Real‐time quantitative PCR analysis of pediatric ependymomas identifies novel candidate genes including TPR at 1q25 and CHIBBY at 22q12‐q13

Abstract

Loss of chromosome 22 and gain of 1q are the most frequent genomic aberrations in ependymomas, indicating that genes mapping to these regions are critical in their pathogenesis. Using real-time quantitative PCR, we measured relative copy numbers of 10 genes mapping to 22q12.3-q13.33 and 10 genes at 1q21-32 in a series of 47 pediatric intracranial ependymomas. Loss of one or more of the genes on 22 was detected in 81% of cases, with RAC2 and C22ORF2 at 22q12-q13.1 being deleted most frequently in 38% and 32% of ependymoma samples, respectively. Combined analysis of quantitative-PCR with methylation-specific PCR and bisulphite sequencing revealed a high rate (>60% ependymoma) of transcriptional inactivation of C22ORF2, indicating its potential importance in the development of pediatric ependymomas. Increase of relative copy numbers of at least one gene on 1q were detected in 61% of cases, with TPR at 1q25 displaying relative copy number gains in 38% of cases. Patient age was identified as a significant adverse prognostic factor, as a significantly shorter overall survival time (P = 0.0056) was observed in patients <2 years of age compared with patients who were >2 years of age. Loss of RAC2 at 22q13 or amplification of TPR at 1q25 was significantly associated with shorter overall survival in these younger patients (P = 0.0492 and P = < 0.0001, respectively). This study identifies candidate target genes within 1q and 22q that are potentially important in the pathogenesis of intracranial pediatric ependymomas.

Genetic expression profiles of adult and pediatric ependymomas: Molecular pathways, prognostic indicators, and therapeutic targets

“…Intracranial ependymomas have also demonstrated hypermethylation of the tumor suppressor gene HIC-1 (17p13.3) in 83% of cases, while such findings were not present in spinal cord ependymomas [4,59,60].…”

Pediatric Ependymoma: Biological Perspectives

“…Reduced expression of other genes within 22q13.1-13.33 has been observed, including CBX7, G22P1, and MCM5, which may be involved in gene silencing, DNA repair, and cell proliferation, respectively (77,148). Real-time quantitative PCR of 47 pediatric intracranial ependymomas revealed frequent loss of C22orf2 and RAC2, the latter being associated with reduced overall survival in the cohort (112).…”

“…These genes and the locus 1q25 merit further investigation with high resolution genomic techniques and gene expression studies that analyze larger numbers of pediatric ependymomas as an independent cohort. These methods could also establish the prognostic role of genes such as NRXN2, TPR, SEMA5, NRCAM, CDK4, and ADRM1 that have already been associated with outcome in small studies of pediatric patients with intracranial ependymoma (83,112), or examine other regions of genomic imbalance potentially harboring markers of disease progression and prognosis in children including the loss of chromosomes 22q and 6q.…”

Chibby1 knockdown promotes mesenchymal-to-epithelial transition-like changes

“…24,25 It has been reported that Cby1 expression is significantly downregulated in chronic myeloid leukemia 26 and pediatric ependymomas. 27 To gain insights into the function of Cby1 in colorectal tumorigenesis, we created Cby1-knockdown (K D ) SW480 clones stably expressing Cby1 small-hairpin (sh) RNAs.…”