St. Jude Children’s Research Hospital researchers have identified the first genetic alterations responsible for the brain tumor choroid plexus carcinoma using an approach that could help find oncogenes in other cancers
Researchers have identified three genes that play a pivotal role in the brain tumor choroid plexus carcinoma (CPC), a discovery that lays the groundwork for more effective treatment of this rare, often fatal cancer. St. Jude Children’s Research Hospital scientists led the study, which appears today in the journal Cancer Cell.
The genes – TAF12, NFYC and RAD54L – are involved in DNA repair and regulation. Researchers showed that CPC often has at least one extra copy of each gene and demonstrated that the genes work cooperatively to launch and sustain the tumor.
Investigators also found evidence that investigational drugs called ATR inhibitors that are already in development for cancer treatment may be effective against CPC. The drugs work by blocking certain DNA repair enzymes, increasing the susceptibility of tumor cells to chemotherapy or radiation. Planning has begun for a possible international clinical trial featuring an ATR inhibitor.
The findings suggest that disruption of normal DNA maintenance and repair plays a central role in CPC, a tumor with few treatment options. Of the estimated 50 pediatric CPC patients identified each year in the U.S., about two-thirds will die of their disease. While CPC occurs in both children and adults, most CPC patients are ages 2 or younger.
“This work provides hope for this rare, neglected disease by identifying some significant drivers of the tumor and providing the first real direction for treatment,” said corresponding author Richard Gilbertson, M.D., Ph.D., St. Jude scientific and Comprehensive Cancer Center director. The study’s first author is Yiai Tong, Ph.D., a St. Jude associate scientist.
The strategy used to discover the CPC oncogenes should also help researchers identify oncogenes that play important roles in other adult and pediatric cancers that include genetic changes called copy number alterations (CNAs). These alterations occur frequently in childhood cancer and involve the duplication or deletion of large pieces of DNA.
Of the 23 human CPCs in this study, 61 percent had at least one extra copy of chromosome 1, which carries more than 2,000 genes. “Large copy-number alterations are a common feature of childhood cancer, but until now there was no good way to answer the question of which of those genes was important to initiating or sustaining the cancer,” Gilbertson said.
For CPC, the answer began by chance. Gilbertson and his colleagues developed a mouse model of CPC while working to create an animal model to advance understanding of another pediatric brain tumor.
In this study, investigators used the CPC model to look for blocks of genes that are carried on human chromosome 1 and also duplicated in the mouse tumor. A search of 47 mouse CPCs turned up a chromosome fragment with 671 genes from human chromosome 1 that was duplicated in half of the mouse tumors. Researchers found evidence that 21 of the 671 duplicated genes were “switched on” or overexpressed in the mouse tumors.
CPC develops in cells that line the fluid-filled ventricles in the brain and produce cerebrospinal fluid. When researchers introduced each of the 21 genes into mouse choroid plexus cells in the laboratory, only Taf12, Nfyc and Rad54l led to changes associated with CPC, including cell proliferation. Researchers also showed that all three genes were required to initiate and sustain the tumors in mice.
“This same cross-species mapping approach holds promise for identifying oncogenes located in large regions of chromosomal gain that are a feature of other adult and pediatric cancers,” Gilbertson said.
For CPC patients, the results provide much needed direction for designing tumor-specific therapy. “These oncogenes may function like a mechanic who is always on the spot to keep a junk car running,” Gilbertson said. “Just like the car will break down if you get rid of the mechanic, preclinical trials are underway using different drug combinations to block the hyperactive DNA repair mechanism so the tumors eventually succumb to the accumulated DNA damage.”
The other authors are Birgit Nimmervoll, Yong-Dong Wang, David Finkelstein, James Dalton, David Ellison, Xiaotu Ma and Jinghui Zhang, all of St. Jude; Kirti Gupta, formerly of St. Jude, and Diane Marino and David Malkin, both of The Hospital for Sick Children and the University of Toronto.
The study was funded in part by grants (CA129541, CA96832, CA021765) from the National Institutes of Health; a grant (W81XWH1010674) from the Department of Defense and ALSAC.
St. Jude Children's Research Hospital
St. Jude Children's Research Hospital is leading the way the world understands, treats and cures childhood cancer and other life-threatening diseases. It is the only National Cancer Institute-designated Comprehensive Cancer Center devoted solely to children. Treatments developed at St. Jude have helped push the overall childhood cancer survival rate from 20% to 80% since the hospital opened more than 50 years ago. St. Jude shares the discoveries it makes, and every child saved at St. Jude means doctors and scientists worldwide can use that knowledge to save thousands more children. To learn more, visit stjude.org or follow St. Jude on social media at @stjuderesearch.