Researchers discover a unique origin of severe pediatric brain cancer

A new cause of severe childhood brain cancer has been discovered by scientists. The research from St. Jude Children’s Research Hospital is the first to show how a transposon, a fragment of DNA that “jumps” throughout the genome, may offer its promoter to stimulate oncogene activation. The study was just published in Acta Neuropathologica.

Researchers discover a unique origin of severe pediatric brain cancer
Jinghui Zhang, PhD, chair of the Department of Computational Biology, and Jason Chiang, MD, PhD, Department of Pathology. Image Credit: St. Jude Children’s Research Hospital.

Transposons, which make up around 17% of the human genome, are repeating mobile sequences scattered across the genome. Humans have just one autonomously active transposon, Long Interspersed Element-1 (LINE-1 or L1). Around 80–100 active L1s with the potential to “jump” (retrotranspose) are found in the typical human genome. L1s, like other human genes, have DNA sequences that control the expression of retrotransposition genes.

A promoter is a type of regulatory element that starts gene expression at a specific location. The researchers discovered that the retrotransposition of L1 supplied an active promoter to an oncogene, FOXR2, in this investigation. This resulted in FOXR2 overexpression and, as a result, cancer.

The L1 promoter ‘donation’ mechanism is entirely novel. Our study opens the door for people to investigate this mechanism in initiating cancer and other diseases. This may require developing or enhancing computational methods to detect such events.”

Jinghui Zhang, PhD, Study Co-Corresponding Author and Chair, Computational Biology, St. Jude Children’s Research Hospital

A puzzling cancer classification

When a child cancer patient with a high-grade glioma presented to the clinic, the research began. Because high-grade gliomas are aggressive brain cancers that are typically resistant to therapy, clinicians and scientists are trying to figure out what’s causing them.

Pathologists typically use methylation, a kind of chemical change of DNA, as the gold standard for categorizing brain tumors, and compare it to histology to categorize cancer. This categorization then aids in therapy planning. The methylation sequence and histopathology did not fit in this case, hence the tumor was classed as unclassified.

From a clinical pathologic perspective, the tumor looked like a high-grade glioma, but it shows the methylation profile of a central nervous system embryonal tumor with FOXR2 activation, which is very rare. That prompted us to study this tumor because it suggests that high FOXR2 expression is the driver event.”

Jason Chiang, MD, PhD, Study Co-Corresponding Author, Department of Pathology, St. Jude Children’s Research Hospital

The researchers were interested in the sample’s mismatch, particularly the FOXR2 expression. FOXR2 is a transcription factor, a kind of protein that binds to DNA and regulates the expression of other genes. As a result, FOXR2 appeared to be the cause of cancer. However, the scientists needed to figure out why it was highly expressed in the first place.

Using existing computer algorithms, Zhang’s team was unable to determine why it was triggered. As a result, the researchers examined the raw sequencing data.

One algorithm’s trash is a scientist’s treasure

L1s have been implicated as cancer drivers in the past when their retrotransposition altered normal gene function, such as tumor suppressor expression. However, there have been no scientific reports of L1 promoter donation occurrences that drive oncogene expression prior to this study, because the promoter area is generally lost after retrotransposition into a distinct region of DNA.

Zhang and postdoctoral researcher Xiaolong Chen, PhD, noticed that the snipped pattern in the DNA looks like an L1 inside the FOXR2 gene in part of the data that a regular mapping approach normally clips out. Diane Flasch, PhD, a postdoctoral scholar who had previously worked with L1s, noticed the signals of an L1 regulatory element by chance.

To determine the structure of this retrotransposed L1 in FOXR2, the researchers used a novel approach that sequences larger stretches of DNA.

The researchers utilized samples collected overtime to figure out when the retrotransposition happened throughout the tumor’s growth. Because the L1 promoter donation occurred before other cancer-related mutations, it was probably the catalyst for the cancers.

Existing computational approaches were not intended to identify such an occurrence since implanted L1 regulatory elements were never suspected of being involved in tumorigenesis. For the first time, the pattern had to be seen and understood by a human mind.

Scientists need to keep their eyes open for all the possibilities. Do not filter out information that you think is garbage. Sometimes the gold is in the garbage.”

Jason Chiang, MD, PhD, Study Co-Corresponding Author, Department of Pathology, St. Jude Children’s Research Hospital

Source:
Journal reference:

Flasch, D. A., et al. (2022) Somatic LINE-1 promoter acquisition drives oncogenic FOXR2 activation in pediatric brain tumor. Acta Neuropathologica. doi.org/10.1007/s00401-022-02420-9.

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