differences in molecular genetics between pediatric and adult malignant astrocytomas: age matters

54910.2217/FON.12.51 © 2012 Future Medicine Ltd ISSN 1479-6694Future Oncol. (2012) 8(5), 549–558

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Classic teaching in the field of pediatric oncol-ogy has long stated that differences exist between pediatric oncologic diagnoses that microscopically look similar, best exemplified by the category ‘small round blue cell tumors’ [1–3]. Similar differences can be recognized between adult and pediatric tumors that microscopically appear identical. For example, and as discussed in more detail below, adult low-grade astrocyto-mas transform over time into malignant gliomas that result in death [4], while pediatric low-grade astrocytomas tend to remain low grade and the long-term prognosis remains excellent [5,6]. Interestingly, when the rare malignant transfor-mation does occur in pediatric patients, similar abnormalities to those observed in adults appear to occur [7]. Other indications of differences between adult and pediatric tumors have become evident from the incidence of the tumors; pedi-atric tumors are a combination of low-grade glio-mas (often infratentorial) and medulloblastoma (infratentorial) while adult CNS tumors are predominantly supratentorial malignant glio-mas. While malignant astrocytomas account for approximately 40% of all adult CNS neoplasms [8] , they account for only 10–15% of pediatric CNS tumor diagnoses [9]. Other than location and incidence, however, malignant neoplasms have been shown on a biological level to possess other differences between adults and children [10–20]. In this review, we will discuss important molecular and biological differences between

adult and pediatric tumors of similar histology, highlighting the unique characteristics of pedi-atric CNS lesions, as well as the variability in the reported incidence of abnormalities [21]. This is more than just of academic importance. Many of the treatment strategies targeting pediatric tumors follow successful trials in adults and neg-ative results in adults usually lead to suspension or cancellation of pediatric protocols using the same approach. With our improved molecular basis for pediatric brain tumors, trials will need to be tailored to this group and will result in improved outcome [20,22,23].

Pediatric malignant gliomas are different to adult malignant gliomas

In spite of the reliance on adult clinical trials to guide pediatric protocol development, there is substantial evidence that significant differences exist between these populations. Infants present-ing with WHO grade 3 and grade 4 malignant astrocytomas treated with chemotherapy-based approaches result in a number of long-term survivors [24,25], in contrast to results observed in adults treated with combined radiation and chemotherapy, where outcome remains dismal [26]. Another example of a stark difference in outcome between adult and pediatric malignant gliomas is seen in the response rate to bevacizu-mab. While both adult and pediatric glioblas-toma multiforme (GBM) have vascular prolif-eration as part of the hallmark of this disease,

Differences in molecular genetics between pediatric and adult malignant astrocytomas: age matters

Stephen W Gilheeney* & Mark W Kieran1

1Pediatric Neuro-Oncology, Dana-Farber Children’s Hospital Cancer Center, Boston, MA, USA *Author for correspondence: Memorial Sloan-Kettering Cancer Center, Department of Pediatrics, Howard 1104, 1275 York Avenue, New York, NY 10065, USA n Tel.: +1 212 639 3973 n Fax: +1 212 717 3239 n [email protected]

The microscope – the classical tool for the investigation of cells and tissues – remains the basis for the classification of tumors throughout the body. Nowhere has this been more true than in the grading of astrocytomas. In spite of the fact that our parents warned us not to judge a book by its cover, we have continued to assume that adult and pediatric malignant gliomas that look the same, will have the same mutations, and thus respond to the same therapy. Rapid advances in molecular biology have permitted us the opportunity to go inside the cell and characterize the genetic events that underlie the true molecular heterogeneity of adult and pediatric brain tumors. In this paper, we will discuss some of the important clinical differences between pediatric and adult gliomas, with a focus on the molecular ana lysis of these different age groups.

