Eighteen genes identified that contribute to childhood brain tumor ependymoma

St. Jude Children’s Research Hospital discovery lays the foundation for developing new, much needed chemotherapy agents and finds evidence that anti-cholesterol drugs called statins slow growth of ependymoma tumor cells

St. Jude Children’s Research Hospital scientists have identified eight tumor-promoting oncogenes and 10 tumor suppressor genes that converge on a handful of cell functions and help to launch the pediatric brain tumor ependymoma. The study appeared today in an Advance Online Publication (AOP) of the scientific journal Nature Genetics.

The findings dramatically expand understanding of ependymoma, which until now has been linked to alterations in just two genes. The tumor is discovered in 150 to 200 children and adults annually in the U.S., where it is the third most common pediatric brain tumor. Researchers expect insight from this study will lead to new chemotherapy agents and more effective treatment of a cancer that remains incurable in about 28 percent of pediatric patients.

The method scientists developed in this study to identify oncogenes could aid efforts to find other oncogenes driving adult and pediatric cancers that feature genetic changes called copy number alterations (CNAs). CNAs involve large pieces of DNA that are often duplicated or deleted in tumors, affecting hundreds or even thousands of genes.

The newly identified ependymoma oncogenes and tumor suppressor genes were found in 28 common CNAs in tumors from 83 patients. The oncogenes included seven not previously linked to cancer.

Investigators used mouse models to show the ependymoma oncogenes and tumor suppressor genes were involved in regulating many of the same cell processes. Those include cholesterol production, DNA modification and repair, the immune response and a mechanism called vesicle trafficking that cells use to communicate with their environment.

“In this study we have identified the major cell functions that drive ependymoma, and each of these functions provides possible new avenues for treatment,” said the study’s corresponding author, Richard Gilbertson, M.D., Ph.D., St. Jude scientific and Comprehensive Cancer Center director.

The potential approaches include anti-cholesterol drugs called statins. The new ependymoma oncogenes were all associated with reduced cholesterol production in tumor cells. Cell growth requires cholesterol, which is part of the cell membrane. Previous studies by other researchers reported that adults who took statins for cholesterol control were less likely to develop and more likely to survive certain brain tumors.

Evidence in this study suggested that tumor cells may benefit from some reduction in cholesterol synthesis, but that statins may push the reduction too far. When researchers treated cells growing in the laboratory with six different statins, the growth of mouse ependymoma cells declined sharply compared to the growth of other brain or tumor cells. Work has begun to modify statins so the drugs can gain access to the brain.

For this study, researchers searched two international databases for genes that were commonly deleted or amplified in ependymoma. The effort yielded 84 candidate oncogenes and 39 tumor suppressor genes carried in the 28 CNA of 83 ependymomas.

Working in mice, investigators used a variety of techniques to narrow the field to eight oncogenes. The techniques included tracking which of the candidate oncogenes were most likely to be “switched on” or expressed in mouse brain stem cells growing in the laboratory and to cause ependymoma in specially bred mice. The new oncogenes include RTBDN, a gene whose function remains a mystery.

To identify the 10 ependymoma tumor suppressor genes, scientists used small RNA molecules called shRNAs to silence the 39 candidate genes. Working in mice, researchers used a variety of techniques to track decreased expression of the candidate genes. Investigators also determined how quickly ependymoma developed in mice when the candidate tumor suppressor genes were combined with the mouse Ephb2 oncogene. EPHB2 is one of the two genes previously linked to ependymoma. Gilbertson led the research that identified both genes.

This is the second method that Gilbertson and his collaborators have used to mine copy number alterations to find oncogenes. The first approach led researchers to three genes that are amplified in a rare brain tumor of children and adults that is called choroid plexus carcinoma. That work was published earlier this year in Cancer Cell.

Kumarasamypet Mohankumar, Ph.D., of St. Jude, and David Currle, Ph.D., formerly of St. Jude, are the study’s first authors. The other authors are Elsie White, Nidal Boulos, Jason Dapper, Birgit Nimmervoll, Michele Connelly, Tanya Kranenburg, Geoffrey Neale, Scott Olsen, Yong-Dong Wang, David Finkelstein, Karen Wright, David Ellison and Arzu Onar-Thomas, all of St. Jude; and Christopher Eden, Radhika Thiruvenkatam, and Kirti Gupta, all formerly of St. Jude.

The study was funded in part by grants (CA129541, CA96832, CA021765) from the National Institutes of Health; the Collaborative Ependymoma Research Network and ALSAC.