'Hijacker' drives cancer in some patients with high-risk neuroblastoma

January 22, 2018

Researchers have identified mechanisms that drive about 10 percent of high-risk neuroblastoma cases and have used a new approach to show how the cancer genome "hijacks" DNA that regulates other genes. The resulting insights may help scientists develop more effective therapies, including precision medicines. The research involved investigators at St. Jude Children's Research Hospital; Dana-Farber Cancer Institute, Boston; and the Whitehead Institute for Biomedical Research, Cambridge, Massachusetts. The findings appeared online recently in the journal Cancer Discovery.

Neuroblastoma is a cancer of the sympathetic nervous system diagnosed annually in about 800 U.S. residents, primarily infants and young children. Although the long-term survival rate for patients with low-risk neuroblastoma is about 95 percent, the prognosis is worse for the 40 percent of patients with high-risk neuroblastoma. About half of those patients are alive five years after diagnosis.

c-MYC belongs to a family of transcription factors that regulates a wide range of important cellular processes. It is the second MYC family member that has been linked to neuroblastoma. About 25 percent of high-risk neuroblastoma patients have extra copies of MYCN. But c-MYC is not amplified in neuroblastoma. Until this study, evidence was lacking about the gene's role in neuroblastoma, which develops in immature nerve cells called neuroblasts.

"These findings establish c-MYC as a bona fide oncogene in a clinically significant group of high-risk childhood neuroblastoma," the authors noted. c-MYC can be detected in the clinic, and the protein offers another focus for precision drug development, particularly for 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, to identify additional genetic abnormalities driving pediatric cancer. The tool is also known as 3-D genomics. The approach helps researchers capture genomic interactions that bring widely separated pieces of DNA together through the loops and folds of the DNA molecule.

Co-corresponding author Jinghui Zhang, Ph.D., chair of the St. Jude Department of Computational Biology, and her colleagues used the technology to show c-MYC sometimes hijacks the regulatory DNA of other genes to drive its own expression.

Evidence against c-MYC

Prior to completing the whole genome sequencing and analysis required for 3-D genomics, Zhang and her colleagues showed that c-MYC was overexpressed in about 10 percent of the 123 neuroblastoma patient tumors included in the study. The samples were part of National Cancer Institute's Therapeutically Applicable Research to Generate Effective Treatments-or TARGET initiative.

Researchers showed that patients with high production of c-MYC were distinct from the 25 percent of high-risk neuroblastoma patients with MYCN amplifications. But patients in both groups had similarly poor survival.

Meanwhile, working in zebrafish, A. Thomas Look, M.D., and his colleagues at Dana-Farber showed that overexpression of c-MYC transformed normal neuroblasts to malignant cells and caused neuroblastoma. In this laboratory model, overexpression of c-MYC was a more potent oncogene than MYCN. In zebrafish, c-MYC overexpression led to a shorter time of onset and higher penetrance (greater likelihood) of neuroblastoma than 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 like MYCN in childhood neuroblastoma, leading to in- depth studies by Dr. Zhang and her colleagues to investigate other genomic mechanisms," Look said.

Further analysis of the tumor data by co-first author Yu Liu, Ph.D., revealed chromosomal rearrangements that occurred close to c-MYC in some tumors. Such rearrangements, or translocations, happen when chromosomes break and re-assemble, sometimes with disastrous results. Liu is a postdoctoral fellow in Zhang's St. Jude laboratory. Co-first author Mark Zimmerman, Ph.D., is a member of Look's laboratory.

Zhang and her colleagues combined whole genome sequencing of neuroblastoma cell lines with 3-D genomics to reveal how the translocation led to overexpression of c-MYC. The researchers showed that the translocation put c-MYC next to pieces of DNA called super-enhancers that normally regulate and rev-up expression of other genes. c-MYC hijacked the super-enhancers, driving gene expression and fueling development of neuroblastoma.

Hi-C allowed us to profile the genome comprehensively and establish rather than infer the connection between the super-enhancer and the oncogene," Zhang said.

Genome architecture provides evidence

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," Zhang said.

Working in neuroblastoma cell lines, Richard Young, Ph.D., of the Whitehead Institute and his colleagues identified another route to c-MYC overexpression. The researchers found DNA regions that enhance c-MYC expression were amplified, or increased, in neuroblastoma cell lines with c-MYC overexpression. Enhancer amplification has been reported in other cancers, including leukemia and lung cancer, where it helps promote the transformation of normal cells to malignant ones.
-end-
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.

St. Jude Children's Research Hospital

Related Cancer Articles from Brightsurf:

New blood cancer treatment works by selectively interfering with cancer cell signalling
University of Alberta scientists have identified the mechanism of action behind a new type of precision cancer drug for blood cancers that is set for human trials, according to research published in Nature Communications.

UCI researchers uncover cancer cell vulnerabilities; may lead to better cancer therapies
A new University of California, Irvine-led study reveals a protein responsible for genetic changes resulting in a variety of cancers, may also be the key to more effective, targeted cancer therapy.

Breast cancer treatment costs highest among young women with metastic cancer
In a fight for their lives, young women, age 18-44, spend double the amount of older women to survive metastatic breast cancer, according to a large statewide study by the University of North Carolina at Chapel Hill.

Cancer mortality continues steady decline, driven by progress against lung cancer
The cancer death rate declined by 29% from 1991 to 2017, including a 2.2% drop from 2016 to 2017, the largest single-year drop in cancer mortality ever reported.

Stress in cervical cancer patients associated with higher risk of cancer-specific mortality
Psychological stress was associated with a higher risk of cancer-specific mortality in women diagnosed with cervical cancer.

Cancer-sniffing dogs 97% accurate in identifying lung cancer, according to study in JAOA
The next step will be to further fractionate the samples based on chemical and physical properties, presenting them back to the dogs until the specific biomarkers for each cancer are identified.

Moffitt Cancer Center researchers identify one way T cell function may fail in cancer
Moffitt Cancer Center researchers have discovered a mechanism by which one type of immune cell, CD8+ T cells, can become dysfunctional, impeding its ability to seek and kill cancer cells.

More cancer survivors, fewer cancer specialists point to challenge in meeting care needs
An aging population, a growing number of cancer survivors, and a projected shortage of cancer care providers will result in a challenge in delivering the care for cancer survivors in the United States if systemic changes are not made.

New cancer vaccine platform a potential tool for efficacious targeted cancer therapy
Researchers at the University of Helsinki have discovered a solution in the form of a cancer vaccine platform for improving the efficacy of oncolytic viruses used in cancer treatment.

American Cancer Society outlines blueprint for cancer control in the 21st century
The American Cancer Society is outlining its vision for cancer control in the decades ahead in a series of articles that forms the basis of a national cancer control plan.

Read More: Cancer News and Cancer Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.