Study finds genetic, epigenetic ‘origin story’ of pediatric liver cancer

ANI | Updated: Sep 26. 2021 21:50 IST

Hiroshima [Japan], Sept. 26 (ANI): Researchers from the University of Hiroshima recently analyzed the molecular findings of nearly 160 pediatric liver cancer cases, leading to the discovery of molecular markers that would help understand and treat the significant variation in prognosis.
The study was recently published in the journal Nature Communications.
Hepatoblastoma (HB) is the most common liver cancer in children. It presents as a painful, tumor-like mass in the abdomen and mainly affects children up to three years old, especially those born prematurely or with very low birth weight.
Surgery to remove the tumor and preoperative chemotherapy prior to such surgery have been shown to cure many patients of the disease, but the prognosis in HB patients also varies widely.
The underlying causes remain unknown and heredity and molecular aberrations leading to these variations in outcomes are not well understood. The term molecular aberration refers to anything unusual about genes that causes changes in the way they are expressed (activated). These can be mutations, duplications of pieces of DNA, or unusual patterns of DNA methylation.
Methylation and demethylation involve the addition or removal of a single carbon and three hydrogen atoms (a methyl group), respectively, to molecules throughout the body, acting like billions of tiny on/off switches. In the case of DNA, the methyl groups are added to or removed from the cytosine nucleotides along arrays of genes.
Methylation of cytosines is heavily involved in gene expression levels, and it also provides an important epigenetic function — or how your environment and even behavior can change how your body reads a DNA sequence — that is fundamental to how cells change themselves into different types for this or that bodily function especially in the development process.
In addition, extensive genomic analyzes of the HB tumor cells (the collection of all the genetic material within them) have shown that they have some of the fewest genetic mutations of all solid pediatric tumors. These highly suggested epigenetic changes contribute to the cause of the disease.
“To improve outcomes in HB patients, we really needed to know what these epigenetic drivers are,” said Eiso Hiyama of Hiroshima University’s Natural Science Center for Basic Research and Development, “and explore what the ‘cell of origin’ is.” — basically where it all begins.”

So the team performed genomic, epigenomic and methylation profiling of 163 untreated pediatric liver tumors. The research consisted of three main parts.
First, the researchers identified genetic variations to clarify the genomic drivers of HB and thus the heritable aspects of cancer predisposition. Second, they profiled the ‘methylome’ – the collection of all methylation modifications in the genome – to discover the different pathways of HB cancer origin.
These different pathways were in turn categorized according to their environmental effects and in doing so, the scientists revealed the different subtypes of cancer origin associated with different pathological features, genomic changes and gene expression. Finally, the team brought together clinical information and all these molecular features to develop an accurate stratification of different types of HB patients.
In most cases, they found that cancer development is driven by a boost in the production of the transcription factor ASCL2 and the selective methylation patterns of insulin-like growth factor 2 (ILGF2).
Transcription factors determine the rate of transcription of genetic information from DNA to messenger RNA (the chain of molecules that plays an intermediate role in genetic activity. Messenger RNA reads and replicates the DNA recipe in a form that can then ‘translate’ the recipe in the different types of proteins that make up most parts of the body. The ASCL2 transcription factor in particular plays an essential role in this process in the cells turning into tissue in the area of ​​the body where HB cancers appear.
Meanwhile, IGF2 is believed to stimulate tissue growth and cell differentiation in children.
The methylation profiling also revealed that HB cancers are characterized by a decrease in the number of methylated cytosines in enhancer regions. Enhancer regions of genetic code are the sites where transcription factors bind to it – in this case, the regions where ASCL2 binds to the DNA. This results in long-term additional production of ASCL2.
This, together with methylation patterns of IGF2 similar to those of fetal livers, suggest that the ‘origin cell’ is a premature hepatoblast. A hepatoblast is a precursor in the fetus of a hepatocyte or fully formed liver cell and is very similar in several respects to intestinal epithelial cells – the protective cells that line the outer surfaces of organs and which, like cancers, tend to multiply. wild.
This systematic profiling of HB tumors should now allow for a more accurate classification of the risks faced by different patients and of genomic therapies that are better suited to their specific circumstances. (ANI)

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