Promoter hypermethylation of the <i>RASSF1A</i> gene predicts the poor outcome of patients with hepatoblastoma

Sugawara, Waka; Haruta, Masayuki; Sasaki, Fumio; Watanabe, Naoki; Tsunematsu, Yukiko; Kikuta, Atsushi; Kaneko, Yasuhiko

doi:10.1002/pbc.21031

Cited by 36 publications

(33 citation statements)

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“…The present and previous studies evaluated the methylation status of at least 20 genes in hepatoblastoma and found that only 3 genes were methylated (Table IV). 9,34,35 The limited number of methylated genes suggest that this profile may be specific for hepatoblastoma, 38 and the survival and stage distribution analyses disclosed that combined RASSF1A and SOCS1 or CASP8 methylation, or joint methylation of the 3 genes are not correlated with the advanced stage of disease or a poor outcome, contrary to the findings that methylation of multiple genes were correlated with a poor outcome, reported in neuroblastoma. 39 The present multivariate analysis identified unresectable tumor stages of disease (3B and 4) as the most significant factor predicting overall survival, followed by RASSF1A methylation.…”

Section: Discussionmentioning

confidence: 91%

“…31 Previous studies, including ours, have repeatedly shown that promoter hypermethylation of RASSF1A correlated with loss of expression in various cancers, and treatment with a demethylating agent reactivated RASSF1A gene expression in various cancer cell lines, including a hepatoblastoma cell line HepG2. 9,34,36,37 RASSF1A inhibits tumor formation by apoptosis, and regulates microtubule dynamics and mitotic arrest via multiple effectors. By dysregulation of the Ras signaling pathway, RASSF1A methylation is correlated with poor differentiation and vascular invasion of cancer cells, and an unfavorable outcome.…”

Section: Discussionmentioning

confidence: 99%

“…4,24 Bisulfite treatment and conventional methylation-specific PCR (MSP) analysis Genomic DNA from tumor samples was treated with sodium bisulfite, and the methylation status of the promoter region in various genes was analyzed by MSP, as previously described. 9,27 The genes examined were RASSF1A, RASSF2A, NORE1A, SOCS1, CASP8, RUNX3, RIZ1, BLU, HOXA9, HOXB5, p16INK4A, p14ARF and DCR2. [13][14][15][16][17][18][19][20][21][22] The primer sequences and their location in the original genomic sequences are listed in Table I, and the location of the analyzed fragments for RASSF1A, SOCS1 and CASP8 are shown in Figure 1a.…”

Section: Patients and Samplesmentioning

confidence: 99%

“…9 Nevertheless, the article had some limitations that the number of tumors was not enough, the method used to detect the hypermethylation was suboptimal, and the prognostic significance of RASSF1A methylation was ambiguous by multivariate analysis.…”

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The methylation status of RASSF1A promoter predicts responsiveness to chemotherapy and eventual cure in hepatoblastoma patients

Honda

Haruta

Sugawara

et al. 2008

Intl Journal of Cancer

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Despite the progress of therapy, outcomes of advanced hepatoblastoma patients who are refractory to standard preoperative chemotherapy remain unsatisfactory. To improve the mortality rate, novel prognostic markers are needed for better therapy planning. We examined the methylation status of 13 candidate tumor suppressor genes in 20 hepatoblastoma tumors by conventional methylation-specific PCR (MSP) and found hypermethylation in 3 of the 13 genes. We analyzed the methylation status of these 3 genes (RASSF1A, SOCS1 and CASP8) in 97 tumors and found hypermethylation in 30.9, 33.0 and 15.5%, respectively. Univariate analysis showed that only the methylation status of RASSF1A but not the other 2 genes predicted the outcome, and multivariate analysis showed a weak contribution of RASSF1A methylation to overall survival. Using quantitative MSP, we found RASSF1A methylation in 44.3% of the 97 tumors. CTNNB1 mutation was detected in 67.0% of the 97 tumors. While univariate analysis demonstrated RASSF1A methylation, CTNNB1 mutation and other clinicopathological variables as prognostic factors, multivariate analysis identified RASSF1A methylation (p 5 0.043; relative risk 9.39) and the disease stage (p 5 0.002; relative risk 7.67) but not CTNNB1 mutation as independent prognostic factors. In survival analysis of 33 patients in stage 3B or 4, patients with unmethylated tumor had better overall survival than those with methylated tumor (p 5 0.035). RASSF1A methylation may be a promising moleculargenetic marker to predict the treatment outcome and may be used to stratify patients when clinical trials are carried out. ' 2008 Wiley-Liss, Inc.Key words: RASSF1A; CTNNB1; quantitative MSP; hepatoblastoma; prognostic factor Hepatoblastoma is a rare malignant neoplasm of the liver, with an incidence of 0.5-1.5 per million children. 1 Remarkable progress in clinical outcome has been achieved in the past 20 years due to advances in chemotherapy and surgical procedures; however, the mortality rate remains 20-30% and treatment results in patients in advanced stages who are refractory to standard preoperative chemotherapy regimens are unsatisfactory. 2,3 To improve the mortality of these patients, innovative treatment and potent prognostic markers for better therapy planning are needed. The present clinical factors predicting outcome include the level of alpha-feto protein, histology, disease stage and growth pattern of the tumor. 2-4 Chromosomal gains of 2q, 8q and 20 and high expression of telomerase or PLK1 were shown to be moleculargenetic markers predicting poor outcome 5-8 ; however, none have been proven to be independent prognostic factors by multivariate analysis.We previously reported that RASSF1A (RAS association domain family protein 1) methylation, found in 39% of 39 hepatoblastoma tumors, was correlated with poor outcome by univariate analysis. 9 Nevertheless, the article had some limitations that the number of tumors was not enough, the method used to detect the hypermethylation was suboptimal, and the prognostic signifi...

