-EPN-A)
The most common posterior fossa ependymoma subgroup is PF-EPN-A and is characterized by the following:
  • Presentation in young children (median age, 3 years).[126,130]
  • Low rates of mutations that affect protein structure, approximately five per genome.[127]
  • Gain of chromosome 1q, a known poor prognostic factor for ependymoma,[131] in approximately 25% of cases.[126,128,132]
  • A balanced chromosomal profile with few chromosomal gains or losses.[126,127]
  • Loss of the H3 K27 trimethylation mark and globally hypomethylated DNA.[133] Loss of the H3 K27 trimethylation mark occurs by one of the following two mechanisms:
    • Recurrent mutations of CXorf67/EZHIP in 10% of cases, with high CXorf67/EZHIP mRNA expression across almost all PF-EPN-A.[134,135] CXorf67/EZHIP expression (with or without mutation) results in inhibition of the methyltransferase EZH2 leading to loss of the H3 K27 trimethylation mark.[135,136]
    • Recurrent K27M mutations in histone H3 variants in a small proportion of cases.[137,138] Unlike diffuse intrinsic pontine gliomas, mutations in H3.1 (HIST1H3B and HIST1H3C) are more common than mutations in H3.3 (H3F3A).[134] Histone mutations are mutually exclusive with high expression of CXorf67/EZHIP,[134] and they also lead to loss of the H3 K27 trimethylation mark though EZH2 inhibition.
A study that included over 600 cases of PF-EPN-A used methylation array profiling to divide this population into two distinctive subgroups, PFA-1 and PFA-2.[134] Gene expression profiling suggested that these two subtypes may arise in different anatomic locations in the hindbrain. Within both of the PFA-1 and PFA-2 groups, distinctive minor subtypes could be identified, suggesting the presence of heterogeneity. Additional study will be required to define the clinical significance of these subtypes.
Posterior fossa B ependymoma (PF-EPN-B)
The PF-EPN-B subgroup is less common than the PF-EPN-A subgroup, representing 15% to 20% of all posterior fossa ependymomas in children. PF-EPN-B is characterized by the following:
  • Presentation primarily in adolescents and young adults (median age, 30 years).[126,130]
  • Low rates of mutations that affect protein structure (approximately five per genome), with no recurring mutations.[128]
  • Numerous cytogenetic abnormalities, primarily involving the gain/loss of whole chromosomes.[126,128]
  • Retained H3 K27 trimethylation.[133]
Supratentorial tumors
Supratentorial ependymomas with RELA fusions (ST-EPN-RELA)
ST-EPN-RELA is the largest subset of pediatric supratentorial ependymomas and is characterized by gene fusions involving RELA,[139,140] a transcriptional factor important in NF-κB pathway activity. ST-EPN-RELA is characterized by the following:
  • Represents approximately 70% of supratentorial ependymomas in children,[139,140] and presents at a median age of 8 years.[126]
  • Presence of C11orf95-RELA fusions resulting from chromothripsis involving chromosome 11q13.1.[139]
  • Low rates of mutations that affect protein structure and absence of recurring mutations outside of C11orf95-RELA fusions.[139]
  • Evidence of NF-κB pathway activation at the protein and RNA level.[139]
  • Gain of chromosome 1q, in approximately one-quarter of cases, with an indeterminate effect on survival.[126]
Supratentorial ependymomas with YAP1 fusions (ST-EPN-YAP1)
ST-EPN-YAP1 is the second, less common subset of supratentorial ependymomas and has fusions involving YAP1 on chromosome 11. ST-EPN-YAP1 is characterized by the following:
  • Median age at diagnosis of 1.4 years.[126]
  • Presence of a gene fusion involving YAP1, with MAMLD1 being the most common fusion partner.[126,139]
  • A relatively stable genome with few chromosomal changes other than the YAP1 fusion.[126]
Supratentorial ependymomas without RELA or YAP1 fusions (on chromosome 11) are an undefined entity, and it is unclear what these samples represent. By DNA methylation analysis, these samples often cluster with other entities such as high-grade gliomas and embryonal tumors; caution should be taken when diagnosing a supratentorial ependymoma that does not harbor a fusion involving chromosome 11.[108,141]
(Refer to the PDQ summary on Childhood Ependymoma Treatment for information about the treatment of childhood ependymoma.)
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