Keywords

n BRAF n EGF receptor n high-grade glioma n isocitrate dehydrogenase 1 n low-grade glioma n methylguanine methyltransferase n p53 n PDGF receptor n PTEN n Ras

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Review Gilheeney & Kieran

the combination of irinotecan and bevacizumab showed responses in numerous adult Phase II studies resulting in US FDA approval [27,28] while the same approach in pediatric malignant g liomas demonstrated no durable responses [29].

These two examples speak to clinical and molecular differences of malignant astrocy-tomas in children and adults. Work over the past 10 years has shown that underlying this dichotomous behavior are differences in genetic profiles of the tumors [30]. A review of some of the more commonly mutated or altered genetic pathways in pediatric malignant astrocytomas, and the corresponding differences in adults, will be d iscussed below.

Ras/BRAFResults from The Cancer Genome Atlas (TCGA) ana lysis of adult GBM revealed a number of interesting findings, including the identification of mutations in neurofibromin [31], the protein linked to patients with neurofibromatosis type I (NF1). While an association of NF1 with malig-nant gliomas has long been known in both adult and pediatric patients [32,33], this mutation was not previously known to be associated with spo-radic GBM. By contrast, NF1-associated ras acti-vation has been a hallmark of pediatric low-grade gliomas, particularly for optic pathway gliomas [33]. These tumors lack many of the character-istic abnormalities observed in other astrocytic tumors and may help explain their excellent long-term prognosis [34]. The rarity of low-grade glioma-development in adults with NF1 suggests a developmental period of sensitivity to this m utation in prenatal or early childhood [35].

Non-NF1-associated low-grade gliomas in pediatric patients are classically associated with a truncated duplication of BRAF [36–40], with some variability in the breakpoint and partner rearrangement [41]. Various research-ers have shown that in these low-grade tumors, the fusion of BRAF with KIAA1549 leads to oncogene-induced senescence and improved clinical outcome [6,42]. Similar rearrangements have been observed in adult pilocytic astrocyto-mas [43] but not other adult gliomas or pediatric grade 2–4 gliomas [44]. The role of truncated duplicated BRAF in both the pathogenesis and response to therapy of these tumors remains to be determined, especially in light of the overall good prognosis of these tumors in children [45]. Gangliogliomas [46], pleomorphic xanthoastro-cytomas [47], fibrillary astrocytomas [46] and higher-grade astrocytomas [44] can possess the BRAFV600E activating mutation [48], a finding

that is again significantly less common in simi-lar tumors in adulthood. The ability of Clinical Laboratory Improvement Amendments (CLIA)-certified tests to assess for BRAF mutations and truncated duplications will assist in the develop-ment of targeted clinical trials for patients with these abnormalities [49].

p53The p53 tumor suppressor gene codes for a nuclear phosphoprotein involved in cell cycle arrest, apoptosis, and genetic stability and p53 mutations are among the most common muta-tions found in human cancers [50,51]. Previous work by multiple groups has found the presence of p53 mutations and/or overexpression in adult malignant astrocytomas, raising question as to their incidence in pediatric neoplasms. While early reports had suggested that multiple altera-tions of the TP53 genes were uncommon in pediatric patients, subsequent work suggests a different picture. Multiple groups have charac-terized pediatric WHO grade 3 and 4 tumors and found mutations or overexpression in the p53 gene in approximately 35–50% of these tumors, similar to the incidence seen in reports of adult tumors [52,53]. A specific p53 mutation (P53 Arg72Pro) in both adult and pediatric high-grade astrocytomas suggests that certain mutations are common between these two popu-lations [54]. Pollack et al. analyzed tumor samples from the CCG-945 study, a large Children’s Cancer Group study from 1985 to 1992 that treated newly diagnosed high-grade astrocyto-mas [55]. Their results demonstrated a frequency of TP53 mutations in pediatric tumors that was greater than that observed in previous pediat-ric studies, and similar to the incidence seen in young adults. The mutations that were seen in the pediatric tumors were overwhelmingly observed in patients >3 years old and further supports the differences in the biology of GBM in young children [55]. Analysis of expression (but not mutation) of p53 in 115 pediatric gli-oma specimens confirmed the importance of this marker as an independent outcome variable, with TP53 expression associated with poorer progno-sis (5-year progression-free survival 44 ± 6% vs 17 ± 6% in low-expressing and high-expressing tumors, respectively) [56]. Most recently, the role of both overexpression and mutation of p53 were confirmed in cohorts of pediatric patients with high-grade gliomas [18], while results from pedi-atric pilocytic astrocytomas failed to associate with outcome [57], which is likely related to the overall excellent prognosis in this group. These

