Coordinated cancer germline antigen promoter and global DNA hypomethylation in ovarian cancer: Association with the BORIS/CTCF expression ratio and advanced stage

Anna Woloszynska-Read, Wa Zhang, Jihnhee Yu, Petra A. Link, Paulette Mhawech-Fauceglia, Golda Collamat, Stacey N. Akers, Kelly R. Ostler, Lucy A. Godley, Kunle Odunsi, Adam R. Karpf

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Abstract

Purpose: Cancer germline (CG) antigens are frequently expressed and hypomethylated in epithelial ovarian cancer (EOC), but the relationship of this phenomenon to global DNA hypomethylation is unknown. In addition, the potential mechanisms leading to DNA hypomethylation, and its clinicopathologic significance in EOC, have not been determined. Experimental Design: We used quantitative mRNA expression and DNA methylation analyses to determine the relationship between expression and methylation of X-linked (MAGE-A1, NY-ESO-1, XAGE-1) and autosomal (BORIS, SOHLH2) CG genes, global DNA methylation (5mdC levels, LINE-1, Alu, and Sat-α methylation), and clinicopathology, using 75 EOC samples. In addition, we examined the association between these parameters and a number of mechanisms proposed to contribute to DNA hypomethylation in cancer. Results: CG genes were coordinately expressed in EOC and this was associated with promoter DNA hypomethylation. Hypomethylation of CG promoters was highly correlated and strongly associated with LINE-1 and Alu methylation, moderately with 5mdC levels, and rarely with Sat- αmethylation. BORIS and LINE-1 hypomethylation, and BORIS expression, were associated with advanced stage. GADD45A expression, MTHFR genotype, DNMT3B isoform expression, and BORIS mRNA expression did not associate with methylation parameters. In contrast, the BORIS/CTCF expression ratio was associated with DNA hypomethylation, and furthermore correlated with advanced stage and decreased survival. Conclusions: DNA hypomethylation coordinately affects CG antigen gene promoters and specific repetitive DNA elements in EOC, and correlates with advanced stage disease. The BORIS/CTCF mRNA expression ratio is closely associated with DNA hypomethylation and confers poor prognosis in EOC.

Original languageEnglish (US)
Pages (from-to)2170-2180
Number of pages11
JournalClinical Cancer Research
Volume17
Issue number8
DOIs
StatePublished - Apr 15 2011

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Ovarian Neoplasms
Antigens
Methylation
DNA
Neoplasms
Neoplasm Genes
DNA Methylation
Messenger RNA
Ovarian epithelial cancer
Protein Isoforms
Research Design
Genotype
Genes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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Coordinated cancer germline antigen promoter and global DNA hypomethylation in ovarian cancer : Association with the BORIS/CTCF expression ratio and advanced stage. / Woloszynska-Read, Anna; Zhang, Wa; Yu, Jihnhee; Link, Petra A.; Mhawech-Fauceglia, Paulette; Collamat, Golda; Akers, Stacey N.; Ostler, Kelly R.; Godley, Lucy A.; Odunsi, Kunle; Karpf, Adam R.

In: Clinical Cancer Research, Vol. 17, No. 8, 15.04.2011, p. 2170-2180.

Research output: Contribution to journalArticle

Woloszynska-Read, A, Zhang, W, Yu, J, Link, PA, Mhawech-Fauceglia, P, Collamat, G, Akers, SN, Ostler, KR, Godley, LA, Odunsi, K & Karpf, AR 2011, 'Coordinated cancer germline antigen promoter and global DNA hypomethylation in ovarian cancer: Association with the BORIS/CTCF expression ratio and advanced stage', Clinical Cancer Research, vol. 17, no. 8, pp. 2170-2180. https://doi.org/10.1158/1078-0432.CCR-10-2315
Woloszynska-Read, Anna ; Zhang, Wa ; Yu, Jihnhee ; Link, Petra A. ; Mhawech-Fauceglia, Paulette ; Collamat, Golda ; Akers, Stacey N. ; Ostler, Kelly R. ; Godley, Lucy A. ; Odunsi, Kunle ; Karpf, Adam R. / Coordinated cancer germline antigen promoter and global DNA hypomethylation in ovarian cancer : Association with the BORIS/CTCF expression ratio and advanced stage. In: Clinical Cancer Research. 2011 ; Vol. 17, No. 8. pp. 2170-2180.
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abstract = "Purpose: Cancer germline (CG) antigens are frequently expressed and hypomethylated in epithelial ovarian cancer (EOC), but the relationship of this phenomenon to global DNA hypomethylation is unknown. In addition, the potential mechanisms leading to DNA hypomethylation, and its clinicopathologic significance in EOC, have not been determined. Experimental Design: We used quantitative mRNA expression and DNA methylation analyses to determine the relationship between expression and methylation of X-linked (MAGE-A1, NY-ESO-1, XAGE-1) and autosomal (BORIS, SOHLH2) CG genes, global DNA methylation (5mdC levels, LINE-1, Alu, and Sat-α methylation), and clinicopathology, using 75 EOC samples. In addition, we examined the association between these parameters and a number of mechanisms proposed to contribute to DNA hypomethylation in cancer. Results: CG genes were coordinately expressed in EOC and this was associated with promoter DNA hypomethylation. Hypomethylation of CG promoters was highly correlated and strongly associated with LINE-1 and Alu methylation, moderately with 5mdC levels, and rarely with Sat- αmethylation. BORIS and LINE-1 hypomethylation, and BORIS expression, were associated with advanced stage. GADD45A expression, MTHFR genotype, DNMT3B isoform expression, and BORIS mRNA expression did not associate with methylation parameters. In contrast, the BORIS/CTCF expression ratio was associated with DNA hypomethylation, and furthermore correlated with advanced stage and decreased survival. Conclusions: DNA hypomethylation coordinately affects CG antigen gene promoters and specific repetitive DNA elements in EOC, and correlates with advanced stage disease. The BORIS/CTCF mRNA expression ratio is closely associated with DNA hypomethylation and confers poor prognosis in EOC.",
author = "Anna Woloszynska-Read and Wa Zhang and Jihnhee Yu and Link, {Petra A.} and Paulette Mhawech-Fauceglia and Golda Collamat and Akers, {Stacey N.} and Ostler, {Kelly R.} and Godley, {Lucy A.} and Kunle Odunsi and Karpf, {Adam R.}",
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T1 - Coordinated cancer germline antigen promoter and global DNA hypomethylation in ovarian cancer

