Childhood liver cancer actually originates from hepatoblasts!

Hepatoblastoma (HB) is the most common malignant tumor in children, and one of the malignant tumors with the highest incidence in children under 5 years of age

HB is believed to be derived from liver precursor cells, and its morphology is similar to immature liver cells

Due to the large differences in the prognosis of patients, tumor distribution, tumor staging, and complete tumor resection are all prognostic indicators of HB

Researchers at Hiroshima University analyzed molecular studies of nearly 160 cases of childhood liver cancer and discovered molecular markers that help understand and treat differences in prognosis

This research was published in the September 20th issue of "Nature Communications"

Hepatoblastoma (HB) is the most common liver cancer in children

Surgical removal of tumors and preoperative chemotherapy have been proven to cure HB patients, but the prognosis of HB patients is also very different

The underlying cause is not clear, nor is the genetic susceptibility and molecular aberrations that cause these differences

Methylation and demethylation involve the addition or removal of one carbon atom and three hydrogen atoms (a set of methyl groups) in molecules throughout the body, like billions of small switches

Cytosine methylation is closely related to the level of gene expression

In addition, a comprehensive genomic analysis of HB tumor cells (collecting all their genetic material) showed that they are the least mutated cells of all solid tumors in children

"In order to improve the prognosis of HB patients, we really need to know what these epigenetic driving factors are," said Eiso Hiyama of the Center for Basic Research and Development of Natural Sciences at Hiroshima University.

Therefore, the research team performed genomic, epigenome, and methylation analysis on 163 untreated childhood liver tumors

First, the researchers identified genetic variants to clarify the genomic drivers of HB, thereby elucidating the genetic aspects of cancer susceptibility

According to their impact on the environment, these different approaches are categorized in turn

Finally, the research team combined clinical information with all these molecular characteristics to accurately stratify different types of HB patients

In most cases, they found that the occurrence of cancer is driven by the increased production of the transcription factor ASCL2 and the selective methylation pattern of insulin-like growth factor 2 (IGF2)
.

Transcription factors control the rate at which genetic information is transcribed from DNA to messenger RNA (the molecular chain that plays an intermediary role in genetic activities)
.
Messenger RNA reads and copies the DNA molecular formula, and then continues to "translate" the molecular formula into various proteins that make up most parts of the human body
.
At the site of HB cancer, the ASCL2 transcription factor plays a vital role in this process
.

At the same time, IGF2 is believed to stimulate the growth of children's tissues and cell differentiation
.

Methylation analysis also showed that HB cancer is characterized by a decrease in the number of methylated cytosines in the enhancer region
.
The enhancer region of the genetic code is where the transcription factor binds—in this case, the region where ASCL2 binds to DNA
.

This resulted in an abnormally prolonged production time for ASCL2
.
This, coupled with the IGF2 methylation pattern similar to that of fetal liver, indicates that the "origin cell" is the hepatoblast
.
Hepatoblasts are the precursors of fetal liver cells
.

They are very similar to intestinal epithelial cells in many ways
.
Intestinal epithelial cells are protective cells that line the outer surface of organs
.
Like cancer cells, they tend to proliferate in large numbers
.

This systematic analysis of HB tumors should now allow a more accurate ranking of the risks faced by different patients, as well as genomic therapies that are more suitable for their specific circumstances
.

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