Chromosome 1p Status Research Articles

Chromosome 1p status in neuroblastoma correlates with higher expression levels of miRNAs targeting neuronal differentiation pathway.

Neuroblastoma (NB) is characterized by acquired segmental and numerical chromosome aberrations. Although deletions of distal 1p and 11q are frequent alterations, no candidate tumor suppressor gene residing in these chromosomal sites could be identified so far. In the present study, we detected the genomic imbalances of six neuroblastoma cell lines using the multiplex ligation-dependent probe amplification (MLPA) technique and the microRNA (miRNA) expression profiles of the cell lines by a microarray study. According to MLPA results, we aimed to assess the miRNA expression profiles of the cell lines harboring 11q and 1p deletions. The cell lines with 1p deletions revealed statistically significant higher levels of expression for 29 miRNAs in contrast to the cell lines without 1p deletion in microarray study. We also performed GO enrichment analysis for predicted targets of the differentially expressed miRNAs. According to GO enrichment analysis, miRNAs that showed the high change in expression was associated with neuronal differentiation. We showed that hsa-miR-494, hsa-miR-495, and hsa-miR-543 target most of mRNAs in neuronal differentiation pathway. Although limited to the cell lines, our results highly suggest that NBs with different segmental chromosome abnormalities may have different dysregulated miRNA expression signatures that target the genes involved in neuronal differentiation.

Health-related quality of life in patients with high-risk low-grade glioma (EORTC 22033-26033): a randomised, open-label, phase 3 intergroup study

Temozolomide chemotherapy versus radiotherapy in patients with a high-risk low-grade glioma has been shown to have no significant effect on progression-free survival. If these treatments have a different effect on health-related quality of life (HRQOL), it might affect the choice of therapy. We postulated that temozolomide compromises HRQOL and global cognitive functioning to a lesser extent than does radiotherapy. We did a prospective, phase 3, randomised controlled trial at 78 medical centres and large hospitals in 19 countries. We enrolled adult patients (aged ≥18 years) with histologically confirmed diffuse (WHO grade II) astrocytoma, oligodendroglioma, or mixed oligoastrocytoma, with a WHO performance status of 2 or lower, without previous chemotherapy or radiotherapy, who needed active treatment other than surgery. We randomly assigned eligible patients (1:1) using a minimisation technique, stratified by WHO performance status (0-1 vs 2), age (<40 years vs ≥40 years), presence of contrast enhancement on MRI, chromosome 1p status (deleted vs non-deleted vs indeterminate), and the treating medical centre, to receive either radiotherapy (50·4 Gy in 28 fractions of 1·8 Gy for 5 days per week up to 6·5 weeks) or temozolomide chemotherapy (75 mg/m2 daily, for 21 of 28 days [one cycle] for 12 cycles). The primary endpoint was progression-free survival (results published separately); here, we report the results for two key secondary endpoints: HRQOL (assessed using the European Organisation for Research and Treatment of Cancer's [EORTC] QLQ-C30 [version 3] and the EORTC Brain Cancer Module [QLQ-BN20]) and global cognitive functioning (assessed using the Mini-Mental State Examination [MMSE]). We did analyses on the intention-to-treat population. This study is closed and is registered at EudraCT, number 2004-002714-11, and at ClinicalTrials.gov, number NCT00182819. Between Dec 6, 2005, and Dec 21, 2012, we randomly assigned 477 eligible patients to either radiotherapy (n=240) or temozolomide chemotherapy (n=237). The difference in HRQOL between the two treatment groups was not significant during the 36 months' follow-up (mean between group difference [averaged over all timepoints] 0·06, 95% CI -4·64 to 4·75, p=0·98). At baseline, 32 (13%) of 239 patients who received radiotherapy and 32 (14%) of 236 patients who received temozolomide chemotherapy had impaired cognitive function, according to the MMSE scores. After randomisation, five (8%) of 63 patients who received radiotherapy and three (6%) of 54 patients who received temozolomide chemotherapy and who could be followed up for 36 months had impaired cognitive function, according to the MMSE scores. No significant difference was recorded between the groups for the change in MMSE scores during the 36 months of follow-up. The effect of temozolomide chemotherapy or radiotherapy on HRQOL or global cognitive functioning did not differ in patients with low-grade glioma. These results do not support the choice of temozolomide alone over radiotherapy alone in patients with high-risk low-grade glioma. Merck Sharp & Dohme-Merck & Co, National Cancer Institute, Swiss Cancer League, National Institute for Health Research, Cancer Research UK, Canadian Cancer Society Research Institute, National Health and Medical Research Council, European Organisation for Research and Treatment of Cancer Cancer Research Fund.

