Cytogenetics in pediatric low‐grade astrocytomas

Orr, Lesley C; Fleitz, Julie; McGavran, Loris; Wyatt-Ashmead, Josephine; Handler, Michael; Foreman, Nicholas

doi:10.1002/mpo.1305

Cited by 32 publications

(15 citation statements)

References 24 publications

(32 reference statements)

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“…In agreement with findings in previous studies (Neumann et al, 1993;Agamanolis and Malone 1995;Roberts et al, 2001;Orr et al, 2002), the PAs and (Deshmukh et al, 2008;Jones et al, 2008;Pfister et al, 2008;Jacob et al, 2009). As it was present in both infratentorial and supratentorial PAs, the gain does not seem to be specific for tumours of a given anatomic location.…”

Section: Genome-wide Array Comparative Genomic Hybridisation (Acgh)supporting

confidence: 92%

Genomic aberrations in 80 cases of primary glioblastoma multiforme: Pathogenetic heterogeneity and putative cytogenetic pathways

Dahlback

Brandal

Meling

et al. 2009

Genes Chromosomes & Cancer

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Screening the whole glioblastoma multiforme (GBM) genome for aberrations is a good starting point when looking for molecular markers that could potentially stratify patients according to prognosis and optimal treatment. We investigated 80 primary untreated GBM using both G‐banding analysis and high‐resolution comparative genomic hybridization (HR‐CGH). Abnormal karyotypes were found in 83% of the tumors. The most common numerical chromosome aberrations were +7, −10, −13, −14, −15, +20, and −22. Structural abnormalities most commonly involved chromosomes 1 and 3, and the short arm of chromosome 9. HR‐CGH verified these findings and revealed additional frequent losses at 1p34‐36, 6q22‐27, and 19q12‐13 and gains of 3q26 and 12q13‐15. Although most karyotypes and gain/loss patterns were complex, there was also a distinct subset of tumors displaying simple karyotypic changes only. There was a statistically significant association between trisomy 7 and monosomy 10, and also between +7/−10 as putative primary aberrations and secondary losses of 1p, 9p, 13q, and 22q. The low number of tumors in the rarer histological tumor subgroups precludes definite conclusions, but there did not seem to be any clear‐cut cytogenetic‐pathological correlations, perhaps with the exception of ring chromosomes in giant cell glioblastomas. Our findings demonstrate that although GBM is a pathogenetically very heterogeneous group of diseases, distinct genomic aberration patterns exist. © 2009 Wiley‐Liss, Inc.

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Section: Genome-wide Array Comparative Genomic Hybridisation (Acgh)supporting

confidence: 92%

Genomic aberrations in 80 cases of primary glioblastoma multiforme: Pathogenetic heterogeneity and putative cytogenetic pathways

Dahlback

Brandal

Meling

et al. 2009

Genes Chromosomes & Cancer

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“…114 Most of these low-grade gliomas in children also show no significant change in copy number and have normal karyotypes, [115][116][117] but one consistent finding between studies was the identification of trisomy of chromosome 5 and 7 or gains of 1q. [117][118][119] The mitogen-activated protein kinase pathway activation in low-grade gliomas has been described in several studies and recently linked to duplication of the BRAF gene locus.…”

Section: Future Directions For Low-grade Gliomasmentioning

confidence: 98%

Pediatric Brain Tumors: Current Treatment Strategies and Future Therapeutic Approaches

2009

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Summary:Pediatric CNS tumors are the most common solid tumors of childhood and the second most common cancer after hematological malignancies accounting for approximate 20 to 25% of all primary pediatric tumors. With over 3,000 new cases per year in the United States, childhood CNS tumors are the leading cause of death related to cancer in this population. The prognosis for these patients has improved over the last few decades, but current therapies continue to carry a high risk of significant side effects, especially for the very young. Currently a combination of surgery, radiation, and chemotherapy is often used in children greater than 3 years of age. This article will outline current and future therapeutic strategies for the most common pediatric CNS tumors, including primitive neuroectodermal tumors such as medulloblastoma, as well as astrocytomas and ependymomas.

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“…Interestingly, diffuse astrocytomas in children show malignant transformation in only around 10% of cases (2), while the majority (60%-70%) of these tumors in adults eventually progress to anaplastic astrocytoma or secondary glioblastoma (1,3). In addition to the WHO grade, the prognosis of low-grade astrocytoma patients depends on the tumor localization, with survival being particularly poor for diffuse brain stem astrocytomas (4). The usual first-line treatment of pilocytic and diffuse astrocytomas consists of surgical resection.…”

Section: Introductionmentioning

confidence: 99%

“…Genetic alterations frequently observed in adult anaplastic astrocytomas and/or glioblastomas, such as mutations of TP53 or PTEN, homozygous deletion of CDKN2A, amplification of CDK4 or EGFR, and losses of chromosome 10, are only rarely encountered in pediatric pilocytic and low-grade diffuse astrocytomas (5). Previous studies investigating copy number changes in these tumors have shown normal karyotypes in the vast majority of cases (4,6). Analyses of copy number changes in a total of more than 160 cases examined in different studies employing a variety of technologies revealed only a few consistent findings.…”

Section: Introductionmentioning

confidence: 99%

BRAF gene duplication constitutes a mechanism of MAPK pathway activation in low-grade astrocytomas

et al. 2008

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The molecular pathogenesis of pediatric astrocytomas is still poorly understood. To further understand the genetic abnormalities associated with these tumors, we performed a genome-wide analysis of DNA copy number aberrations in pediatric low-grade astrocytomas by using array-based comparative genomic hybridization. Duplication of the BRAF protooncogene was the most frequent genomic aberration, and tumors with BRAF duplication showed significantly increased mRNA levels of BRAF and a downstream target, CCND1, as compared with tumors without duplication. Furthermore, denaturing HPLC showed that activating BRAF mutations were detected in some of the tumors without BRAF duplication. Similarly, a marked proportion of low-grade astrocytomas from adult patients also had BRAF duplication. Both the stable silencing of BRAF through shRNA lentiviral transduction and pharmacological inhibition of MEK1/2, the immediate downstream phosphorylation target of BRAF, blocked the proliferation and arrested the growth of cultured tumor cells derived from low-grade gliomas. Our findings implicate aberrant activation of the MAPK pathway due to gene duplication or mutation of BRAF as a molecular mechanism of pathogenesis in low-grade astrocytomas and suggest inhibition of the MAPK pathway as a potential treatment.

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Cytogenetics in pediatric low‐grade astrocytomas

Abstract: It appears unlikely that, for children with LGA, those with normal cytogenetics have a better prognosis than those with abnormal. Histologic grade is a better predictor of outcome than cytogenetics.

Cited by 32 publications

References 24 publications

Genomic aberrations in 80 cases of primary glioblastoma multiforme: Pathogenetic heterogeneity and putative cytogenetic pathways

Genomic aberrations in 80 cases of primary glioblastoma multiforme: Pathogenetic heterogeneity and putative cytogenetic pathways

Pediatric Brain Tumors: Current Treatment Strategies and Future Therapeutic Approaches

BRAF gene duplication constitutes a mechanism of MAPK pathway activation in low-grade astrocytomas

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