Association of epigenetic inactivation of RASSF1A with poor outcome in human neuroblastoma

Qiwei Yang, Peter Zage, David Kagan, Yufeng Tian, Roopa Seshadri, Helen R. Salwen, Shuqing Liu, Alexandre Chlenski, Susan L. Cohn

Research output: Contribution to journalArticle

74 Citations (Scopus)

Abstract

Purpose: To investigate the prevalence and potential clinical significance of epigenetic aberrations in neuroblastoma (NB). Experimental Design: The methylation status of 11 genes that are frequently epigenetically inactivated in adult cancers was assayed in 13 NB cell lines. The prevalence of RASSF1A and TSP-1 methylation was also analyzed in 56 NBs and 5 ganglioneuromas by methylation-specific PCR. Associations between the methylation status of RASSF1A and TSP-1 and patient age, tumor stage, tumor MYCN status, and patient survival were evaluated. Results: Epigenetic changes were detected in all 13 NB cell lines, although the pattern of gene methylation varied. The putative tumor suppressor gene RASSF1A was methylated in all 13 cell lines, and TSP-1 and CASP8 were methylated in 11 of 13 cell lines. Epigenetic changes of DAPK and FAS were detected in only small numbers of cell lines, whereas none of the cell lines had methylation of p 16, p21, p73, RAR-β2, SPARC, or T1MP-3. RASSF1A was also methylated in 70% of the primary NB tumors tested, and TSP-1 methylation was detected in 55% of the tumors. RASSF1A methylation was significantly associated with age >1 year (P < 0.01), high-risk disease (P < 0.016), and poor survival (P < 0.001). In contrast, no association between TSP-1 methylation and prognostic factors or survival was observed. Conclusions: Our results suggest that epigenetic inactivation of RASSF1A may contribute to the clinically aggressive phenotype of high-risk NB.

Original languageEnglish (US)
Pages (from-to)8493-8500
Number of pages8
JournalClinical Cancer Research
Volume10
Issue number24
DOIs
StatePublished - Dec 15 2004

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Neuroblastoma
Epigenomics
Methylation
Thrombospondin 1
Cell Line
Neoplasms
Survival
Ganglioneuroma
Tumor Suppressor Genes
Genes
Research Design
Phenotype
Polymerase Chain Reaction

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Yang, Q., Zage, P., Kagan, D., Tian, Y., Seshadri, R., Salwen, H. R., ... Cohn, S. L. (2004). Association of epigenetic inactivation of RASSF1A with poor outcome in human neuroblastoma. Clinical Cancer Research, 10(24), 8493-8500. https://doi.org/10.1158/1078-0432.CCR-04-1331

Association of epigenetic inactivation of RASSF1A with poor outcome in human neuroblastoma. / Yang, Qiwei; Zage, Peter; Kagan, David; Tian, Yufeng; Seshadri, Roopa; Salwen, Helen R.; Liu, Shuqing; Chlenski, Alexandre; Cohn, Susan L.

In: Clinical Cancer Research, Vol. 10, No. 24, 15.12.2004, p. 8493-8500.

Research output: Contribution to journalArticle

Yang, Q, Zage, P, Kagan, D, Tian, Y, Seshadri, R, Salwen, HR, Liu, S, Chlenski, A & Cohn, SL 2004, 'Association of epigenetic inactivation of RASSF1A with poor outcome in human neuroblastoma', Clinical Cancer Research, vol. 10, no. 24, pp. 8493-8500. https://doi.org/10.1158/1078-0432.CCR-04-1331
Yang, Qiwei ; Zage, Peter ; Kagan, David ; Tian, Yufeng ; Seshadri, Roopa ; Salwen, Helen R. ; Liu, Shuqing ; Chlenski, Alexandre ; Cohn, Susan L. / Association of epigenetic inactivation of RASSF1A with poor outcome in human neuroblastoma. In: Clinical Cancer Research. 2004 ; Vol. 10, No. 24. pp. 8493-8500.
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AU - Yang, Qiwei

AU - Zage, Peter

AU - Kagan, David

AU - Tian, Yufeng

AU - Seshadri, Roopa

AU - Salwen, Helen R.

AU - Liu, Shuqing

AU - Chlenski, Alexandre

AU - Cohn, Susan L.

PY - 2004/12/15

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N2 - Purpose: To investigate the prevalence and potential clinical significance of epigenetic aberrations in neuroblastoma (NB). Experimental Design: The methylation status of 11 genes that are frequently epigenetically inactivated in adult cancers was assayed in 13 NB cell lines. The prevalence of RASSF1A and TSP-1 methylation was also analyzed in 56 NBs and 5 ganglioneuromas by methylation-specific PCR. Associations between the methylation status of RASSF1A and TSP-1 and patient age, tumor stage, tumor MYCN status, and patient survival were evaluated. Results: Epigenetic changes were detected in all 13 NB cell lines, although the pattern of gene methylation varied. The putative tumor suppressor gene RASSF1A was methylated in all 13 cell lines, and TSP-1 and CASP8 were methylated in 11 of 13 cell lines. Epigenetic changes of DAPK and FAS were detected in only small numbers of cell lines, whereas none of the cell lines had methylation of p 16, p21, p73, RAR-β2, SPARC, or T1MP-3. RASSF1A was also methylated in 70% of the primary NB tumors tested, and TSP-1 methylation was detected in 55% of the tumors. RASSF1A methylation was significantly associated with age >1 year (P < 0.01), high-risk disease (P < 0.016), and poor survival (P < 0.001). In contrast, no association between TSP-1 methylation and prognostic factors or survival was observed. Conclusions: Our results suggest that epigenetic inactivation of RASSF1A may contribute to the clinically aggressive phenotype of high-risk NB.

AB - Purpose: To investigate the prevalence and potential clinical significance of epigenetic aberrations in neuroblastoma (NB). Experimental Design: The methylation status of 11 genes that are frequently epigenetically inactivated in adult cancers was assayed in 13 NB cell lines. The prevalence of RASSF1A and TSP-1 methylation was also analyzed in 56 NBs and 5 ganglioneuromas by methylation-specific PCR. Associations between the methylation status of RASSF1A and TSP-1 and patient age, tumor stage, tumor MYCN status, and patient survival were evaluated. Results: Epigenetic changes were detected in all 13 NB cell lines, although the pattern of gene methylation varied. The putative tumor suppressor gene RASSF1A was methylated in all 13 cell lines, and TSP-1 and CASP8 were methylated in 11 of 13 cell lines. Epigenetic changes of DAPK and FAS were detected in only small numbers of cell lines, whereas none of the cell lines had methylation of p 16, p21, p73, RAR-β2, SPARC, or T1MP-3. RASSF1A was also methylated in 70% of the primary NB tumors tested, and TSP-1 methylation was detected in 55% of the tumors. RASSF1A methylation was significantly associated with age >1 year (P < 0.01), high-risk disease (P < 0.016), and poor survival (P < 0.001). In contrast, no association between TSP-1 methylation and prognostic factors or survival was observed. Conclusions: Our results suggest that epigenetic inactivation of RASSF1A may contribute to the clinically aggressive phenotype of high-risk NB.

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