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Differences in molecular genetics between pediatric & adult malignant astrocytomas Review

results therefore suggest an overlapping role for p53 in older pediatric and younger adult patients with high-grade astrocytomas, and are con-trasted by results for infants and the elderly. P53 abnormalities in 35% of cases are also observed in pilocytic low-grade pediatric tumors with an excellent prognosis [58]. Of importance in this ana lysis was the significantly higher incidence of p53 abnormality compared with other pub-lications, suggesting that as newer technologies become available, we may become more accurate at identifying expression or mutational events ([58] compared with [59]).

EGF receptor & EGF receptor variant IIIEGF receptor (EGFR; also known as ErbB-1) is a 170-kDa transmembrane tyrosine kinase and is a product of the c-erbB1 proto-oncogene [60,61]. Aberrant patterns in the expression of this pro-tein, including amplification, have been found in 40–50% of malignant astrocytomas aris-ing de novo in adults and have been associated with enhanced tumorigenicity [62,63]. Of those tumors with an amplified gene locus, nearly half express the mutant receptor EGFR variant III (EGFRvIII) [64]. This mutant receptor is caused by deletion of exons 2–7, resulting in a protein with no ligand-binding domain constitutive activation, and is further resistant to downreg-ulation through decreased receptor endocyto-sis [65]. This mutation has also been shown to confer resistance to both radiation therapy and c hemotherapy [66,67].

Many authors have looked at the role of EGFR and EGFRvIII in adult malignant astrocytomas. Investigation to the same extent has not been undertaken in pediatric tumors until recently. Bredel et al. examined 27 archival specimens of pediatric high-grade nonbrainstem gliomas via immunohistochemistry and EGFR gene ampli-fication using competitive PCR [68]. Whereas 22 out of 27 tumors stained positive for EGFR, amplification of EGFR was observed in only two of the 27 malignant astrocytomas, notably lower than that seen in the adult population [68]. Similar results in other cohorts have confirmed these findings [15,53]. In infant GBM, none of six cases had significant EGFR expression [25]. EGFR expression in both pontine and diffusely infiltrative brainstem gliomas (WHO grades 2–4) found that the incidence of ERBB1 immu-noreactivity and gene amplification increased with tumor grade [69]. Analysis of the cohort of high-grade astrocytomas from the CCG-945 study for the presence of EGFR amplifications identified that 14 of 38 (37%) tumors stained

positive for EGFR overexpression while only one of 34 (3%) showed EGFR amplification [68,70]. In another series of 90 malignant astro-cytomas from patients under the age of 19 years, EGFR amplification was observed in eight of 74 evaluable cases (11%), with overexpression by immuno histochemistry in all eight sam-ples [71]. The authors make the argument that their data show a higher incidence due to the use of chromogenic in situ hybridization, which allows concomitant histological evaluation and molecular ana lysis. Nonetheless, all these data support the notion that mutation of EGFR in pediatric malignant astrocytomas is notably less frequent than that seen in the same tumors in the adult population [72]. Similar results have been reported for EGFR expression in differ-ent brainstem tumors, particularly those of the pons, a unique pediatric lesion [69], and have led to plans to optimize the use of EGFR inhibitors against this rapidly fatal disease [73].

While expression of EGFR has been fre-quently reported in malignant gliomas, includ-ing those associated with NF1 [74], targeting this pathway has proven to be more difficult, both in adults and children. For example, small molecule inhibitors of EGFR or antibodies targeting the receptor have been tested as single agents and in combination with radiation and/or chemother-apy [75–78]. To date, reports have demonstrated only limited clinical benefit in both supratento-rial malignant gliomas and in diffuse pontine glioma, although the reason for this remains poorly understood. In the few pilot studies where activity was identified [79], follow-up ana lysis has not replicated these findings.