Tumours arising in the setting of paediatric chronic epilepsy

Along with malformations of cortical development or cortical dysplasia, hippocampal sclerosis, and remote ischaemic damage, tumours are among the more commonly identifiable causes of medically intractable seizures in paediatric age patients. This study reviews one institution's 20 year experience with tumours arising in this clinical setting. Retrospective review of 129 paediatric patients [less than 19 years of age, 65 females (50.4%)] with tumours and medically intractable seizures encountered during a 20 year period of time (1989-2009). Using the most recent World Health Organization (WHO) classification of brain tumours, tumour type and grade were assessed. The most common sites of origin included temporal lobe (n = 77, 59.7%), parietal lobe (n = 20, 15.5%), and frontal lobe (n = 15, 11.6%). WHO grade included 73 (56.6%) grade I tumours, 32 (24.8%) grade II tumours, and 18 (14%) grade I/II tumours. In six cases (4.7%), a WHO grade was not associated with mass. Tumour types included: ganglioglioma (n = 48, 37.2%), dysembryoplastic neuroepithelial tumour (n = 17, 13.2%), low grade astrocytoma (n = 15, 11.6%), low grade mixed glioma (n = 8, 6.2%), low grade oligodendroglioma (n = 5, 3.9%), meningioangiomatosis (n = 4, 3.1%) angiocentric glioma (n = 3, 2.3%), and dysembryoplastic neuroepithelial tumour/ganglioglioma composite tumour (n = 3, 2.3%). Less frequently observed lesions (n = 1 or 2) included pilocytic astrocytoma, protoplasmic astrocytoma, pleomorphic xanthoastrocytoma, and glioneuronal hamartoma. In 18 cases, distinction between low grade glioma and low grade glioneuronal tumour could not be definitively made. Coexisting malformation of cortical development/cortical dysplasia was noted in 29.8% of evaluable cases. In four tumours, coexistent hippocampal sclerosis was identified. Ki-67 labelling indices were less than 5% in all (n = 51) cases assessed. Of 25 tumours evaluated for chromosome 1p status, only one low grade mixed glioma demonstrated evidence of deletion; only one of 22 evaluated tumours (a low grade mixed glioma) showed evidence of chromosome 19q deletion. Collectively, WHO grade I glioneuronal tumours account for slightly more than half of all neoplasms which cause intractable epilepsy in paediatric patients. A significant minority of tumours (n = 18, 14%) were difficult to definitively classify as glioma versus glioneuronal tumour, due to extent of sampling. Coexistent pathologies including malformation of cortical development/cortical dysplasia may be observed in a significant minority of tumours, suggesting a possible developmental origin for some tumours arising in this setting.

Impact of chromosome 1p status in response of oligodendroglioma to temozolomide: preliminary results.

In this IRB-approved retrospective study, we analyzed the efficacy of temozolomide on World Health Organization Grade II and III oligodendrogliomas, as well as mixed oligoastrocytomas, to determine if a correlation exists between the tumors' 1p status and control of growth by this new oral agent. We assessed six patients with oligodendrogliomas with 1p intact (38%) and 10 patients with 1p loss (62%), who received temozolomide. Chromosome 1p status was significantly associated with response to treatment using temozolomide. While nine of 10 patients (90%) with 1p loss responded to temozolomide, only two of six patients (33%) with 1p intact benefited from this treatment (p = 0.04). Although the number of patients evaluated was small, there was no association between 1p status and gender, age, and tumor grade. Gender, age, and tumor grade were similarly not correlated with response to chemotherapy. This report is the first to find that patients harboring oligodendrogliomas with 1p loss are more likely to be sensitive to treatment with temozolomide than those that retain this chromosomal element. Larger prospective trials are needed to confirm these findings; however, temozolomide should be considered in the management of these tumors.

Chromosome 1p allelic loss by fluorescence in situ hybridization is not observed in dysembryoplastic neuroepithelial tumors.

Differentiation of dysembryoplastic neuroepithelial tumor (DNT) from cystic low-grade oligodendroglioma, particularly in a limited biopsy orfragmented specimen, may be impossible. Research has shown that allelic loss of chromosome 1p is a relatively common finding in oligodendrogliomas. Little is known about chromosome 1p status in DNT. We retrospectively evaluated 14 DNTs for loss of heterozygosity (LOH) on chromosome 1p by fluorescence in situ hybridization (FISH) and compared the results with 1p FISH analysis in 57 low-grade oligodendrogliomas (World Health Organization grade II). The 14 DNTs arose in 8 females and 6 males (mean age, 20.9 years at the time of surgery). All 14 DNTs were 1p intact by FISH analysis. The 57 low-grade oligodendrogliomas arose in 31 males and 26 females (mean age, 43.2 years). LOH on chromosome 1p was present in 31 (54%) of 57 tumors; the remaining 26 tumors were 1p intact. LOH on chromosome 1p is not a feature of DNTs. LOH on chromosome 1p may be a useful differential diagnostic feature (favoring oligodendroglioma) in a subset of cases in which specimen fragmentation or size raises the differential diagnosis of DNT vs oligodendroglioma.

