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Childhood Liver Cancer’s Cellular Origin and Molecular Drivers Uncovered

A large collaborative team led by scientists at Hiroshima University, Japan, has conducted systematic molecular profiling of pediatric liver cancer based on data collected from 154 hepatoblastomas and nine hepatocellular carcinomas. Markers discovered by this study will help to understand and treat the considerable variation in prognoses of pediatric liver cancers.

Hepatoblastoma is the most common liver cancer in children. Primarily detected in children less than three years old who were born prematurely or with very low birth weight, hepatoblastoma presents as painful tumors in the abdomen. Underlying hereditary or acquired genetic mutations responsible for the highly variable prognoses in hepatoblastomas remain unclear.

The findings of the study are reported in an article in the journal Nature Communications, titled “Genetic and epigenetic basis of hepatoblastoma diversity”  and emphasize the efficacy of systematic molecular profiling in identifying epigenetic drivers of pediatric liver tumors and in providing valuable pointers for assigning risk levels to patients (risk stratification).

Childhood and adult liver malignancies characterized by molecular aberrations and cell of origin. [Eiso Hiyama/Hiroshima University]

The researchers probe into genetic variations to clarify the genomic drivers of hepatoblastomas and thereby the hereditary aspects of cancer predisposition. Next, they profile the “methylome”—the set of all methylation modifications in genomic DNA. And finally, the team compares clinical data and molecular features to stratify hepatoblastoma patients.

The researchers report the total number of somatic mutations in these liver cancers is low compared to other pediatric solid tumors—0.52/megabase in protein-coding, exonic regions, but these correlate with age at diagnosis. They observe mutations in the promoter region of the telomerase reverse transcriptase (TERT) are common in tween hepatoblastomas and less common in transitional liver cell tumors (TLCT) in children over 8 years. The paucity of linked genetic mutation strongly suggests epigenetic changes contribute to the rise of these tumors.

“In order to improve outcomes of hepatoblastoma patients, we really needed to know what these epigenetic drivers are,” says Eiso Hiyama, PhD, a research scientist at Hiroshima University’s Natural Science Center for Basic Research and Development, “and explore what the ‘cell of origin’ is—basically where it all starts.”

To explore epigenetic triggers, the authors perform DNA methylation profiling that shows decreased methylation in regulatory enhancer regions enriched for binding sites of ASCL2 is the hallmark of classical hepatoblastomas. ASCL2 is a transcription factor important in the Wnt signaling pathway that is central in the development of the definitive endoderm that gives rise to the liver.

DNA methylation and de-methylation—the addition and removal of methyl groups–work as targeted on/off switches that control the decoding of genes. Methylation of cytosine residues in DNA provides important epigenetic modulation of gene expression, controlling how the environment and behaviors regulate DNA decoding.

The authors note, sustained upregulation of ASCL2, and methylation patterns on promotors of the gene called insulin-like growth factor 2 (IGF2) that match the liver in the fetal stage, suggests that the cell of origin of hepatoblastomas is derived from an undifferentiated fetal state of the liver cell, called the hepatoblast, that like cells that line the intestines, divide rapidly. IGF2 stimulates the growth of tissues and differentiation of cells in children.

The systematic profiling of liver tumors in pediatric patients should now allow for a more accurate ranking of risk in patients and help identify specific genomic therapies linked to the patient’s precise disease profile.

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