Changes in gene dosage are a major driver of cancer, engineered from a finite, but increasingly well annotated, repertoire of mutational mechanisms1. This can potentially generate correlated copy number alterations across hundreds of linked genes, as exemplified by the 2% of childhood acute lymphoblastic leukemia (ALL) with recurrent amplification of megabase regions of chromosome 21 (iAMP21)2,3. We used genomic, cytogenetic and transcriptional analysis, coupled with novel bioinformatic approaches, to reconstruct the evolution of iAMP21 ALL. We find that individuals born with the rare constitutional Robertsonian translocation between chromosomes 15 and 21, rob(15;21)(q10;q10)c, have ~2700-fold increased risk of developing iAMP21 ALL compared to the general population. In such cases, amplification is initiated by a chromothripsis event involving both sister chromatids of the Robertsonian chromosome, a novel mechanism for cancer predisposition. In sporadic iAMP21, breakage-fusion-bridge cycles are typically the initiating event, often followed by chromothripsis. In both sporadic and rob(15;21)c-associated iAMP21, the final stages frequently involve duplications of the entire abnormal chromosome. The end-product is a derivative of chromosome 21 or the rob(15;21)c chromosome with gene dosage optimised for leukemic potential, showing constrained copy number levels over multiple linked genes. Thus, dicentric chromosomes may be an important precipitant of chromothripsis, as we show rob(15;21)c to be constitutionally dicentric and breakage-fusion-bridge cycles generate dicentric chromosomes somatically. Furthermore, our data illustrate that several cancer-specific mutational processes, applied sequentially, can co-ordinate to fashion copy number profiles over large genomic scales, incrementally refining the fitness benefits of aggregated gene dosage changes.
Pediatric ependymomas are enigmatic tumors that continue to present a clinical management challenge despite advances in neurosurgery, neuroimaging techniques, and radiation therapy. Difficulty in predicting tumor behavior from clinical and histological factors has shifted the focus to the molecular and cellular biology of ependymoma in order to identify new correlates of disease outcome and novel therapeutic targets. This article reviews our current understanding of pediatric ependymoma biology and includes a meta-analysis of all comparative genomic hybridization (CGH) studies done on primary ependymomas to date, examining more than 300 tumors. From this meta-analysis and a review of the literature, we show that ependymomas in children exhibit a different genomic profile to those in adults and reinforce the evidence that ependymomas from different locations within the central nervous system (CNS) are distinguishable at a genomic level. Potential biological markers of prognosis in pediatric ependymoma are assessed and the ependymoma cancer stem cell hypothesis is highlighted with respect to tumor resistance and recurrence. We also discuss the shifting paradigm for treatment modalities in ependymoma that target molecular alterations in tumor-initiating cell populations. (Mol Cancer Res 2009;7(6):765-86)
The outcome of pediatric ependymomas is difficult to predict based on clinical and histological parameters. To address this issue, we have performed a comparative genomic hybridization screen of 42 primary and 11 recurrent pediatric ependymomas and correlated the genetic findings with clinical outcome. Three distinct genetic patterns were identified in the primary tumors and confirmed by hierarchical cluster analysis. The first group of structural tumors, showed few, mainly partial imbalances (n ؍ 19). A second numerical group showed 13 or more chromosome imbalances with a nonrandom pattern of whole chromosome gains and losses (n ؍ 5). The remaining tumors (n ؍ 18) showed a balanced genetic profile that was significantly associated with a younger age at diagnosis (P < 0.0001), suggesting that ependymomas arising in infants are biologically distinct from those occurring in older children. Multivariate analysis showed that the structural group had a significantly worse outcome compared to tumors with a numerical (P ؍ 0.05) or balanced profile (P ؍ 0.02). Moreover genetic group and extent of surgical resection contributed significantly to outcome whereas histopathology, age, and other clinical parameters did not. We conclude that patterns of genetic imbalances in pediatric intracranial ependymomas may help to predict clinical outcome. Pediatric ependymomas are enigmatic tumors whose behavior is difficult to predict based on clinical and histological factors. These tumors are thought to derive from ependymal cells lining the ventricular system and fall into the broad group of gliomas.1 Ependymomas comprise ϳ10% of all childhood intracranial neoplasms and with Ͼ50% arising in children younger than 5 years of age present a distinct management challenge.2-4 In contrast to adults in which spinal tumors predominate, Ͼ90% of all pediatric ependymomas are intracranial in origin with most tumors arising infratentorially.2,3,5
Detailed analysis of mechanisms of genetic loss for specific tumor suppressor genes (TSGs; e.g., RB1, APC and NF1) indicates that TSG inactivation can occur by allelic loss of heterozygosity (LOH), without any alteration in DNA copy number. However, the role and prevalence of such events in the pathogenesis of specific malignancies remains to be established on a genome-wide basis. We undertook a detailed molecular assessment of chromosomal defects in a panel of nine cell lines derived from primary medulloblastomas, the most common malignant brain tumors of childhood, by parallel genome-wide assessment of LOH (allelotyping) and copy number aberrations (comparative genomic hybridization and fluorescence in situ hybridization). The majority of genetic losses observed were detected by both copy number and LOH methods, indicating they arise through the physical deletion of chromosomal material. However, a significant proportion of losses (17/42, 40%) represented regions of allelic LOH without any associated copy number reduction; these events involved both whole chromosomes (10/17) and sub-chromosomal regions (7/17). Using this approach, we identified medulloblastoma-characteristic alterations, e.g., isochromosome for 17q, MYC amplification and losses on chromosomes 10, 11, and 16, alongside novel regions of genetic loss (e.g., 10q21.1-26.3, 11q24.1-qter). This detailed genetic characterization of the majority of medulloblastoma cell lines provides important precedent for the widespread involvement of copy number-neutral genetic losses in medulloblastoma and demonstrates that combined assessment of copy number aberrations and LOH will be necessary to accurately determine the contribution of chromosomal defects to tumor development.
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