Lack of evidence for mutations or deletions in the CDKN2A/p16 and CDKN2B/p15 genes of Brazilian neuroblastoma patients

Bassi, C.; Martelli, Lúcia Regina; Cipolotti, Rosana; Scrideli, Carlos Alberto; Defavery, Ricardo; Tone, L.G.

doi:10.1590/s0100-879x2004001100014

Cited by 5 publications

(5 citation statements)

References 14 publications

(21 reference statements)

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“…Inactivation of p14 ARF by epigenetic mechanisms can interfere with the p53 pathway, as this increases MDM2 levels, which in turn inactivates p53 (38). Homozygous deletion of p14 ARF was observed in a higher proportion of cases than previous reports (20, 39-42). It is also possible that small deletions in the 9p21 locus, specifically at the exon 1β locus exist, which are being detected by duplex PCR but not other methods.…”

Section: Discussioncontrasting

confidence: 60%

High Frequency of p53/MDM2/p14ARF Pathway Abnormalities in Relapsed Neuroblastoma

Carr-Wilkinson

O'Toole

Wood

et al. 2010

Clinical Cancer Research

147

152

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Purpose: Most neuroblastomas initially respond to therapy but many relapse with chemoresistant disease. p53 mutations are rare in diagnostic neuroblastomas, but we have previously reported inactivation of the p53/MDM2/p14 ARF pathway in 9 of 17 (53%) neuroblastoma cell lines established at relapse. Hypothesis: Inactivation of the p53/MDM2/p14 ARF pathway develops during treatment and contributes to neuroblastoma relapse. Methods: Eighty-four neuroblastomas were studied from 41 patients with relapsed neuroblastoma including 38 paired neuroblastomas at different stages of therapy. p53 mutations were detected by automated sequencing, p14 ARF methylation and deletion by methylation-specific PCR and duplex PCR, respectively, and MDM2 amplification by fluorescent in situ hybridization.Results: Abnormalities in the p53 pathway were identified in 20 of 41 (49%) cases. Downstream defects due to inactivating missense p53 mutations were identified in 6 of 41 (15%) cases, 5 following chemotherapy and/or at relapse and 1 at diagnosis, postchemotherapy, and relapse. The presence of a p53 mutation was independently prognostic for overall survival (hazard ratio, 3.4; 95% confidence interval, 1.2-9.9; P = 0.02). Upstream defects were present in 35% of cases: MDM2 amplification in 3 cases, all at diagnosis and relapse and p14 ARF inactivation in 12 of 41 (29%) cases: 3 had p14 ARF methylation, 2 after chemotherapy, and 9 had homozygous deletions, 8 at diagnosis and relapse. Conclusions: These results show that a high proportion of neuroblastomas which relapse have an abnormality in the p53 pathway. The majority have upstream defects suggesting that agents which reactivate wild-type p53 would be beneficial, in contrast to those with downstream defects in which p53-independent therapies are indicated. Clin Cancer Res; 16(4); 1108-18. ©2010 AACR.Neuroblastoma is the most common extracranial pediatric solid tumor. It remains one of the most difficult cancers to cure, with <40% of patients with high-risk disease (stage 4 over 18 months of age or MYCN-amplified disease) becoming long-term survivors. Most high-risk neuroblastomas initially respond to cytotoxic therapy, however, over half relapse with chemoresistant disease and this often correlates with the intensity of therapy (1).The p53 gene is inactivated by mutation in >50% of human malignancies (2). p53 is a key regulator of cell cycle checkpoints and apoptosis, which upon activation by cellular stress, particularly DNA damage, binds DNA in a sequence-specific manner to activate the transcription of a large number of downstream genes, including p21 and MDM2, which results in apoptosis, cell cycle arrest, differentiation, and DNA repair (reviewed in ref.3). MDM2 functions upstream of p53 as a ubiquitin ligase that targets p53 for proteosome-mediated degradation, forming an autoregulatory feedback loop which tightly regulates p53 cellular levels (4). MDM2 amplification has been shown in some tumors and could suppress the activity of p53 by increasing its degradation.The INK4...

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Section: Discussioncontrasting

confidence: 60%

High Frequency of p53/MDM2/p14ARF Pathway Abnormalities in Relapsed Neuroblastoma

Carr-Wilkinson

O'Toole

Wood

et al. 2010

Clinical Cancer Research

147

152

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“…They used multiplex PCR technique for homozygous deletion analysis and; single-strand conformation polymorphism and nucleotide sequencing for mutation analysis. By these methods they analyzed all exons of both genes, but no deletion was detected [17]. In previous studies hypermethylation of tumor-suppressor genes is found to be related to NB evolution.…”

Section: Discussionmentioning

confidence: 99%

“…Michalowski et al found RASSF1A to be hypermethylated in 100% of cell lines and in 50-90% of tumor specimens. Other genes that were frequently methylated in NBs were CASP8, DcR1, DcR2, genes mainly associated with apoptosis [2].…”

Section: Discussionmentioning

confidence: 99%

“…The best characterized genetic aberration in NB is MYCN amplification, which has been clearly related to prognosis. Several potential tumor-suppressor genes have been described as frequently silenced by hypermethylation in pediatric NB [1][2][3]. These studies indicated that hypermethylation of tumor-suppressor genes is related to NB evolution.…”

Section: Introductionmentioning

confidence: 98%

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Expression and Methylation Pattern of p16 in Neuroblastoma Tumorigenesis

Aktaş

Çelebiler

Zadeoğluları

et al. 2009

Pathol. Oncol. Res.

