Aberrant promoter methylation and silencing of the RASSF1A gene in pediatric tumors and cell lines

Harada, Kiyoshi; Toyooka, Shinichi; Maitra, Anirban; Maruyama, Riichiroh; Toyooka, Kiyomi O.; Timmons, Charles F.; Tomlinson, Gail E.; Milardi, Domenico; Hay, Robert J.; Minna, John D.; Gazdar, Adi F.

doi:10.1038/sj.onc.1205446

Cited by 215 publications

(175 citation statements)

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“…The frequency of SLIT2 methylation in NB was less than that for RASSF1A and CASP8, but is still a significant finding as other candidate TSGs that demonstrate frequent promoter methylation in some cancers (e.g. p16INK4A, MGMT, RARâ, DAPK, APC, GSTP1, CDH1 and CDH13) are rarely methylated in NB (Harada et al, 2002a).…”

Section: Discussionmentioning

confidence: 87%

SLIT2 promoter methylation analysis in neuroblastoma, Wilms' tumour and renal cell carcinoma

et al. 2004

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The 3p21.3 RASSF1A tumour suppressor gene (TSG) provides a paradigm for TSGs inactivated by promoter methylation rather than somatic mutations. Recently, we identified frequent promoter methylation without somatic mutations of SLIT2 in lung and breast cancers, suggesting similarities between SLIT2 and RASSF1A TSGs. Epigenetic inactivation of RASSF1A was first described in lung and breast cancers and subsequently in a wide range of human cancers including neuroblastoma, Wilms' tumour and renal cell carcinoma (RCC). These findings prompted us to investigate SLIT2 methylation in these three human cancers. We analysed 49 neuroblastomas (NBs), 37 Wilms' tumours and 48 RCC, and detected SLIT2 promoter methylation in 29% of NB, 38% of Wilms' tumours and 25% of RCC. Previously, we had demonstrated frequent RASSF1A methylation in the same tumour series and frequent CASP8 methylation in the NB and Wilms' tumour samples. However, there was no significant association between SLIT2 promoter methylation and RASSF1A or CASP8 methylation in NB and RCC. In Wilms' tumour, there was a trend for a negative association between RASSF1A and SLIT2 methylation, although this did not reach statistical significance. No associations were detected between SLIT2 promoter methylation and specific clinicopathological features in the tumours analysed. These findings implicate SLIT2 promoter methylation in the pathogenesis of both paediatric and adult cancers and suggest that further investigations of SLIT2 in other tumour types should be pursued. However, epigenetic inactivation of SLIT2 is less frequent than RASSF1A in the tumour types analysed.

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Section: Discussionmentioning

confidence: 87%

SLIT2 promoter methylation analysis in neuroblastoma, Wilms' tumour and renal cell carcinoma

et al. 2004

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“…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%

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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“…6 Previous studies have shown that epigenetic TSG inactivation plays a role in medulloblastoma development. [7][8][9][10][11][12][13][14][15] To date, 3 genes have demonstrated strong and consistent evidence of epigenetic inactivation by promoter methylation in a significant proportion of medulloblastomas: RASSF1A, CASP8 and HIC-1. [8][9][10][11][12]14,15 Together these data suggest that further epigenetic events are involved in medulloblastoma; however, the role of hypermethylation events in stPNET pathogenesis has not been widely investigated.…”

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confidence: 99%

“…[7][8][9][10][11][12][13][14][15] To date, 3 genes have demonstrated strong and consistent evidence of epigenetic inactivation by promoter methylation in a significant proportion of medulloblastomas: RASSF1A, CASP8 and HIC-1. [8][9][10][11][12]14,15 Together these data suggest that further epigenetic events are involved in medulloblastoma; however, the role of hypermethylation events in stPNET pathogenesis has not been widely investigated.MCJ (also DNAJD1) is a recently discovered gene on chromosome 13q14.1 which is inactivated in over 50% of ovarian cancer cell lines and primary tumours by epigenetic transcriptional silencing (through hypermethylation of a CpG island which lies within the 5 0 transcribed region of the MCJ gene) and genetic deletion. 16,17 MCJ contains a highly conserved 70-amino acid DNAJ domain (or J domain), first described in the Escherichia coli Hsp DNAJ.…”

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confidence: 99%

Epigenetic inactivation ofMCJ (DNAJD1) in malignant paediatric brain tumours

et al. 2006

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Newcastle upon Tyne, United Kingdom MCJ (DNAJD1) is a recently discovered member of the DNAJ protein family whose expression is controlled epigenetically by methylation of a CpG island located within the 5 0 transcribed region of its gene. Methylation-dependent transcriptional silencing of MCJ has been observed in ovarian cancers and associated with increased resistance to chemotherapeutic agents; however, its role in other cancer types has not been widely investigated. We examined the status of MCJ in intracranial primitive neuroectodermal tumours [PNETs, comprising cerebellar PNETs (medulloblastomas) and supratentorial PNETs (stPNETs)] and ependymomas, together representing the most common malignant brain tumours of childhood. Evidence of MCJ hypermethylation was found in all 3 tumour types [medulloblastomas, 3/9 (33%) cell lines, 2/28 (7%) primary tumours; stPNETs, 2/2 (100%) cell lines, 3/10 (30%) primary tumours; and ependymomas, 2/20 (10%) primary tumours] but not in nonneoplastic brain tissues (n 5 11), indicating that MCJ methylation is a tumour-specific event. In methylated cases, the distribution of methylated CpG sites across the CpG island could be broadly divided into 2 patterns: (i) extensive methylation of the majority of CpG sites across the island or (ii) limited methylation of individual CpG sites concentrated towards the 5 0 end of the island. Extensive methylation patterns were associated with the methylation-dependent transcriptional silencing of MCJ in medulloblastoma and stPNET cell lines. Further investigations of the mechanism of MCJ inactivation revealed that its loss could occur either through biallelic epigenetic methylation or by methylation in association with genetic loss of its second allele. These data indicate that epigenetic inactivation of MCJ may play a role in the development of a range of paediatric brain tumour types, and its role in disease pathogenesis and chemotherapeutic resistance should now be investigated further. ' 2005 Wiley-Liss, Inc.Key words: MCJ; DNAJD1; primitive neuroectodermal tumour; medulloblastoma; ependymoma; hypermethylation Medulloblastoma is a PNET which arises in the cerebellum and accounts for approximately 20% of childhood brain tumours. 1 stPNETs are histologically similar to medulloblastomas but arise in the cerebrum or pineal body and appear to exhibit different genetic aberrations. 2,3 Medulloblastomas and stPNETs are highly malignant, and overall 5-year survival rates following multimodal therapy are poor (approx. 60%). Current treatment regimes are also associated with long-term neurologic and endocrinologic side effects, and disease course is difficult to predict based on current clinical and pathologic indices. 1,4 Thus, a better understanding of the molecular events underlying the development of these tumours could provide the basis of an improved outlook for these patients, through identification of molecular markers for disease stratification and development of molecularly targeted therapeutic regimens.There has been significant inter...

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Aberrant promoter methylation and silencing of the RASSF1A gene in pediatric tumors and cell lines

Cited by 215 publications

References 23 publications

SLIT2 promoter methylation analysis in neuroblastoma, Wilms' tumour and renal cell carcinoma

SLIT2 promoter methylation analysis in neuroblastoma, Wilms' tumour and renal cell carcinoma

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

Epigenetic inactivation ofMCJ (DNAJD1) in malignant paediatric brain tumours

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