PDGF receptor-a/bAbnormalities in the PDGF receptor (PDGFR)-a (45%) and -b (31%) signaling pathway have been frequently identified in pediatric malignant gliomas [19,53,80] with an incidence similar to that reported in adults [81]. While overall expression of these pathways can be used to correlate with outcome, the need to consider whether the pathway is activated rather than just present may explain many of the con-flicting results [82]. For brainstem gliomas, an ana lysis of 11 autopsy cases showed copy number alterations distinct from pediatric supratentorial high-grade astrocytomas. Of the DIPGs, 36% had gains in PDGFR-a (PDGFRA; 4–18 copies) and all showed PDGFR-a expression. Low-level gains in PARP-1 were also identified in three cases [83]. In an ana lysis of 20 pediatric cases of pilocytic astrocytoma, PDGFR expression was



localized to the tumor vasculature but not tumor cells. This includes the one patient treated with imatinib that had a near complete response to therapy [84].

PTENPTEN is a known human tumor suppressor gene involved in the regulation of the cell cycle [85]. The protein product of this gene is a phospha-tidylinositol-triphosphate phosphatase which specifically catalyzes the dephosphorylation of PIP3 to PIP2, resulting in inhibition of the Akt signaling pathway [86]. Mutations and/or deletions in this pathway can lead to dysregula-tion of the Akt pathway and have been found in numerous cancer types, including endome-trial cancer, prostate cancer and glioblastoma. PTEN mutations are also seen in the familial Cowden’s syndrome [87], in which patients can have additional predisposition to tumors of the breast and thyroid [88]. Altered expression or loss of PTEN can also be observed in NF1-associated pilocytic astrocytomas [89]. In the adult popula-tion, malignant astrocytomas commonly dem-onstrate mutations or deletions of PTEN, which may make cells more resistant to undergoing cell death in response to conventional or targeted therapies [90,91]. Given the increasing under-standing of molecular differences in adult versus pediatric astrocytomas, a number of groups have looked at differences in PTEN mutations in this population. A number of studies have shown that adult GBMs have rates of PTEN mutation or deletion of at least 50% [62]. Examination of 39 pediatric malignant astrocytomas identified PTEN mutations with increasing frequency by tumor grade (20% in grade 4 [26], 6% in grade 3 [26] and 0% in grade 2 tumors) [72]. When assessed by immunohistochemistry, up to 67% of pediatric high-grade gliomas (HGGs) were positive for PTEN [53]. PTEN mutations were also found to be a negative prognostic indica-tor, concurring with data published at the time in the adult-based literature. In the CCG-945 cohort of 22 GBMs, the frequency of detect-able and potential PTEN mutations (found by sequencing ana lysis, FISH and allelic imbalance ana lysis) was 31.8%, whereas the frequency was 0% in 17 anaplastic astrocytomas. While this ana lysis might be seen to suggest that pediatric levels of PTEN mutation approach that of the adult population, it should be noted that in 62 pediatric GBM samples available for sequenc-ing ana lysis, only one had a detectable muta-tion [70]. Similar results have been reported by others [15,92,93]. Further research in this area

is necessary to confirm or dispel the disparity between pediatric and adult malignant astro-cytomas with regards to PTEN mutations or deletions.

