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Genetic and epigenetic basis of hepatoblastoma diversity.

ABSTRACT: Hepatoblastoma (HB) is the most common pediatric liver malignancy; however, hereditary predisposition and acquired molecular aberrations related to HB clinicopathological diversity are not well understood. Here, we perform an integrative genomic profiling of 163 pediatric liver tumors (154 HBs and nine hepatocellular carcinomas) based on the data acquired from a cohort study (JPLT-2). The total number of somatic mutations is precious low (0.52/Mb on exonic regions) but correlated with age at diagnosis. Telomerase reverse transcriptase (TERT) promoter mutations are prevalent in the tween HBs, selective in the transitional liver cell tumor (TLCT, > 8 years old). DNA methylation profiling reveals that classical HBs are characterized by the specific hypomethylated enhancers, which are enriched with binding sites for ASCL2, a regulatory transcription factor for definitive endoderm in Wnt-pathway. Prolonged upregulation of ASCL2, as well as fetal-liver-like methylation patterns of IGF2 promoters, suggests their "cell of origin" derived from the premature hepatoblast, similar to intestinal epithelial cells, which are highly proliferative. Systematic molecular profiling of HB is a promising approach for understanding the epigenetic drivers of hepatoblast carcinogenesis and deriving clues for risk stratification.

SUBMITTER: Nagae G

PROVIDER: S-EPMC8450290 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature

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Genetic and epigenetic basis of hepatoblastoma diversity.

Nagae Genta G Yamamoto Shogo S Fujita Masashi M Fujita Takanori T Nonaka Aya A Umeda Takayoshi T Fukuda Shiro S Tatsuno Kenji K Maejima Kazuhiro K Hayashi Akimasa A Kurihara Sho S Kojima Masato M Hishiki Tomoro T Watanabe Kenichiro K Ida Kohmei K Yano Michihiro M Hiyama Yoko Y Tanaka Yukichi Y Inoue Takeshi T Ueda Hiroki H Nakagawa Hidewaki H Aburatani Hiroyuki H Hiyama Eiso E

Nature communications 20210920 1

Hepatoblastoma (HB) is the most common pediatric liver malignancy; however, hereditary predisposition and acquired molecular aberrations related to HB clinicopathological diversity are not well understood. Here, we perform an integrative genomic profiling of 163 pediatric liver tumors (154 HBs and nine hepatocellular carcinomas) based on the data acquired from a cohort study (JPLT-2). The total number of somatic mutations is precious low (0.52/Mb on exonic regions) but correlated with age at dia ...[more]

PMID: 34538872

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Project description:Uncovering the functionally essential variations related to tumorigenesis and tumor progression from cancer genomics data is still challenging due to the genetic diversity among patients, and extensive inter- and intra-tumoral heterogeneity at different levels of gene expression regulation, including but not limited to the genomic, epigenomic, and transcriptional levels. To minimize the impact of germline genetic heterogeneities, in this study, we establish multiple primary cultures from the primary and recurrent tumors of a single patient with hepatocellular carcinoma (HCC). Multi-omics sequencing was performed for these cultures that encompass the diversity of tumor cells from the same patient. Variations in the genome sequence, epigenetic modification, and gene expression are used to infer the phylogenetic relationships of these cell cultures. We find the discrepancy among the relationships revealed by single nucleotide variations (SNVs) and transcriptional/epigenomic profiles from the cell cultures. We fail to find overlap between sample-specific mutated genes and differentially expressed genes (DEGs), suggesting that most of the heterogeneous SNVs among tumor stages or lineages of the patient are functionally insignificant. Moreover, copy number alterations (CNAs) and DNA methylation variation within gene bodies, rather than promoters, are significantly correlated with gene expression variability among these cell cultures. Pathway analysis of CNA/DNA methylation-related genes indicates that a single cell clone from the recurrent tumor exhibits distinct cellular characteristics and tumorigenicity, and such an observation is further confirmed by cellular experiments both in vitro and in vivo. Our systematic analysis reveals that CNAs and epigenomic changes, rather than SNVs, are more likely to contribute to the phenotypic diversity among subpopulations in the tumor. These findings suggest that new therapeutic strategies targeting gene dosage and epigenetic modification should be considered in personalized cancer medicine. This culture model may be applied to the further identification of plausible determinants of cancer metastasis and relapse.

Dataset Information

Genetic and epigenetic basis of hepatoblastoma diversity.

Publications

Genetic and epigenetic basis of hepatoblastoma diversity.

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