By St. Jude Children’s Research Hospital
Scientists have discovered a new cause of aggressive childhood brain cancer. Jude Children’s Research Hospital study is the first of its kind to document how transposons, a piece of DNA that “jumps” around the genome, can donate its promoter to drive expression of an oncogene. This work was recently published in Acta Neuropathologic.
Transposons are repetitive motile sequences scattered throughout the genome that make up about 17% of the human genome. Long scattered element 1 (LINE-1 or L1) is the only active transposon in humans. The average human genome contains approximately 80-100 active L1s with the ability to ‘jump’ (retransport). Like most human genes, L1s contain portions of DNA that regulate the expression of genes required for the retrograde transformation process. One of these regulatory elements is called a promoter, which initiates gene expression at a specific site. In this study, the scientists found that L1 retrograde transduction provides an active promoter of the oncogene, FOXR2. This resulted in the overexpression of FOXR2, and eventually cancer.
“The ‘donation’ mechanism for the L1 promoter is completely new,” said co-author Jingwei Zhang, PhD, chair of the St. Jude Institute for Computational Biology. “Our study opens the door for people to investigate this mechanism in the initiation of cancer and other diseases. This may require the development or enhancement of computational methods to detect such events.”
A confusing classification of cancer
The research began when a pediatric cancer patient arrived at the clinic with a high-grade glioma. Doctors and scientists want to know the underlying cause of high-grade gliomas because they are often highly treatment-resistant brain cancers.
Typically, pathologists view a specific type of chemical modification of DNA, called methylation, as the gold standard for classifying brain tumors, matching it with histopathology to classify cancer. This classification then helps guide treatments. In this case, the methylation pattern did not match histopathology, so the tumor was unclassified.
“From a clinical perspective, the tumor appeared to be a high-grade glioma, but it shows the orthologous profile of a CNS embryonal tumor with FOXR2 activation, which is very rare,” said co-author Jason Chiang, MD. Ph.D., Department of Pathology St. Jude. “This prompted us to study this tumor because it suggests that high expression of FOXR2 is the driver event.”
Investigators were impressed by the sample mismatch presented, especially FOXR2 expression. FOXR2 is a type of protein called a transcription factor, which binds to DNA and alters the expression of other genes. Therefore, it appears that FOXR2 is driving the cancer. But the researchers needed to know why it was overexpressed.
Zhang’s group was unable to determine the reason for its activation using the available computational algorithms. Therefore, the researchers looked closely at the raw sequencing data.
The trash of an algorithm is a scientist’s treasure
L1s were previously reported as drivers of cancer when retrograde transduction disrupted normal gene function, for example, the correct expression of tumor suppressors. However, prior to this work, there had been no scientific reports of L1 promoter donation events that drive the expression of oncogenes, as usual, the promoter region is lost during retrograde conversion to a new region of DNA.
Within some of the data that a standard mapping algorithm typically cuts, Zhang and fellow postdoc Xiaolong Chen, PhD, realized that the truncated pattern in DNA is similar to L1 within the FOXR2 gene. In a moment of serendipity, Dianne Flash, PhD, a postdoctoral fellow who previously worked with L1s, learned about the signs of an L1 regulatory component. The researchers performed a special technique that sequences longer regions of DNA to decode the L1 transposon structure in FOXR2.
The scientists used samples obtained over time to find out when retrograde transformation occurred during tumor development. L1 promoter donation occurred before other cancer-associated mutations, so it is likely that the driving event caused the cancer.
Since the regulatory elements inserted in L1 were never suspected to be involved in tumorigenesis, current computational algorithms were not designed to detect such an event. It took a human mind to see and understand the pattern for the first time.
“Scientists need to keep their eyes open to all possibilities,” Chiang said. “Don’t filter out information that you think is rubbish. Sometimes the gold is in the trash.”
Epigenetic study provides new insights into the origins of glioma
Flash et al, Somatic LINE-1 promoter acquisition drives oncogenic FOXR2 activation in pediatric brain tumor, Acta Neuropathologic (2022). DOI: 10.1007/s00401-022-02420-9
Presented by St. Jude Children’s Research Hospital
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