Epigenetic footprint enables molecular risk stratification of hepatoblastoma with clinical implications

Abstract

HB patients GENOMIC STUDY TRANSCRIPTOMIC STUDY METHYLATION STUDY CytoScan HD ®-array RNA-sequencing/ ddPCR HTA ®-array/ RT-qPCR 850K (EPIC)-array/ QUAlu Dysregulation of global RNA & BLCAP editing Overexpression of 14q32 DLK1-DIO3 genes 16 + VIM-gene signature (C1/C2/C2B) 2 epigenomic HB subtypes (Epi-CA & Epi-CB) CLINICAL PARAMETERS: prognostic marker identification Poor prognostic factors:-4q,-18, 17q11.2 AI (NF1) CHKA new therapeutic target Molecular risk stratification MRS1 MRS2 MRS3 Strong 14q32 Epi-CB Time Survival Highlights Hepatoblastoma (HB) involves global dysregulation of RNA editing, including in the tumor suppressor BLCAP. Overexpression of a 300 kb region within the 14q32 DLK1/DIO3 locus is a new hallmark of HB. We identified 2 epigenomic HB subtypes-Epi-CA and Epi-CB-with distinct degrees of DNA hypomethylation and CpG island hypermethylation. The molecular risk stratification of HB, based on the 14q32-signature and epigenomic subtypes, is associated with patient outcomes. The enzyme CHKA could be a novel therapeutic target for patients with HB.

A MicroRNA Cluster in the DLK1-DIO3 Imprinted Region on Chromosome 14q32.2 Is Dysregulated in Metastatic Hepatoblastomas

“…Nonetheless, miRNAs and snoRNAs located in the 14q32.2 cluster showed significantly upregulated expression in metastatic tumors. Interestingly, our results resemble recent findings within a stemlike subtype of HCC, which is known to be associated with overexpression of miRNAs located in this cluster (23), and they are also very similar to a recent report showing that genes in the DLK1-DIO3 imprinted region are hypomethylated and overexpressed in HB, enabling stratification of patient outcomes (24). These studies suggest that certain molecular mechanisms, such as Wnt signaling pathways or TGF-beta, might be related to the tumorigenesis of this unique stem-like subtype of HCC.…”

“…These studies suggest that certain molecular mechanisms, such as Wnt signaling pathways or TGF-beta, might be related to the tumorigenesis of this unique stem-like subtype of HCC. Indeed, in their very recent paper Carrillo-Reixach et al (24) investigated a large cohort of HB patients, and demonstrated that overexpression and hypomethylation of genes in the 14q32 DLK1-DIO3 imprinted region, which includes the largest known cluster of miRNAs and snoRNAs in the human genome, is associated with HB patient outcome, and activation of the Wnt/beta-catenin pathway. Activation of the Wnt/b-catenin is a hallmark in HB (4,25), and the Hippo pathway has also been reported in HB (26,27).…”

“…imprinted region were overexpressed in a stem-like subtype of hepatocellular carcinoma (23), and very recently Carrillo-Reixach et al (2020) have reported that genes in the DLK1-DIO3 imprinted region are hypomethylated and overexpressed in HB, enabling stratification of patient outcome (24).…”

Hepatoblastomas exhibit markedNNMTdownregulation driven by promoter DNA hypermethylation

“…7 Recently, a new approach adding epigenomics to genomic/transcriptomic data resulted in an HBL risk stratification model composed of three subgroups, based on the degree of hypomethylation, as well as the expression pattern of genes located at the 14q32 locus. 14 In a previous work, we explored the role of epigenetic mechanisms in HBL by analyzing changes in DNA methylation (DNAm) in comparison to control embryonic and differentiated liver samples; 15 a widespread and non-stochastic pattern of global low-level hypomethylation was disclosed in tumors, with enrichments at intergenic CpG sites. Loss of DNAm in HBL was also reported by Cui et al 16 Furthermore, aberrant DNAm in specific loci has been described in HBL samples, suggesting that epigenetic alterations are an important mechanism associated with their development.…”

Dna Methylation as a Key Epigenetics Player for Hepatoblastoma Stratification

“…Moreover, amplification of the oncogenic 14q32 DLK1-DIO3 locus in part of the HBs delineated signatures of moderate or strong expression of genes mapped to this region. Using both findings, a molecular risk stratification of three categories was proposed (MRS-HB) 37 . Despite using a smaller cohort of 21 HB samples in our study, we also showed that DNA methylation is a strong biomarker for HB stratification, pinpointing to specific DNA methylation genes as important players.…”