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'Hijacker' gene drives high-risk neuroblastomas
Neuroblastoma is cancer of the sympathetic nervous system. It develops in neuroblasts or immature nerve cells and is diagnosed annually in about 800 people in the US, mostly infants and very young children.
Although the long-term survival rate is about 95 percent for patients with low-risk neuroblastoma, prognosis for the 40 percent of patients with high-risk neuroblastoma, is perhaps five years following diagnosis. Researchers in Memphis and Boston now find c-MYC, an oncogene, drives neuroblastoma in some high-risk patients. The findings help set the stage for development of precision medicines targeting the molecular interactions described in the research published in the journal Cancer Discovery.
In about 10 percent of high-risk neuroblastoma cases — cancer "hijacks" the DNA regulating other genes. The c-Myc oncogene is a “master regulator” gene that controls many aspects of cell growth and cell metabolism. It belongs to a family of transcription factors that "read" genes in order to create proteins, and is the second in the MYC (Myelocytomatosis Viral Oncogene Homolog) family to be linked to neuroblastoma. About 25 percent of high-risk neuroblastoma patients have extra copies of MYCN. However, c-MYC is not amplified in neuroblastoma. Until this study, there was little evidence of c-MYC's role in neuroblastoma. "These findings establish c-MYC as a bona fide oncogene in a clinically significant group of high-risk childhood neuroblastoma," the authors state.
C-MYC can be detected in the clinic, and the protein offers another focus for precision drug development, particularly in an emerging class of drugs that work by degrading proteins like c-MYC.
The research also marks the apparent debut of a technology called in-situ chromosome conformation capture, or Hi-C and also known as 3-D genomics. By any name, it is a process that identifies additional genetic abnormalities driving pediatric cancers. It's approach is to bring widely separated pieces of DNA together, through manipulating the loops and folds in the DNA molecule, to capture genomic interactions between otherwise widely separated pieces of the DNA molecule.
Co-corresponding author Jinghui Zhang PhD, Chair, St. Jude Department of Computational Biology, and her colleagues used this technology to show c-MYC sometimes hijacks regulatory DNA in other genes to drive its own gene expression.
Prior to completing the whole genome sequencing and analysis required for 3-D genomics, Zhang's group showed how c-MYC was overexpressed in about 10 percent of the 123 patient neuroblastoma tumors observed in the study. Tumor samples used were from the National Cancer Institute's Therapeutically Applicable Research to Generate Effective Treatments or TARGET initiative. Patients with a high production of c-MYC were distinct from the 25 percent of high-risk neuroblastoma patients with MYCN amplification. However, patients in both groups had poor survival rates.
Using zebrafish as their model, A. Thomas Look MD, and colleagues at Dana-Farber Institute, found overexpression of c-MYC transformed normal neuroblasts into malignant neuroblastoma cells. Overexpression of c-MYC was also a more potent oncogene than MYCN. C-MYC overexpression led to a shorter time before the onset of cancer, with a greater likelihood of neuroblastoma than seen with MYCN overexpression.
"Studies in the zebrafish model indicated that c-MYC could in fact cause neuroblastoma. Even though, it was never amplified at the gene level as seen in MYCN childhood neuroblastoma."
Further analysis of tumor data by Yu Liu PhD, co-first author, revealed how some chromosomal rearrangements (translocations) resulted in cancers. Combining whole genome sequencing of neuroblastoma cell lines with 3-D genomics, Zhang and her colleagues found some translocations placed c-MYC next to pieces of DNA called super-enhancers which rev-up expression of genes. "Hi-C allowed us to profile the genome comprehensively and establish a connection between the super-enhancer and the oncogene," Zhang explained.
Research to understand the genetic abnormalities driving cancer has focused on mutations in coding regions of DNA that lead to changes in protein structure and function or on translocations that result in fusion genes and abnormal proteins. "This study shows that rearrangements that affect non-coding regions of the genome could be an important class of structural variations that drive cancer by disrupting the regulation of oncogenes," says Zhang.
Richard Young PhD, and colleagues at the Whitehead Institute, have also identified another route of c-MYC overexpression in neuroblastoma cells — DNA regions that enhanced or amplified c-MYC expression. Enhanced amplification has been reported in other cancers, including leukemia and lung cancer, promoting transformation of normal cells into malignant cells.
The amplified MYCN gene serves as an oncogenic driver in approximately 20% of high-risk pediatric neuroblastomas. Here we show that the family member c-MYC is a potent transforming gene in a separate subset of high-risk neuroblastoma cases (~10%), based on (i) its upregulation by focal enhancer amplification or genomic rearrangements leading to enhancer hijacking, and (ii) its ability to transform neuroblastoma precursor cells in a transgenic animal model. The aberrant regulatory elements associated with oncogenic c-MYC activation include focally amplified distal enhancers and translocation of highly active enhancers from other genes to within topologically associating domains containing the c-MYC gene locus. The clinical outcome for patients with high levels of c-MYC expression is virtually identical to that of patients with amplification of the MYCN gene, a known high-risk feature of this disease. Together, these findings establish c-MYC as a bona fide oncogene in a clinically significant group of high-risk childhood neuroblastomas.
Authors: Mark W. Zimmerman, Yu Liu, Shuning He, Adam D. Durbin, Brian J. Abraham, John Easton, Ying Shao, Beisi Xu, Shizhen Zhu, Xiaoling Zhang, Zhaodong Li, Nina Weichert-Leahey, Richard A. Young, Jinghui Zhang and A. Thomas Look.
The study's other authors are John Easton, Ying Shao and Beisi Xu, all of St. Jude; Shuning He, Adam Durbin, Zhaodong Li and Nina Weichert-Leahey, all of Dana-Farber; Brian Abraham of the Whitehead Institute; and Shizhen Zhu and Xiaoling Zhang, both of the Mayo Clinic.
The research was funded in part by grants (CA210064, CA180692, CA021765) from the National Institutes of Health; Alex's Lemonade Stand Foundation; Damon Runyon Cancer Research Foundation; Jake Wetchler Foundation; and ALSAC, the fundraising and awareness organization of St. Jude.
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Study authors (from left) Ying Shao, John Easton PhD, and Yu Liu PhD. Image credit: Seth Dixon / St. Jude Children's Research Hospital