When scientists discover new cancer-related genes, their primary concern is learning how the mutation triggers runaway cell growth. It is often much easier to see how things go awry than to decipher the gene’s normal function — and to determine if that function is actually important for survival.
A key example is a gene called PGBD5. When abnormally activated, PGBD5 makes a protein that snips out DNA segments and flips them or moves them to a different location within the genome. In recent years, researchers at Memorial Sloan Kettering Cancer Center (MSK), led by physician-scientist Alex Kentsis, MD, PhD, linked PGBD5 alterations to many pediatric cancers.
But is PGBD5 all bad? New research from an international team led by Dr. Kentsis suggests the disruptions caused by the gene are also essential to normal brain development in mammals, including humans. The DNA shuffling appears to contribute to the healthy formation of distinct types of brain neurons.
“PGBD5 appears to be nature’s double-edged genetic operator, which can both build us and break us,” Dr. Kentsis says. “It’s a telling example of a tradeoff in nature and evolution, where a gene can be both a risk factor for disease and fundamentally important for healthy human development.”
The finding, published in Science Advances, sheds more light on the origins of early onset cancers and their link to brain development.
‘Jumping Genes’ That Fuel Childhood Cancers
Researchers had long been puzzled by why tumors develop in children, who presumably haven’t had enough time for large numbers of random mutations to accumulate. In 2017, Dr. Kentsis and his team discovered that it was the PGBD5 gene itself that produces the mutations and turns cells malignant. The finding represented a major advance in understanding human cancers in general and childhood tumors in particular.
The PGBD5 protein produced by the gene is related to enzymes called DNA transposases. These enzymes rearrange DNA segments known as transposons, which move, or transpose, from one site on a chromosome to another. The discovery about transposons (also called “jumping genes”) and how they affect gene expression earned Barbara McClintock the Nobel Prize in 1983.
In recent years, researchers have come to understand that some transposon-derived genes are necessary for normal human development, in addition to sometimes triggering cancer. Dr. Kentsis and colleagues suspected that might be the case with PGBD5, which is strongly conserved through evolution among all vertebrate animals — from fish to reptiles to mice to humans. This suggests PGBD5 is important to some essential process in all vertebrates.
There also were clues that PGBD5 plays an important role in normal nerve cell formation and growth. Most solid tumors that affect children and young adults are related to nerve cells during development. In addition, nerve cells in healthy people have some of the highest levels of PGBD5 proteins of all tissues in the body.
PGBD5 in Healthy Brain Development
Dr. Kentsis worked with Miklos Toth, MD, PhD, the Rifkind Professor in Pharmacology of Weill Cornell Medicine, and Michael Kruer, MD, of Phoenix Children’s Hospital, along with an international group of collaborators, to confirm the importance of PGBD5 in brain formation.
- They identified people with inherited PGBD5 mutations and found that they suffered from intellectual disability, movement disorders, and seizures.
- Mice engineered to have similar PGBD5 mutations had the same seizures and behavioral problems.
The researchers also did genetic analysis of the brain tissue of PGBD5-mutated mice and normal mice and found that normal brain development in the mice involved PGBD5-induced DNA rearrangements.
The discovery highlights a new area of cancer research called developmental mutagenesis, which focuses on mutations that occur during normal growth and development early in life. MSK’s Tow Center for Developmental Oncology, led by Dr. Kentsis, was founded in 2021 to help understand how developmental processes are specifically dysregulated to cause cancer.
“Findings like this give us a better understanding of the biological pathways involved in cancers occurring in children and young adults, which should pave the way for safer, more effective therapies,” Dr. Kentsis says.
Key Takeaways
- Researchers had long been puzzled by why tumors develop in children, since they haven’t lived long enough to accumulate large numbers of random genetic mutations.
- MSK physician-scientist Alex Kentsis, MD, PhD, and his colleagues discovered in 2017 that the PGBD5 gene itself was producing the mutations that turned cells malignant.
- New research from an international team led by Dr. Kentsis suggests that while PGBD5 triggers pediatric cancers, it’s also essential to normal brain development.
- The new finding sheds light on the origins of early-onset cancers and could pave the way for safer, more effective treatments for pediatric cancers.
Dr. Kentsis is Director of the Tow Center for Developmental Oncology.
Additional Authors, Funding, and Disclosures
Additional MSK authors on the study are Luz Jubierre Zapater, Xiaolan Zhao, Makiko Yamada, Daniel Cameron, Phillip Demarest, Helen S. Mueller, Casie Reed, Tzippora Chwat-Edelstein, and Nicholas D. Socci.
Funding for this research includes support for Dr. Kentsis from National Institutes of Health (NIH) grant R01 CA214812, NIH grant P30 CA008748, the St. Baldrick’s Foundation, the Burroughs Wellcome Fund, the Rita Allen Foundation, the Pershing Square Sohn Cancer Research Alliance, and The G. Harold and Leila Y. Mathers Foundation.
Dr. Kentsis is a consultant for Novartis, Rgenta, Blueprint, Syndax, and Sellas.
Read the paper: A transposase-derived gene required for human brain development
DOI: 10.1126/sciadv.adv7530