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Section: Discussionmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Section: Patients and Samplesmentioning

confidence: 99%

mentioning

confidence: 99%

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The methylation status of RASSF1A promoter predicts responsiveness to chemotherapy and eventual cure in hepatoblastoma patients

Honda

Haruta

Sugawara

et al. 2008

Intl Journal of Cancer

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“…To improve the mortality of these patients, innovative treatment based on a specific molecular target is needed. The molecular mechanism involved in the development and progression of HB includes overexpression of insulin-like growth factor-II (IGF2) (Li et al, 1998b;Gray et al, 2000;Hartmann et al, 2000), downregulation of RASSF1A by promoter hypermethylation (Sugawara et al, 2007;Honda et al, 2008) and alterations of genes in the Wnt signalling pathway; most notably, the high incidence of CTNNB1 (catenin, b1) mutation (Koch et al, 1999;Taniguchi et al, 2002).…”

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Loss of imprinting of IGF2 correlates with hypermethylation of the H19 differentially methylated region in hepatoblastoma

Honda

Arai²,

Haruta

et al. 2008

Br J Cancer

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IGF2, a maternally imprinted foetal growth factor gene, is implicated in many childhood tumours including hepatoblastoma (HB); however, the genetic and epigenetic alterations have not comprehensively been studied. We analysed the methylation status of the H19 differentially methylated region (DMR), loss of heterozygosity (LOH) and allelic expression of IGF2 in 54 HB tumours, and found that 12 tumours (22%) with LOH, 9 (17%) with loss of imprinting (LOI) and 33 (61%) with retention of imprinting (ROI). Biallelic and monoallelic IGF2 expressions correlated with hypermethylation and normal methylation of H19 DMR, respectively, in two tumours with LOI and seven tumours with ROI. Quantitative RT -PCR analysis showed minimal expression of H19 mRNA and substantial expression of IGF2 mRNA in tumours with LOH or LOI, and substantial expression of both H19 and IGF2 mRNAs in tumours with ROI. Increased IGF2 expression with predominant embryonic P3 transcript was found in the majority of HBs with ROI and foetal livers. In contrast to the earlier reports, our findings suggest that the disruption of the enhancer competition model reported in Wilms' tumour may also occur in HB. Both frequencies of LOH and LOI seem to be lower in HB than in Wilms' tumour, reflecting the different tissue origins.

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Phase I pharmacokinetic study of the vascular endothelial growth factor receptor tyrosine kinase inhibitor vatalanib (PTK787) plus imatinib and hydroxyurea for malignant glioma

Reardon

Egorin

Desjardins

et al. 2009

Cancer

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A number of unique genetic features are observed in hepatoblastoma that have provided insights into the origins of hepatoblastoma. Hallmark cytogenetic changes in hepatoblastoma include the acquisition of additional copies of whole chromosomes and a recurring unbalanced translocation involving 1q. Genetic syndromes are associated with approximately 15% of hepatoblastoma and the understanding and recognition of these syndromes will be important in determining future surveillance studies needed to prevent additional cancers in survivors as well as in some case guide the care of family members. This article will review the genetic changes, both germ line and acquired, that are recurring events in hepatoblastoma, with emphasis on how these genetic changes could work together with other developmental factors and influence cancer predisposition, tumor growth, as well as aid in prognosis. Tumor‐specific signatures based on transcriptional or epigenetic alterations will be reviewed that might be used in the future to better diagnose and subtype the disease as well as predict prognosis and response to therapy. Pediatr Blood Cancer 2012; 59: 785–792. © 2012 Wiley Periodicals, Inc.

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Promoter hypermethylation of the RASSF1A gene predicts the poor outcome of patients with hepatoblastoma

Abstract: RASSF1A methylation may be a novel molecular-genetic marker for treatment outcome in hepatoblastoma if confirmed by studies examining a larger number of hepatoblastomas.

Cited by 36 publications

References 27 publications

The methylation status of RASSF1A promoter predicts responsiveness to chemotherapy and eventual cure in hepatoblastoma patients

The methylation status of RASSF1A promoter predicts responsiveness to chemotherapy and eventual cure in hepatoblastoma patients

Loss of imprinting of IGF2 correlates with hypermethylation of the H19 differentially methylated region in hepatoblastoma

Phase I pharmacokinetic study of the vascular endothelial growth factor receptor tyrosine kinase inhibitor vatalanib (PTK787) plus imatinib and hydroxyurea for malignant glioma

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