Allelic loss of chromosome 1p and radiotherapy plus chemotherapy in patients with oligodendrogliomas

Introduction: Allelic loss of the short arm of chromosome 1 predicts radiographic response to chemotherapy and long overall survival times in patients with anaplastic oligodendrogliomas. Using a database of patients with oligodendrogliomas in whom chromosome 1p status was known, we explored whether allelic loss of 1p also predicted longer duration of tumor control when radiotherapy was part of the initial treatment of these patients. Materials and Methods: We measured progression-free survival following radiotherapy in a cohort of patients with World Health Organization (WHO) Grade II and WHO Grade III oligodendrogliomas. The effects on progression-free survival of patient age, Karnofsky performance score (KPS), tumor grade when irradiated and chromosome 1p status were examined by univariate and multivariate statistical analyses. For the subset of patients with newly diagnosed anaplastic oligodendrogliomas, relationships between use of chemotherapy, chromosome 1p status and progression-free survival were also examined. Results: Fifty-five patients (29 male, 26 female; ages 18–75 years; median, 44 years; KPS 50–90, median 80) were irradiated for either a WHO Grade II ( n = 19) or Grade III ( n = 36) oligodendroglioma. Twenty-eight patients had chemotherapy immediately prior to radiotherapy, and 27 had chemotherapy at progression following radiotherapy. The median radiation dose was 54 Gy in 30 fractions. Loss of heterozygosity (LOH) at chromosome 1p was evident in 36 tumors and absent in 19. Overall median progression-free survival after radiotherapy was 40.4 months. Median progression-free survival was 55.0 months for patients whose tumors harbored 1p loss vs. 6.2 months for those patients whose tumors retained both copies of chromosome 1p ( p < 0.001). On both univariate and multivariate analyses, chromosome lp loss was the principal independent predictor of longer progression-free survival for patients with Grade II and III oligodendrogliomas. For Grade III oligodendrogliomas, chemotherapy as an adjunct to radiotherapy prolonged tumor control for those patients whose tumors harbored allelic loss of chromosome 1p ( p = 0.004). Conclusion: These data suggest allelic loss of chromosome 1p in patients with oligodendroglial neoplasms predicts longer progression-free survival among patients receiving radiotherapy ± chemotherapy as part of their initial treatment. Chromosome 1p loss may be an important stratification variable in future therapeutic trials of oligodendroglioma.

O-11-175 - Clinical features of gliomas involving the corpus callosum

Along with malformations of cortical development or cortical dysplasia, hippocampal sclerosis, and remote ischaemic damage, tumours are among the more commonly identifiable causes of medically intractable seizures in paediatric age patients. This study reviews one institution’s 20 year experience with tumours arising in this clinical setting.Retrospective review of 129 paediatric patients [less than 19 years of age, 65 females (50.4%)] with tumours and medically intractable seizures encountered during a 20 year period of time (1989–2009). Using the most recent World Health Organization (WHO) classification of brain tumours, tumour type and grade were assessed.The most common sites of origin included temporal lobe (n = 77, 59.7%), parietal lobe (n = 20, 15.5%), and frontal lobe (n = 15, 11.6%). WHO grade included 73 (56.6%) grade I tumours, 32 (24.8%) grade II tumours, and 18 (14%) grade I/II tumours. In six cases (4.7%), a WHO grade was not associated with mass. Tumour types included: ganglioglioma (n = 48, 37.2%), dysembryoplastic neuroepithelial tumour (n = 17, 13.2%), low grade astrocytoma (n = 15, 11.6%), low grade mixed glioma (n = 8, 6.2%), low grade oligodendroglioma (n = 5, 3.9%), meningioangiomatosis (n = 4, 3.1%) angiocentric glioma (n = 3, 2.3%), and dysembryoplastic neuroepithelial tumour/ganglioglioma composite tumour (n = 3, 2.3%). Less frequently observed lesions (n = 1 or 2) included pilocytic astrocytoma, protoplasmic astrocytoma, pleomorphic xanthoastrocytoma, and glioneuronal hamartoma. In 18 cases, distinction between low grade glioma and low grade glioneuronal tumour could not be definitively made. Coexisting malformation of cortical development/cortical dysplasia was noted in 29.8% of evaluable cases. In four tumours, coexistent hippocampal sclerosis was identified. Ki-67 labelling indices were less than 5% in all (n = 51) cases assessed. Of 25 tumours evaluated for chromosome 1p status, only one low grade mixed glioma demonstrated evidence of deletion; only one of 22 evaluated tumours (a low grade mixed glioma) showed evidence of chromosome 19q deletion.Collectively, WHO grade I glioneuronal tumours account for slightly more than half of all neoplasms which cause intractable epilepsy in paediatric patients. A significant minority of tumours (n = 18, 14%) were difficult to definitively classify as glioma versus glioneuronal tumour, due to extent of sampling. Coexistent pathologies including malformation of cortical development/cortical dysplasia may be observed in a significant minority of tumours, suggesting a possible developmental origin for some tumours arising in this setting.