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Understanding migration, population and differentiation of primordial neural crest cells will help in evolving biology of neuroblastoma. P16 is a tumour suppressor gene contributing in cell cycle arrest as cyclin dependent kinase inhibitor. Methylation is an important mechanism for silencing tumor suppressor genes. The aim of this study was to evaluate the role of p16 and its methylation pattern in neuroblastoma tumorigenesis. This study included 23 cases (11 male; 12 female) and 31 samples from archival paraffin embedded tissues. P16 was studied in 5 samples of normal adrenal medullar tissue, 5 samples of adrenal tissue including blastic rests, 5 samples of neuroblastoma in situ tissue and in 8 samples of neuroblastoma tissues primary and after chemotherapy in each group. The adrenal gland tissues were obtained from paediatric autopsy cases. Expression of p16 was searched by immunohistochemistry. Methylation specific PCR was used to detect the methylation rate of p16. The age range of autopsy cases was between 20 weeks of foetal age and 36 months of infant age. The mean age of neuroblastoma cases was 45 months. P16 expression was positive in normal adrenal tissues, in one of 5 samples of adrenal blastic rest tissue and in all of samples of after chemotherapy; while no expression was observed in neuroblastoma and neuroblastoma in situ tissues. P16 methylation was observed in samples of neuroblastoma in situ and primary neuroblastoma tissues. Our results suggest that p16 and its methylation seems to play role in neuroblastoma tumorigenesis and in the migration, population and differentiation of primordial neural crest cells. Inhibitors of DNA methylation may provide a useful tool for restoring p16 activity in neuroblastoma treatment.

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“…Although research on ALK inhibitors is underway, this research has not led to the discovery of molecular-targeted drugs (12). Mutations in the CDKN2A gene in NB cell lines have led to dramatic reductions in the production of p16 INK4a protein (13,14). Another report confirmed the expression of p16 protein in neuroblastoma cell lines and cited reduction in 12 of 19 cases (63%) (15).…”

Section: Introductionmentioning

confidence: 90%

Molecular targeting of neuroblastoma with a novel p16INK4a transporter system

Kawaguchi

Yoshikawa

Kawamoto³

et al. 2014

International Journal of Oncology

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Abstract. Potential molecular targets in neuroblastoma include ALK mutations, p16 deletion and CDK2A mutations; however, targeted therapeutics have not been developed for these factors. We developed Wr-T, a new system for intracellular peptide and protein delivery with a 30-residue sequence that mediates molecule entrapment and intracellular permeability. Wr-T was used to introduce the p16INK4a functional peptide to restore the tumor suppressor function of p16 INK4a . Introduction of Wr-T into rats with subcutaneous grafts of neuroblastoma produced an astonishing 75.6% tumor suppression (p<0.0005). Thus, the p16INK4a functional peptide can be introduced in low doses and, because it exists in vivo, it should produce fewer side-effects than standard chemotherapy. We suggest this system could be used for molecular-targeted peptides other than p16INK4a and should be pursued for further development. IntroductionNeuroblastomas (NB) are tumors that arise from the embryonic neural crest. In Japan, NBs are the most common childhood malignancy after leukemia and the most common solid malignant tumor in childhood. Differentiation and maturation of tumor cells occurs during the clinical course, and spontaneous tumor regression is sometimes observed. Prognosis differs with age at onset; while the prognosis is favorable for children up to 12 months old, the prognosis is poor for children past the age of 12 months. Three-year overall survival in the high-risk group is >30%, based on the Children's Oncology Group (COG) risk stratification (1).Therapeutic strategies for NB have always been based on risk. For high-risk patients, multidisciplinary treatment is necessary; in addition to surgical resection, treatment includes proactive chemotherapy, high-dose chemotherapy + autologous hematopoietic cell transplantation and radiotherapy (1,2). However, even with these treatments, 3-year progression-free survival is low at 20-40% and new, effective treatments are needed (3-5).In the 1980s, MYCN gene amplification was reported to be a cause of NB (6). MYCN gene amplification, an abnormality observed in ~10% of NB cases, has been closely correlated with NB prognosis (7). However, the development of therapeutic agents targeting this gene is not easy, and no progress is being made. ALK mutations in NB were reported in 2008 (8-11). Although research on ALK inhibitors is underway, this research has not led to the discovery of molecular-targeted drugs (12). Mutations in the CDKN2A gene in NB cell lines have led to dramatic reductions in the production of p16 INK4a protein (13,14). Another report confirmed the expression of p16 protein in neuroblastoma cell lines and cited reduction in 12 of 19 cases (63%) (15). Non-function of the cell cycle shutdown system due to absence of p16INK4a at the G1 checkpoint is also considered a possible cause of NB.Recently, protein transduction domain systems (PTDs) have been garnering attention as an effective and safe system for intracellular drug delivery. PTDs can pass through the membranes of living cell...

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Lack of evidence for mutations or deletions in the CDKN2A/p16 and CDKN2B/p15 genes of Brazilian neuroblastoma patients

Cited by 5 publications

References 14 publications

High Frequency of p53/MDM2/p14ARF Pathway Abnormalities in Relapsed Neuroblastoma

High Frequency of p53/MDM2/p14ARF Pathway Abnormalities in Relapsed Neuroblastoma

Expression and Methylation Pattern of p16 in Neuroblastoma Tumorigenesis

Molecular targeting of neuroblastoma with a novel p16INK4a transporter system

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