Methylguanine methyltransferaseMost recent treatment protocols that have attempted to use alkylator-based chemother-apy regimens for the treatment of pediatric malignant astrocytoma employ temozolomide. Temozolomide works by alkylating three specific residues on replicating DNA – the O6 position of guanine, the N3 position of adenine and the N7 position of guanine [94]. When the O6 posi-tion of guanine is methylated, the methylgua-nine residue incorrectly pairs with thymidine, and the mismatch repair system is triggered. Activity of this system results in repeated and incorrect reinsertion of thymidine. DNA repli-cation cannot take place, strand breaks occur and eventually apoptosis is signaled. This pro-cess can be overcome by activity of the enzyme methylguanine methyltransferase (MGMT), which stoichiometrically removes the methyl group from the O6 position of guanine and allows proper replication. Work by many groups has shown the presence of MGMT (determined either by gene promoter methylation status or immunohistochemistry) can distinguish a group of patients and tumors with a poorer prognosis [95–97]. Depletion of this enzyme, most nota-bly through the use of the substrate analog O6-benzylguanine has been shown to resensitize the tumor cells to temozolomide both in vitro and in vivo [98–100]. Resistance to temozolomide has also been shown to exist in tumor cells deficient in the DNA mismatch repair system, where tolerance develops to O6-methylguanine and the presence of persistent DNA damage [94].

As with many of the discoveries regarding molecular genetics in malignant astrocytomas, the bulk of the early work on MGMT has been undertaken in adult populations. Of note, work within the past 5 years has been performed on malignant pediatric astrocytomas. In 109 pediatric HGG samples using immunohisto-chemistry, 11% (12 of 109 samples) demon-strated overexpression of MGMT, with higher levels of expression correlating with decreased survival [97]. Another study of ten snap-fro-zen pediatric glioblastoma samples identified MGMT promoter methylation in four samples [101]. Comparing adult and pediatric malignant astrocytomas, Ezaki et al. showed that MGMT expression via immunohistochemistry was sig-nificantly higher in pediatric gliomas, while



other markers of mismatch repair (MSH6) were approximately equal [102]. Further methylation-specific PCR showed a trend toward less frequent methylation (and thus less frequent epigenetic silencing of MGMT ) in pediatric versus adult malignant gliomas. These differences highlight the therapeutic history of temozolomide in the pediatric malignant glioma population. In spite of these differences, temozolomide is routinely used for newly diagnosed adult malignant gli-oma based on improvement in outcome when compared with radiation therapy alone [103]. A recently completed single-arm clinical trial in pediatric patients with HGG showed accept-able results with radiation and temozolomide that appear approximately equivalent to other alkylator-based approaches [104]. Unfortunately, both adult and pediatric patients treated with radiation and temozolomide will eventually suc-cumb to disease. Pontine gliomas that are typi-cally anaplastic astrocytoma or GBM in histol-ogy (often taken at the time of autopsy) achieved no benefit with the addition of temozolomide to radiation therapy [105], a further example of the heterogeneity of GBMs in the pons and s upratentorial compartment.

Isocitrate dehydrogenaseIsocitrate dehydrogenase catalyzes the oxidative decarboxylation of isocitrate to a-ketoglutarate, thereby reducing NADP+ to NADPH. Mutation of the amino acid arginine at position 132 alters the binding site to isocitrate. There is a role in protection of cells from oxidative stress by this enzyme [106].

Mutations in the gene IDHR132H have been the subject of a great deal of investiga-tion in recent literature. In adult tumors, R132 mutations have been identified in a very high percentage of WHO grade 2 and 3 tumors as well as secondary grade 4 tumors (malignant tumors arising from lower-grade precursors) [107]. No association with mutations in TP53 or loss of heterozygosity of 1p/19q [108], as well as an inverse relationship between IDH1 muta-tions and EGFR amplification was observed [109]. Patients with primary GBM and those with anaplastic astrocytoma were significantly younger than patients with wild-type IDH genes [106]. In another ana lysis of 939 tumor samples, 161 mutations at R132 – 88% of which were R132H – were observed [107]. Furthermore, 80% of anaplastic astrocytoma samples assessed had a concurrent mutation of TP53, but only 3% had mutations in a variety of other genes known to promote tumorigenicity including PTEN and

EGFR [107]. This information, including the cor-relation of the R132H mutation with adults of a younger age as well as correlation of R132H mutations with younger age [106] suggests a role of isocitrate dehydrogenase in the early tumori-genicity of lower-grade malignant astrocytomas that transform to higher grade.

