Clustering of gene hypermethylation associated with clinical risk groups in neuroblastoma Journal Article
| Authors: | Alaminos, M.; Dávalos, V.; Cheung, N. K. V.; Gerald, W. L.; Esteller, M. |
| Article Title: | Clustering of gene hypermethylation associated with clinical risk groups in neuroblastoma |
| Abstract: | Background: Neuroblastoma is the most common extracranial solid malignancy in infancy and childhood, but the biological factors involved in its development and progression are still unclear. Transcriptional silencing of tumor suppressor genes mediated by hypermethylation of promoter CpG islands is a hallmark of human tumors. We addressed the clinical relevance of promoter hypermethylation in neuroblastoma. Methods: We examined the methylation status of 45 candidate genes representative of many cellular pathways in 10 neuroblastoma cell lines and of 10 of these genes in 145 tumor samples (118 of them were primary neuroblastomas). We used Fisher's exact test to examine the association of CpG island methylation and clinical subgroups and Kaplan-Meier analysis to determine the association between methylation and survival in primary tumors. Cluster analysis was used to group cell lines and tumors by gene methylation status. Bonferroni-corrected statistical tests were two-sided. Results: Clustering of neuroblastoma cell lines on the basis of hypermethylation distinguished lines with MYCN amplification (a negative prognostic factor) from those without it (P = .012). Promoter hypermethylation of the developmental gene HOXA9 was associated with mortality in noninfant patients (P = .04) and in tumors lacking MYCN amplification (P = .023). Hypermethylation of the proapoptotic gene TMS1 and the cell cycle gene CCND2 was associated with stage 4-progressing tumors (P<.001), but the genes were never methylated in stage 4S tumors, which undergo spontaneous regression. Hypermethylation of the differentiation gene RARβ2 was associated with patient survival (P = .032). Unsupervised hierarchical cluster analysis of all tumors based on methylation of the 10 genes separated several clinically relevant groups of tumors. Conclusions: Profiling the status of CpG island hypermethylation in human primary neuroblastomas may have clinicopathologic value. © Oxford University Press 2004, all rights reserved. |
| Keywords: | cancer survival; child; unclassified drug; oncoprotein; human cell; major clinical study; promoter region; genetics; cancer risk; cancer staging; cell cycle protein; metabolism; cluster analysis; gene amplification; nuclear protein; risk factors; gene product; cancer cell culture; tumor regression; pathology; cell line, tumor; dna methylation; risk factor; cancer mortality; risk assessment; nuclear proteins; gene expression regulation; gene expression regulation, neoplastic; dna; infant; neuroblastoma; neuroblastoma cell; cpg island; cpg islands; oncogene proteins; tumor cell line; dna, neoplasm; transforming growth factor beta1; androgen receptor; tumor necrosis factor receptor; caspase 8; gene silencing; methylated dna protein cysteine methyltransferase; kaplan meier method; homeodomain protein; cell clone; progesterone receptor; cadherin; zinc finger protein; clone cells; genetic marker; genetic markers; protein mycn; tissue inhibitor of metalloproteinase 2; tissue inhibitor of metalloproteinase 3; multigene family; mycn protein, human; cyclin d2; retinoic acid receptor beta; retinoic acid receptor beta2; chemokine receptor cxcr4; dipeptidyl peptidase iv; promoter regions (genetics); protein p14arf; death associated protein kinase; catechol methyltransferase; humans; prognosis; human; priority journal; article; fragile histidine triad protein; homeodomain a9 protein; protein tms1; retinol binding protein; thromboxane a2 receptor; transcription factor runx3 |
| Journal Title: | JNCI: Journal of the National Cancer Institute |
| Volume: | 96 |
| Issue: | 16 |
| ISSN: | 0027-8874 |
| Publisher: | Oxford University Press |
| Date Published: | 2004-08-18 |
| Start Page: | 1208 |
| End Page: | 1219 |
| Language: | English |
| DOI: | 10.1093/jnci/djh224 |
| PROVIDER: | scopus |
| PUBMED: | 15316056 |
| DOI/URL: | |
| Notes: | J. Natl. Cancer Inst. -- Cited By (since 1996):76 -- Export Date: 16 June 2014 -- CODEN: JNCIA -- Source: Scopus |
Altmetric
Citation Impact
BMJ Impact Analytics
Related MSK Work