Researchers Uncover Genetic and Epigenetic ‘Origin Story’ of Pediatric Liver Cancer

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Researchers at Hiroshima University analyzed the molecular results of nearly 160 cases of pediatric liver cancer and found molecular markers that should help understand and treat the vast variation in prognosis.

The study appears in the journal Nature Communications on September 20.

Hepatoblastoma (HB) is the most common liver cancer in children. It presents as a painful tumor mass in the abdomen and mainly affects children up to three years old, especially those who are born prematurely or have very low birth weight.

Surgery to remove the tumor and preoperative chemotherapy before such an operation 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 the hereditary predisposition and molecular aberrations that lead to these variations in outcome are not well understood. The term molecular aberration refers to anything unusual about genes that causes alterations in the way they are expressed (turned on). These may be mutations, duplications of DNA extensions, or unusual patterns of DNA methylation.

Methylation and demethylation involve the addition or removal, respectively, of a single carbon and three hydrogen atoms (a methyl group) to molecules throughout the body, functioning like billions of small on / off switches . In the case of DNA, methyl groups are added to or removed from cytosine nucleotides along stretches of genes.

Methylation of cytosines is heavily involved in gene expression levels, and it also provides important epigenetic function – or how your environment and even behaviors can change the way your body reads a DNA sequence – which is fundamental. for how cells turn into different types for this. or this particular bodily function in the development process.

Additionally, complete genomic analyzes of HB tumor cells (all of the genetic material they contain) have shown that they have some of the weakest genetic mutations of any pediatric solid tumor. These strongly suggested epigenetic changes contribute to what gives rise to the disease.

“In order to improve outcomes for HB patients, we really needed to know what these epigenetic drivers are,” said Eiso Hiyama of the Natural Science Center for Basic Research and Development at Hiroshima University, “and explore what the “original cell” is where it all begins.

The team therefore performed genomic, epigenomic and methylation profiling of 163 untreated pediatric liver tumors. The survey consisted of three main parts.

First, the researchers identified genetic variations to clarify the genomic drivers of HB and therefore the hereditary aspects of predisposition to cancer. Second, they profiled the “methylome”, the set of all methylation changes in the genome, to uncover the various pathways of HB cancer origin. These different pathways were in turn categorized based on their environmental effects, and in doing so, scientists revealed the distinct subtypes of cancer origin that are linked to different pathological features, genomic alterations, and gene expression. Finally, the team gathered clinical information and all these molecular characteristics to develop a precise stratification of the different types of HB patients.

Common to most cases, they found that the genesis of cancer is driven by increased production of the transcription factor ASCL2 and patterns of selective methylation of insulin-like growth factor 2 (ILGF2).

Transcription factors control the rate at which genetic information is transcribed from DNA to messenger RNA (the chain of molecules that plays an intermediary role in genetic activity. Messenger RNA reads and reproduces the recipe. DNA in a form that can then “translate” the ASCL2 transcription factor in particular plays a critical role in this process in cells that turn into tissue in the very area of ​​the body where HB cancers appear.

IGF2, on the other hand, is believed to stimulate tissue growth and cell differentiation in children.

Methylation profiling also revealed that HB cancers are characterized by a decrease in the number of methylated cytosines in enhancer regions. Amplifier regions of the genetic code are the sites where transcription factors bind to them – in this case, the regions where ASCL2 binds to DNA. This results in prolonged additional production of ASCL2. This, together with IGF2 methylation patterns similar to those in fetal livers, suggests that the “parent cell” is a premature hepatoblast. A hepatoblast is the precursor in the fetus of a hepatocyte, or fully formed liver cell, and is very similar in various respects to intestinal epithelial cells – the protective cells that line the outer surfaces of organs and which, like the cancers, tend to proliferate wildly.

This systematic profiling of HB tumors should now allow a more precise classification of the risks incurred by different patients and genomic therapies more suited to their particular situation.

Journal: Nature Communications

Title: Genetic and epigenetic basis of hepatoblastoma diversity

Authors: Genta Nagae, Shogo Yamamoto, Masashi Fujita, Takanori Fujita, Aya Nonaka, Takayoshi Umeda, Shiro Fukuda, Kenji Tatsuno, Kazuhiro Maejima, Akimasa Hayashi, Sho Kurihara, Masato Kojima, Tomoro Hishiki, Kenichiro Yanoko Yanabe, Michhiro Yanoko Hiyama, Yukichi Tanaka, Takeshi Inoue, Hiroki Ueda, Hidewaki Nakagawa, Hiroyuki Aburatani & Eiso Hiyama

DOI: 10.1038 / s41467-021-25430-9


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