Hypermethylation of 18S and 28S ribosomal DNAs predicts progression-free survival in patients with ovarian cancer

Michael W Y Chan, Susan H. Wei, Ping Wen, Zailong Wang, Daniela Matei, Joseph C. Liu, Sandya Liyanarachchi, Robert Brown, Kenneth Nephew, Pearlly S. Yan, Tim H M Huang

Research output: Contribution to journalArticle

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Abstract

Purpose: Repetitive ribosomal DNA (rDNA) genes are GC-rich clusters in the human genome. The aim of the study was to determine the methylation status of two rDNA subunits, the 18S and 28S genes, in ovarian tumors and to correlate methylation levels with clinicopathologic features in a cohort of ovarian cancer patients. Experimental Design: 18S and 28S rDNA methylation was examined by quantitative methylation-specific PCR in 74 late-stage ovarian cancers, 9 histologically uninvolved, and 11 normal ovarian surface epithelial samples. In addition, methylation and gene expression levels of 18S and 28S rDNAs in two ovarian cancer cell tines were examined by reverse transcription-PCR before and after treatment with the demethytating drug 5′-aza-2′-deoxycvtidine. Results: The methylation level (amount of methylated rDNA/β-actin) of 18S and 28S rDNAs was significantly higher (P < 0.05) in tumors than in normal ovarian surface epithelial samples. Methylation of 18S and 28S rDNA was highly correlated (R2 = 0.842). Multivariate analysis by Cox regression found that rDNA hypermethylation [hazard ratio (HR), 0.25; P < 0.01], but not age (HR, 1.29; P = 0.291) and stage (HR, 1.09; P = 0.709), was independently associated with longer progression-free survival. In ovarian cancer cell fines, methylation levels of rDNA correlated with gene down-regulation and 5′-aza-2′-deoxycytidine treatment resulted in a moderate increase in 18S and 28S rDNA gene expressions. Conclusion: This is the first report of rDNA hypermethylation in ovarian tumors. Furthermore, rDNA methylation levels were higher in patients with long progression-free survival versus patients with short survival. Thus, rDNA methylation as a prognostic marker in ovarian cancer warrants further investigation.

Original languageEnglish
Pages (from-to)7376-7383
Number of pages8
JournalClinical Cancer Research
Volume11
Issue number20
DOIs
StatePublished - Oct 15 2005

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Ribosomal DNA
Ovarian Neoplasms
Disease-Free Survival
Methylation
DNA Methylation
decitabine
Genes
Gene Expression
Ribosome Subunits
Neoplasms
Polymerase Chain Reaction
Human Genome
Reverse Transcription
Actins
Research Design
Down-Regulation
Multivariate Analysis

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Hypermethylation of 18S and 28S ribosomal DNAs predicts progression-free survival in patients with ovarian cancer. / Chan, Michael W Y; Wei, Susan H.; Wen, Ping; Wang, Zailong; Matei, Daniela; Liu, Joseph C.; Liyanarachchi, Sandya; Brown, Robert; Nephew, Kenneth; Yan, Pearlly S.; Huang, Tim H M.

In: Clinical Cancer Research, Vol. 11, No. 20, 15.10.2005, p. 7376-7383.