Given the information above, pediatric tumor samples were evaluated from the Children’s Oncology Group Study COG ACNS0423 [110]. In seven of 43 tumors, IDH1 mutations were observed and a ‘striking’ correlation was noted with regard to age. Seven of 20 tumors from chil-dren aged ≥14 years possessed mutations, where as none of the tumors in the 23 children younger than 14 years possessed mutations – results that have been observed by others [19]. The presence of mutations correlated with survival compared with the absence of mutations.

Microsatellites, PI3K, HIF2a & chromosomal ana lysis

A number of other molecular analyses have been performed that demonstrate interesting varia-tions between different malignant gliomas in adult and pediatric patients. For example, mic-rosatellite instability, which is common in adult malignant gliomas, was rarely identified in pedi-atric HGG [111]. The p16INK4a protein (which regulates the Rb protein and cell proliferation) via the (Rb)/p16INK4a/CDK4 pathway was eval-uated in 29 pediatric and 107 adult high-grade astrocytomas and demonstrated homozygous deletions for exon 1a and exon 1b in three of 29 (10%) pediatric cases (two grade 3 and one grade 4), 25 of 107 (23%) adult cases (six grade 3 and 19 grade 4), and eight of nine (89%) glioma cell lines [112]. Loss of pRb is rare in pediatric malig-nant gliomas [113]. Diffuse intrinsic pontine glio-mas have recently been shown to express a high rate of PI3K activating mutations [114], similar to that observed in other pediatric and adult HGGs [115]. HIF2a overexpression has also been linked to pediatric malignant gliomas, a pathway that interacts with EGFR signaling and may account for some of the differences observed with respect to EGFR mutation in this population [116].

In spite of the malignant nature of HGGs, chromosomal analyses have shown that large deletions, amplifications and translocations are absent from the majority of pediatric samples and suggest that genomic instability is not the primary driving force [17]. High-resolution 244K oligonucleotide array comparative genomic hybridization from 38 pediatric HGG and diffuse intrinsic pontine glioma demonstrated



patterns of gains and losses that were distinct from those seen in HGG arising in adults. In particular, 1q gain was identified in 27% of a cohort compared with 9% reported in adults while 13% had no large-scale copy number alter-ations. Homozygous loss at 8p12 was seen in six of 38 (16%) cases and was confirmed by quanti-tative real-time PCR (qPCR). Amplification of PDGFRA and MYCN were also observed [80]. Pediatric and adult glioblastomas can also be distinguished by frequent gain of chromosome 1q (30 vs 9%, respectively), lower frequency of chromosome 7 gain (13 vs 74%, respectively) and 10q loss (35 vs 80%, respectively) [19]. A genome-wide ana lysis of DNA copy number aberrations in 33 astrocytic tumors (grade 1–4) demonstrated ≥ten amplifications in the grade 3 and 4 astrocytomas in MDM4 (1q32), PDGFRA (4q12), MET (7q21), CMYC (8q24), PVT1 (8q24), WNT5B (12p13) and IGF1R (15q26) genes. Homozygous deletions of CDKN2A (9p21), PTEN (10q26) and TP53 (17p3.1) were evident in the grade 2–4 tumors. Five out of seven samples with BRAFV600E mutations had concomitant homozygous deletion of CDKN2A [44]. Abnormal Myb expression may also be a ssociated with pediatric low-grade gliomas [117].

Of further interest, recent work has shown a family of alterations in histone 3 protein, which has been implicated in the possible epi-genetic regulation of DNA. The mutations observed were largely confined to pediatric malignant gliomas, both supratentorial GBM and pontine gliomas, and not found in most adult GBMs [118,119]. The clinical significance of these mutations will require further study

to completely elucidate but further support the unique biology of pediatric malignant gliomas compared with similar lesions in adults.

