Methylation of the RASSF1A promoter is predictive of poor outcome among patients with Wilms tumor

Junjiro Ohshima, Masayuki Haruta, Yuiko Fujiwara, Naoki Watanabe, Yasuhito Arai, Tadashi Ariga, Hajime Okita, Tsugumichi Koshinaga, Takaharu Oue, Shiro Hinotsu, Hisaya Nakadate, Hiroshi Horie, Masahiro Fukuzawa, Yasuhiko Kaneko

Research output: Contribution to journalArticle

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Abstract

Background: Wilms tumor (WT) has a survival rate of 90% following multimodality therapy. Nevertheless, there are some groups of patients with event-free survival rates less than 75%. In addition to clinical prognostic factors, loss of heterozygosity at 1p and/or 16q has been used to determine treatment intensity. However, the incidence of this abnormality is low, and new biomarkers are still needed. Procedure: We analyzed methylation status of three tumor suppressor genes; Ras-association domain family 1 protein, isoform A (RASSF1A), DCR2, and CASP8, in 84 WTs using conventional methylation-specific PCR (cMSP), and the results were correlated with outcome. Furthermore, we analyzed the methylation status of RASSF1A by quantitative MSP (qMSP) in 171 WTs, and evaluated clinical and genetic differences between the methylated and unmethylated tumors. Results: RASSF1A was the most frequently methylated gene identified by cMSP, and associated with a poor outcome. Patients with a RASSF1A-methylated tumor had shorter overall and event-free survival periods (P=0.043 and 0.018, respectively), when a cut-off value of 7% by qMSP was used. The methylation was more frequent in tumors of older children than younger children (P<0.001), and in advanced-stage tumors than early stage tumors (P=0.001). However, multivariate analysis could not confirm the prognostic significance of RASSF1A methylation, possibly because of a small number of advanced stage tumors examined. RASSF1A methylation was correlated with LOH at 1p and/or 16q (P=0.017), but not with WT1 abnormality, suggesting the methylation and LOH to involve the same tumorigenic pathway. Conclusions: The methylation status of RASSF1A might be a novel biomarker to predict outcome of WT patients.

Original languageEnglish
Pages (from-to)499-505
Number of pages7
JournalPediatric Blood and Cancer
Volume59
Issue number3
DOIs
Publication statusPublished - 2012 Sep
Externally publishedYes

Fingerprint

Wilms Tumor
Methylation
Protein Isoforms
Neoplasms
Disease-Free Survival
Survival Rate
Biomarkers
Polymerase Chain Reaction
Loss of Heterozygosity
Tumor Suppressor Genes
Multivariate Analysis
Incidence

Keywords

  • Biomarkers
  • Methylation
  • RASSF1A
  • Wilms tumor

ASJC Scopus subject areas

  • Oncology
  • Pediatrics, Perinatology, and Child Health
  • Hematology

Cite this

Ohshima, J., Haruta, M., Fujiwara, Y., Watanabe, N., Arai, Y., Ariga, T., ... Kaneko, Y. (2012). Methylation of the RASSF1A promoter is predictive of poor outcome among patients with Wilms tumor. Pediatric Blood and Cancer, 59(3), 499-505. https://doi.org/10.1002/pbc.24093

Methylation of the RASSF1A promoter is predictive of poor outcome among patients with Wilms tumor. / Ohshima, Junjiro; Haruta, Masayuki; Fujiwara, Yuiko; Watanabe, Naoki; Arai, Yasuhito; Ariga, Tadashi; Okita, Hajime; Koshinaga, Tsugumichi; Oue, Takaharu; Hinotsu, Shiro; Nakadate, Hisaya; Horie, Hiroshi; Fukuzawa, Masahiro; Kaneko, Yasuhiko.

In: Pediatric Blood and Cancer, Vol. 59, No. 3, 09.2012, p. 499-505.

Research output: Contribution to journalArticle

Ohshima, J, Haruta, M, Fujiwara, Y, Watanabe, N, Arai, Y, Ariga, T, Okita, H, Koshinaga, T, Oue, T, Hinotsu, S, Nakadate, H, Horie, H, Fukuzawa, M & Kaneko, Y 2012, 'Methylation of the RASSF1A promoter is predictive of poor outcome among patients with Wilms tumor', Pediatric Blood and Cancer, vol. 59, no. 3, pp. 499-505. https://doi.org/10.1002/pbc.24093
Ohshima, Junjiro ; Haruta, Masayuki ; Fujiwara, Yuiko ; Watanabe, Naoki ; Arai, Yasuhito ; Ariga, Tadashi ; Okita, Hajime ; Koshinaga, Tsugumichi ; Oue, Takaharu ; Hinotsu, Shiro ; Nakadate, Hisaya ; Horie, Hiroshi ; Fukuzawa, Masahiro ; Kaneko, Yasuhiko. / Methylation of the RASSF1A promoter is predictive of poor outcome among patients with Wilms tumor. In: Pediatric Blood and Cancer. 2012 ; Vol. 59, No. 3. pp. 499-505.
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T1 - Methylation of the RASSF1A promoter is predictive of poor outcome among patients with Wilms tumor

AU - Ohshima, Junjiro

AU - Haruta, Masayuki

AU - Fujiwara, Yuiko

AU - Watanabe, Naoki

AU - Arai, Yasuhito

AU - Ariga, Tadashi

AU - Okita, Hajime

AU - Koshinaga, Tsugumichi

AU - Oue, Takaharu

AU - Hinotsu, Shiro

AU - Nakadate, Hisaya

AU - Horie, Hiroshi

AU - Fukuzawa, Masahiro

AU - Kaneko, Yasuhiko

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N2 - Background: Wilms tumor (WT) has a survival rate of 90% following multimodality therapy. Nevertheless, there are some groups of patients with event-free survival rates less than 75%. In addition to clinical prognostic factors, loss of heterozygosity at 1p and/or 16q has been used to determine treatment intensity. However, the incidence of this abnormality is low, and new biomarkers are still needed. Procedure: We analyzed methylation status of three tumor suppressor genes; Ras-association domain family 1 protein, isoform A (RASSF1A), DCR2, and CASP8, in 84 WTs using conventional methylation-specific PCR (cMSP), and the results were correlated with outcome. Furthermore, we analyzed the methylation status of RASSF1A by quantitative MSP (qMSP) in 171 WTs, and evaluated clinical and genetic differences between the methylated and unmethylated tumors. Results: RASSF1A was the most frequently methylated gene identified by cMSP, and associated with a poor outcome. Patients with a RASSF1A-methylated tumor had shorter overall and event-free survival periods (P=0.043 and 0.018, respectively), when a cut-off value of 7% by qMSP was used. The methylation was more frequent in tumors of older children than younger children (P<0.001), and in advanced-stage tumors than early stage tumors (P=0.001). However, multivariate analysis could not confirm the prognostic significance of RASSF1A methylation, possibly because of a small number of advanced stage tumors examined. RASSF1A methylation was correlated with LOH at 1p and/or 16q (P=0.017), but not with WT1 abnormality, suggesting the methylation and LOH to involve the same tumorigenic pathway. Conclusions: The methylation status of RASSF1A might be a novel biomarker to predict outcome of WT patients.

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