MT1G Hypermethylation: A Potential Prognostic Marker for Hepatoblastoma

Abstract

Hepatoblastoma comprises only 1% of all cancers in childhood. Because of its low frequency, a small number of prognostic factors are described in hepatoblastoma and most of them are related to resectability. Microarray studies showed a large number of underexpressed genes in hepatoblastoma. Because aberrant DNA methylation has been recognized as an alternative mechanism for tumor suppressor gene inactivation, this could be involved with gene downregulation in these tumors. Despite the rarity of hepatoblastoma, this study evaluated the methylation pattern of 25 genes in 20 paraffin-embedded tumor specimens and five non-neoplastic liver samples (normal control) by quantitative methylation-specific PCR (QMSP). The examination of the methylation profile of hepatoblastoma samples and normal liver specimens revealed a high tumorspecific DNA hypermethylation in the promoter regions of five genes (APC, CDH1, MT1G, RASSF1A, and SOCS1). Furthermore, MT1G hypermethylation showed a significant correlation with poor prognosis of patients with hepatoblastoma. This study represents the first quantitative evaluation of promoter hypermethylation in hepatoblastoma and demonstrated that aberrant methylation is a frequent event in this malignancy. Furthermore, our data provide evidence that MT1G hypermethylation may be useful as prognostic indicator for this disease and suggest that patients with hepatoblastoma may benefit from demethylating drug treatments. (Pediatr Res 67: 387-393, 2010) H epatoblastoma is the most common malignant liver tumor in childhood. Data from Surveillance Epidemiology and End Results (SEER) estimate an incidence of 0.5-1.5 cases per million children per year, which accounts for 79% of hepatic neoplasia in children younger than 15-y and for 1% of all cancers in this age group (1).Few prognostic factors are available for hepatoblastoma. The most important features appear to be low alphafetoprotein level, pure fetal histology, gross resectability of the tumor, and the presence of metastases in the lung and small cell undifferentiated tumor type. In fact, complete surgical resection remains the most important intervention required for long-term survival (2,3).Although some chromosomal alterations have been found in hepatoblastoma (1q, 2q, 7q, 8, 17q, and 20 amplifications), no etiological relationship or prognostic value could be attributed to these findings. The majority of tumors from patients with hepatoblastoma do not show any detectable chromosomal anomaly (2,4).DNA methylation, catalyzed by DNA methyltransferases, involves the addition of a methyl group to the carbon 5 position of the cytosine ring in CpG dinucleotides (5). This is associated with several changes in chromatin structure, including the regulation of histone methylation and acetylation and the recruitment of proteins to the methylated sites, which usually leads to the obstruction of the promoter, hindering gene transcription and subsequently silencing the gene (6). There is increasing evidence that in addition to genetic aberrati...

Metallothionein expression in colorectal cancer: relevance of different isoforms for tumor progression and patient survival

“…Importantly, some colorectal tissues and cell lines with MT1G promoter hypermethylation presented high levels of MT1 + 2 protein and MT1X and MT2A mRNA, further supporting the idea that these isoforms are regulated differently. MT1G hypermethylation has also been found in other tumor types and has been associated with higher tumor aggressiveness [30][31][32][33][34][35][36][37]. DAC treatment analysis further suggested that MT1H and MT1A might also be regulated by promoter hypermethylation.…”

The genetic and epigenetic landscapes of hepatoblastomas

“…Aberrant DNA methylation patterns have been associated with several diseases, including cancer [69]. The anomalous methylation pattern often detected in tumor samples [70][71][72] are characterized by global hypomethylation, mainly affecting repetitive sequences, and specific promoter hypermethylation in early stages of tumorigenesis and throughout cancer progression [73], as an alternative mechanism for tumor suppressor gene inactivation. To date, HBs have remained largely unexplored regarding DNA methylation profile, both in coding and repetitive sequences.…”

“…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].…”

Therapeutic Innovations for Targeting Hepatoblastoma

“…Therefore, loss or decrease of expression results in enhanced activity of the pathway and, potentially, contributes to the tumorigenesis process. Finally, APC silencing through hypermethylation has been described in about 30% of hepatoblastoma and is responsible for excess cytosolic β-catenin as the destruction complex is impaired (57).…”