Research output: Contribution to journalArticle

Chan, MWY, Wei, SH, Wen, P, Wang, Z, Matei, D, Liu, JC, Liyanarachchi, S, Brown, R, Nephew, K, Yan, PS & Huang, THM 2005, 'Hypermethylation of 18S and 28S ribosomal DNAs predicts progression-free survival in patients with ovarian cancer', Clinical Cancer Research, vol. 11, no. 20, pp. 7376-7383. https://doi.org/10.1158/1078-0432.CCR-05-1100
Chan, Michael W Y ; Wei, Susan H. ; Wen, Ping ; Wang, Zailong ; Matei, Daniela ; Liu, Joseph C. ; Liyanarachchi, Sandya ; Brown, Robert ; Nephew, Kenneth ; Yan, Pearlly S. ; Huang, Tim H M. / Hypermethylation of 18S and 28S ribosomal DNAs predicts progression-free survival in patients with ovarian cancer. In: Clinical Cancer Research. 2005 ; Vol. 11, No. 20. pp. 7376-7383.
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abstract = "Purpose: Repetitive ribosomal DNA (rDNA) genes are GC-rich clusters in the human genome. The aim of the study was to determine the methylation status of two rDNA subunits, the 18S and 28S genes, in ovarian tumors and to correlate methylation levels with clinicopathologic features in a cohort of ovarian cancer patients. Experimental Design: 18S and 28S rDNA methylation was examined by quantitative methylation-specific PCR in 74 late-stage ovarian cancers, 9 histologically uninvolved, and 11 normal ovarian surface epithelial samples. In addition, methylation and gene expression levels of 18S and 28S rDNAs in two ovarian cancer cell tines were examined by reverse transcription-PCR before and after treatment with the demethytating drug 5′-aza-2′-deoxycvtidine. Results: The methylation level (amount of methylated rDNA/β-actin) of 18S and 28S rDNAs was significantly higher (P < 0.05) in tumors than in normal ovarian surface epithelial samples. Methylation of 18S and 28S rDNA was highly correlated (R2 = 0.842). Multivariate analysis by Cox regression found that rDNA hypermethylation [hazard ratio (HR), 0.25; P < 0.01], but not age (HR, 1.29; P = 0.291) and stage (HR, 1.09; P = 0.709), was independently associated with longer progression-free survival. In ovarian cancer cell fines, methylation levels of rDNA correlated with gene down-regulation and 5′-aza-2′-deoxycytidine treatment resulted in a moderate increase in 18S and 28S rDNA gene expressions. Conclusion: This is the first report of rDNA hypermethylation in ovarian tumors. Furthermore, rDNA methylation levels were higher in patients with long progression-free survival versus patients with short survival. Thus, rDNA methylation as a prognostic marker in ovarian cancer warrants further investigation.",
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AU - Chan, Michael W Y

AU - Wei, Susan H.

AU - Wen, Ping

AU - Wang, Zailong

AU - Matei, Daniela

AU - Liu, Joseph C.

AU - Liyanarachchi, Sandya

AU - Brown, Robert

AU - Nephew, Kenneth

AU - Yan, Pearlly S.

AU - Huang, Tim H M

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AB - Purpose: Repetitive ribosomal DNA (rDNA) genes are GC-rich clusters in the human genome. The aim of the study was to determine the methylation status of two rDNA subunits, the 18S and 28S genes, in ovarian tumors and to correlate methylation levels with clinicopathologic features in a cohort of ovarian cancer patients. Experimental Design: 18S and 28S rDNA methylation was examined by quantitative methylation-specific PCR in 74 late-stage ovarian cancers, 9 histologically uninvolved, and 11 normal ovarian surface epithelial samples. In addition, methylation and gene expression levels of 18S and 28S rDNAs in two ovarian cancer cell tines were examined by reverse transcription-PCR before and after treatment with the demethytating drug 5′-aza-2′-deoxycvtidine. Results: The methylation level (amount of methylated rDNA/β-actin) of 18S and 28S rDNAs was significantly higher (P < 0.05) in tumors than in normal ovarian surface epithelial samples. Methylation of 18S and 28S rDNA was highly correlated (R2 = 0.842). Multivariate analysis by Cox regression found that rDNA hypermethylation [hazard ratio (HR), 0.25; P < 0.01], but not age (HR, 1.29; P = 0.291) and stage (HR, 1.09; P = 0.709), was independently associated with longer progression-free survival. In ovarian cancer cell fines, methylation levels of rDNA correlated with gene down-regulation and 5′-aza-2′-deoxycytidine treatment resulted in a moderate increase in 18S and 28S rDNA gene expressions. Conclusion: This is the first report of rDNA hypermethylation in ovarian tumors. Furthermore, rDNA methylation levels were higher in patients with long progression-free survival versus patients with short survival. Thus, rDNA methylation as a prognostic marker in ovarian cancer warrants further investigation.

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