Oncogenes Implicated in Rare Choroid Plexus Carcinoma

Initiation and progression of the rare and often fatal brain cancer, choroid plexus carcinoma (CPC), depends on the presence of genes transcription initiation factor TFIID subunit 12 (TAF12) and nuclear transcription factor Y (NFYC), both transcription factors that regulate the epigenome, and DNA repair and recombination protein RAD54-like (RAD54L), a component in DNA homologous repair, according to a report published in Cancer Cell.¹

Researchers at St. Jude Children’s Research Hospital in Memphis identified the oncogenes by comparing tumor genomes of mouse model CPC to human tumor genomes. They identified 671 genes that were duplicated in a large proportion of both human and mouse tumors. Of the duplicated genes, 21 were overexpressed in mouse tumors, and further analysis indicated three were required to initiate and sustain CPC-like tumors in mice.

“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,” said Dr. Richard Gilbertson, MD, PhD, director of the Scientific and Comprehensive Cancer Center at the children’s hospital.

“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,” said Dr. Gilbertson in a press release.²

Previous studies of mutation profiles in pediatric cancer show that genes encoding epigenetic regulation are frequently mutated in some pediatric cancers.³ Two of the oncogenes identified as important in CPC, are transcription factors TAF12 and NFYC, which play a role in epigenetic regulation. The other identified oncogene, RAD54L, participates in the repair of DNA double-strand breaks through homologous recombination.

Using the gene mutation information, the researchers found that ataxia telangiectasia and Rad3-related protein (ATR) inhibitors, investigational drugs that block DNA repair processes, may be effective in CPC. CPC is a rare cancer that represents about 3% of brain tumors in children and has few treatment options. An international  clinical trial testing ATR inhibitors in CPC is in the planning stages.

References:

• Tong Y, Merino D, Nimmervoll B, et al. (2015). Cross-Species Genomics Identifies TAF12, NFYC, and RAD54L as Choroid Plexus Carcinoma Oncogenes. Cancer Cell, 27(5): 712-727.
• St. Jude Children's Research Hospital. (2015). First cancer-promoting oncogenes discovered in rare brain tumor of children and adults.
• Huether R, Dong L, Chen X, et al. (2014).The landscape of somatic mutations in epigenetic regulators across 1,000 paediatric cancer genomes. Nature Communications, Apr 8; 5:3630.