RASSF1A methylation indicates a poor prognosis in hepatoblastoma patients

Honda, Susumu; Miyagi, Hisayuki; Suzuki, Hiromu; Matsushima, Masashi; Haruta, Masayuki; Kaneko, Yasuhiko; Hatanaka, Kanako C.; Hiyama, Eiso; Okada, Tadao; Taketomi, Akinobu

doi:10.1007/s00383-013-3371-z

Cited by 21 publications

(26 citation statements)

References 12 publications

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“…The epigenetic alterations contributing to the malignant progression of HB remain unknown. We previously reported that RASSF1A methylation correlates with different histological phenotypes and may be a promising molecular‐genetic marker predictive of treatment outcome in HB patients . This suggests hypermethylation of some critical genes may drive changes in the phenotype of HB cells, resulting in acquisition of aggressive characteristics.…”

Section: Discussionmentioning

confidence: 99%

“…CTNNB1 mutations are seen in the majority of HB tumors, but there have been few reports on genetic alterations of other oncogenes or tumor suppressor genes . We previously reported that RASSF1A methylation is independently correlated with a poor outcome and suggested that RASSF1A may be a promising molecular‐genetic marker predictive of treatment outcome in HB patients . Moreover, disruption of imprinting status, mainly due to aberrant DNA methylation, has been implicated in the pathogenesis of HB .…”

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confidence: 99%

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Clinical prognostic value of DNA methylation in hepatoblastoma: Four novel tumor suppressor candidates

et al. 2016

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Hepatoblastoma (HB) is very rare but the most common malignant neoplasm of the liver occurring in children. Despite improvements in therapy, outcomes for patients with advanced HB that is refractory to standard preoperative chemotherapy remain unsatisfactory. To improve the survival rate among this group, identification of novel prognostic markers and therapeutic targets is needed. We have previously reported that altered DNA methylation patterns are of biological and clinical importance in HB. In the present study, using genome‐wide methylation analysis and bisulfite pyrosequencing with specimens from HB tumors, we detected nine methylated genes. We then focused on four of those genes, GPR180,MST1R,OCIAD2, and PARP6, because they likely encode tumor suppressors and their increase of methylation was associated with a poor prognosis. The methylation status of the four genes was also associated with age at diagnosis, and significant association with the presence of metastatic tumors was seen in three of the four genes. Multivariate analysis revealed that the presence of metastatic tumors and increase of methylation of GPR180 were independent prognostic factors affecting event‐free survival. These findings indicate that the four novel tumor suppressor candidates are potentially useful molecular markers predictive of a poor outcome in HB patients, which may serve as the basis for improved therapeutic strategies when clinical trials are carried out.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Clinical prognostic value of DNA methylation in hepatoblastoma: Four novel tumor suppressor candidates

et al. 2016

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“…To date, HBs have remained largely unexplored regarding DNA methylation profile, both in coding and repetitive sequences. Methylation studies have identified hypermethylation in several gene promoters, including MT1G, that showed a significant correlation with poor prognosis [73]; RASSF1A, which plays a role as a tumor suppressor [74], and SOCS1, CASP8, SFRP1, APC, HHIP and IGFBP3 [73,75,76]. Additionally, a high frequency of H19 gene inactivation has been reported in HBs, including promoter hypermethylation [77].…”

Section: Epigeneticsmentioning

confidence: 99%

The genetic and epigenetic landscapes of hepatoblastomas

et al. 2017

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Primary liver cancers are rare in children, and the most common type is hepatoblastoma (HB), an embryonal tumor with histological features that resemble different stages of liver cell differentiation. However, mainly because of its rarity, molecular data on HB tumorigenesis remain scarce. This article reviews the current knowledge regarding genetic and epigenetic alterations reported in HB cases, with emphasis on the recent findings of next-generation sequencing studies.

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“…Hypermethylation or hypomethylation of gene promoter regions is recognized as one of the mechanisms that can silence or activate the oncogenes (20). It has recently been indicated that aberrant promoter methylation of the RAS association domain family protein 1 may contribute to the pathogenesis of HB and is considered to be a significant prognostic indicator in HB (1,21).…”

Section: Discussionmentioning

confidence: 99%

“…Although it accounts for just 0.5-1.5 cases per million children per year, the mortality rate is 35-50% in high-risk patients (1). Previous studies have suggested an association with familial adenomatous polyposis (FAP) (2), both low and high birth weights (3), and constitutional trisomy 18 (4); however its etiology remains unknown.…”

Section: Introductionmentioning

confidence: 99%

Aberrant KLK4 gene promoter hypomethylation in pediatric hepatoblastomas

et al. 2017

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Abstract. DNA methylation has a crucial role in cancer biology and has been recognized as an activator of oncogenes and inactivator of tumor suppressor genes, both of which are mechanisms for tumorigenesis. Kallikrein-related peptidase 4 (KLK4), has been suggested to be an oncogene in various types of cancer. The aim of the present study was to assess the DNA methylation patterns of the KLK4 gene in cancerous samples harvested from patients with hepatoblastoma (HB). KLK4 mRNA expression levels were detected using reverse transcription-quantitative polymerase chain reaction and assessed its DNA methylation patterns using high-throughput mass spectrometry on a matrix-assisted laser desorption/ionization time-of-flight mass array. A total of 10 HB and 10 normal liver tissue samples were obtained from patients with HB. The results of the present study showed that a significantly higher level of KLK4 mRNA expression levels were detected in HB tissues, as compared with the matched controls. Furthermore, the KLK4 gene promoter region was distinctively less methylated in the HB samples compared with the controls and negatively correlated with KLK4 mRNA expression levels. These findings indicate that aberrant methylation of KLK4 may contribute to its upregulated mRNA expression in HB.

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RASSF1A methylation indicates a poor prognosis in hepatoblastoma patients

Abstract: We confirmed that RASSF1A methylation is a significant prognostic indicator in hepatoblastomas, and it may become a promising molecular marker to stratify patients into appropriate risk groups.

Cited by 21 publications

References 12 publications

Clinical prognostic value of DNA methylation in hepatoblastoma: Four novel tumor suppressor candidates

Clinical prognostic value of DNA methylation in hepatoblastoma: Four novel tumor suppressor candidates

The genetic and epigenetic landscapes of hepatoblastomas

Aberrant KLK4 gene promoter hypomethylation in pediatric hepatoblastomas

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