T2 - Association with the BORIS/CTCF expression ratio and advanced stage

AU - Woloszynska-Read, Anna

AU - Zhang, Wa

AU - Yu, Jihnhee

AU - Link, Petra A.

AU - Mhawech-Fauceglia, Paulette

AU - Collamat, Golda

AU - Akers, Stacey N.

AU - Ostler, Kelly R.

AU - Godley, Lucy A.

AU - Odunsi, Kunle

AU - Karpf, Adam R.

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N2 - Purpose: Cancer germline (CG) antigens are frequently expressed and hypomethylated in epithelial ovarian cancer (EOC), but the relationship of this phenomenon to global DNA hypomethylation is unknown. In addition, the potential mechanisms leading to DNA hypomethylation, and its clinicopathologic significance in EOC, have not been determined. Experimental Design: We used quantitative mRNA expression and DNA methylation analyses to determine the relationship between expression and methylation of X-linked (MAGE-A1, NY-ESO-1, XAGE-1) and autosomal (BORIS, SOHLH2) CG genes, global DNA methylation (5mdC levels, LINE-1, Alu, and Sat-α methylation), and clinicopathology, using 75 EOC samples. In addition, we examined the association between these parameters and a number of mechanisms proposed to contribute to DNA hypomethylation in cancer. Results: CG genes were coordinately expressed in EOC and this was associated with promoter DNA hypomethylation. Hypomethylation of CG promoters was highly correlated and strongly associated with LINE-1 and Alu methylation, moderately with 5mdC levels, and rarely with Sat- αmethylation. BORIS and LINE-1 hypomethylation, and BORIS expression, were associated with advanced stage. GADD45A expression, MTHFR genotype, DNMT3B isoform expression, and BORIS mRNA expression did not associate with methylation parameters. In contrast, the BORIS/CTCF expression ratio was associated with DNA hypomethylation, and furthermore correlated with advanced stage and decreased survival. Conclusions: DNA hypomethylation coordinately affects CG antigen gene promoters and specific repetitive DNA elements in EOC, and correlates with advanced stage disease. The BORIS/CTCF mRNA expression ratio is closely associated with DNA hypomethylation and confers poor prognosis in EOC.

AB - Purpose: Cancer germline (CG) antigens are frequently expressed and hypomethylated in epithelial ovarian cancer (EOC), but the relationship of this phenomenon to global DNA hypomethylation is unknown. In addition, the potential mechanisms leading to DNA hypomethylation, and its clinicopathologic significance in EOC, have not been determined. Experimental Design: We used quantitative mRNA expression and DNA methylation analyses to determine the relationship between expression and methylation of X-linked (MAGE-A1, NY-ESO-1, XAGE-1) and autosomal (BORIS, SOHLH2) CG genes, global DNA methylation (5mdC levels, LINE-1, Alu, and Sat-α methylation), and clinicopathology, using 75 EOC samples. In addition, we examined the association between these parameters and a number of mechanisms proposed to contribute to DNA hypomethylation in cancer. Results: CG genes were coordinately expressed in EOC and this was associated with promoter DNA hypomethylation. Hypomethylation of CG promoters was highly correlated and strongly associated with LINE-1 and Alu methylation, moderately with 5mdC levels, and rarely with Sat- αmethylation. BORIS and LINE-1 hypomethylation, and BORIS expression, were associated with advanced stage. GADD45A expression, MTHFR genotype, DNMT3B isoform expression, and BORIS mRNA expression did not associate with methylation parameters. In contrast, the BORIS/CTCF expression ratio was associated with DNA hypomethylation, and furthermore correlated with advanced stage and decreased survival. Conclusions: DNA hypomethylation coordinately affects CG antigen gene promoters and specific repetitive DNA elements in EOC, and correlates with advanced stage disease. The BORIS/CTCF mRNA expression ratio is closely associated with DNA hypomethylation and confers poor prognosis in EOC.

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