Researchers have identified three genes that play a pivotal role in the brain tumour, choroid plexus carcinoma (CPC), a discovery that lays the groundwork for more effective treatment of this rare, often fatal cancer. The genes, TAF12, NFYC and RAD54L, are all involved in DNA repair and regulation. The 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 tumour.
The team 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 tumour cells to chemotherapy or radiation. Planning has begun for a possible international clinical trial featuring an ATR inhibitor. St. Jude Children’s Research Hospital scientists led the opensource study, which appears in the journal Cancer Cell.
The data findings suggest that disruption of normal DNA maintenance and repair plays a central role in CPC, a tumour with few treatment options. The team state that 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 tumour and providing the first real direction for treatment.
The researchers state that 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 the current 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. For CPC, the answer began by chance.
The team developed a mouse model of CPC while working to create an animal model to advance understanding of another pediatric brain tumour. They used the CPC model to look for blocks of genes that are carried on human chromosome 1 and also duplicated in the mouse tumour. 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 tumours. Researchers found evidence that 21 of the 671 duplicated genes were ‘switched on’ or overexpressed in the mouse tumours.
CPC develops in cells that line the fluid-filled ventricles in the brain and produce cerebrospinal fluid, state the team. When they 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. The results also showed that all three genes were required to initiate and sustain the tumours 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, explain the researchers.
For CPC patients, the results provide much needed direction for designing tumour-specific therapy, state the team. They go on to add that preclinical trials are underway using different drug combinations to block the hyperactive DNA repair mechanism so the tumours eventually succumb to the accumulated DNA damage.
Michelle Petersen is the founder of Healthinnovations, having worked in the health and science industry for over 21 years, which includes tenure within the NHS and Oxford University. Healthinnovations is a publication that has reported on, influenced, and researched current and future innovations in health for the past decade.
Michelle has been picked up as an expert writer for Informa publisher’s Clinical Trials community, as well as being listed as a blog source by the world’s leading medical journals, including the acclaimed Nature-Springer journal series.
Healthinnovations is currently indexed by the trusted Altmetric and PlumX metrics systems, respectively, as a blog source for published research globally. Healthinnovations is also featured in the world-renowned BioPortfolio, BioPortfolio.com, the life science, pharmaceutical and healthcare portal.
Most recently the Texas A&M University covered The Top 10 Healthinnovations series on their site with distinguished Professor Stephen Maren calling the inclusion of himself and his team on the list a reflection of “the hard work and dedication of my students and trainees”.
Michelle Petersen’s copy was used in the highly successful marketing campaign for the mega-hit film ‘Jumanji: The Next Level, starring Jack Black, Karen Gilian, Kevin Hart and Dwayne ‘The Rock’ Johnson. Michelle Petersen’s copywriting was part of the film’s coverage by the Republic TV network. Republic TV is the most-watched English language TV channel in India since its inception in 2017.
An avid campaigner in the fight against child sex abuse and trafficking, Michelle is a passionate humanist striving for a better quality of life for all humans by helping to provide traction for new technologies and techniques within healthcare.