ConclusionThe types and locations of brain tumors in chil-dren are different to those observed in adults. While adults have decades of exposures to a number of environmental toxins, most pediat-ric tumors are likely the result of abnormalities associated with development. Differences in the expression, mutation or regulation of a num-ber of gene or gene products between pediatric and adult gliomas will require an individual-ized approach to understanding the disease in these two populations and o ptimization of therapy (Table 1).

Future perspectiveAs the name implies, GBM can take on a num-ber of different appearances. Many of these different ‘subtypes’ of GBM are now thought to be mediated by the activation of particular pathways that drive the tumors towards certain phenotypes, for example proneuronal versus mesenchymal [81,120]. Not surprisingly, similar heterogeneity in pediatric GBM suggests that, as in adults, these tumors can develop through activation of a number of different aberrant signaling pathways. The important implication of these findings are the need to consider the unique characteristics of each tumor, adult or pediatric, in the development of active treat-ment strategies. While some grouping of cases will be necessary to run clinical trials for the immediate future, we are rapidly reaching the

Table 1. Molecular genetic differences in pediatric and adult malignant astrocytomas.

Pediatric/young adult tumors Older adult tumors

RAS/BRAF Specific mutations (BRAFV600E; BRAFKIAA1549) appear in pediatric low-grade astrocytomas, PXA and gangliogliomas

Significantly less common in similar tumors in the adult population

P53 Overexpression and mutation seen in children >3 years and young adults; possible independent prognostic factor

Less common in elderly patients

EGFR/EGFRvIII Less common in pediatric patients Aberrant expression seen in 40–50% of tumors

PDGFR a/b Abnormalities in signaling pathway observed in 30–45% of malignant gliomas

Similar incidence to that reported in pediatric patients

PTEN Unclear: high incidence seen by immunohistochemistry, mixed picture with sequencing ana lysis

Mutations or deletions common (at least >50%)

MGMT Increased expression and less frequent epigenetic silencing; clinical history of decreased tumor response to alkylators

Lower expression compared with pediatric gliomas; better clinical history of response to alkylator therapy

IDH Less common than in adults; when seen, IDH R132H mutation is most common and found in older pediatric patients

More common in secondary malignant gliomas (younger adults) than primary malignant gliomas (older adults)

Pediatric malignant astrocytomas occur in different locations and with different frequency when compared with adults. Differences in the expression, mutation or regulation of a number of gene products will require an individualized approach within these two populations for optimization of therapy. EGFR: EGF receptor; PDGFR: PDGF receptor; PXA: Pleomorphic xanthoastrocytoma.



era of true personalized medicine, where each patient and each tumor is treated based on the individual characteristics of that particular patient. The heterogeneity reflected in GBM discussed above is also observed in lower-grade gliomas, both between children and adults, and even within different age groups and associated factors (e.g., NF1) in children, suggesting that these principles will be true for other pediatric gliomas, and likely the majority of cancers in general.

Executive summary

�n Significant differences are identified between pediatric and adult gliomas of similar histology.�n Outcome can differ by age; infants with glioblastoma multiforme can do well without radiation therapy, while children and adults do

poorly. Low-grade gliomas in adults tend to transform into high-grade glioma while in pediatrics they rarely do so.�n Mutations can differ by age; IDH1 mutations common in adult low-grade glioma are rare in pediatric low-grade glioma, while

EGF receptor variant III mutations are common in adult high-grade glioma but uncommon in children.�n Response to therapy can differ by age; bevacizumab has very little radiographic effect in children with glioblastoma multiforme but a

good response rate in adult glioblastoma multiforme even though both express VEGF.�n There are a large number of molecular and cytogenetic differences in pediatric malignant gliomas compared with adult malignant

gliomas; for example, EGF receptor variant III, IDH1 and histone 3.�n Temozolomide with radiation therapy is the ‘standard’ for adult and pediatric malignant gliomas but not for pediatric diffuse intrinsic

pontine gliomas.

Financial & competing interests disclosureThe authors have no relevant affiliations or finan-cial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the m anuscript. This includes employment, consultan-cies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

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differences in molecular genetics between pediatric and adult malignant astrocytomas: age matters

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