Bottom Line: A new discovery published in the journal Nature Genetics identifies a mechanism for the triggering of solid tumors — including most types of cancers that affect children and young adults. The enzyme made by the gene PGBD5 cuts DNA segments and then rearranges them. This DNA remodeling can drastically alter normal gene function and cause cancer. Rather than normal cells turning cancerous as a result of random errors or mutations, the molecule encoded by the PGBD5 gene itself can induce specific mutations and turn cells malignant.
Journal: “PGBD5 Promotes Site-Specific Oncogenic Mutations in Human Tumors” appears in the May 15, 2017, issue of Nature Genetics.
Authors: The study was led by Memorial Sloan Kettering’s Alex Kentsis, MD, PhD. The first co-author, Anton Henssen, MD, a former member of the Kentsis lab at MSK, is currently a pediatric oncology physician-scientist at the Charité Hospital in Berlin. Additional first co-authors include Richard Koche, PhD, and Jiali Zhuang, PhD. This study was conducted in concert with an international collaboration of researchers.
Background: PGBD5 was recently found to encode a type of enzyme called a DNA transposase, which is used by a wide range of organisms to control gene expression by rearranging DNA segments known as transposons. Although it is now known that almost 50 percent of the human genome is derived from transposons, very few instances of their functions are known. Rather, they were considered artifacts of evolution, lying within the “dark genome” — the DNA region that doesn’t code for proteins. In recent years, scientists have come to understand that this part of DNA, also referred to as junk DNA, actually serves important functions.
Findings: By studying rhabdoid tumors that express PGBD5, the scientists found evidence of DNA rearrangements at specific sites in human chromosomes associated with PGDB5 activity. PGBD5 expression was found in the majority of childhood solid tumors and distinct tumors in adults. As further proof of PGDB5’s effect, they found that expressing PGDB5 in normal human cells could turn them cancerous both in a lab dish and in mouse models. These cancer cells were found to have similar, specific DNA rearrangements as in human patient tumors. PGBD5 was found to be physically associated with specific DNA sequences, which in turn were sufficient to mediate PGBD5-induced human genome rearrangements. This new study shows that cancer-causing mutations can be specifically induced by a DNA transposase when aberrant in humans. This finding also suggests a solution to a long-standing mystery about many childhood cancers: It is not that these cancers lack mutations, but rather that they harbor unique genomic rearrangements.
Method: The research team made its discovery by analyzing the genes of cells from human rhabdoid tumors. These rare childhood cancers are aggressive and can arise in many different organs, including the brain, kidneys, and liver. Cancer cells in which the PGBD5 enzyme is dysregulated may be especially reliant on mechanisms that repair DNA, and it could make them particularly vulnerable to drugs that inhibit specific aspects of cellular DNA repair signaling. Dr. Kentsis and colleagues are currently investigating these inhibitors in mouse models of childhood cancers in the lab.
“This study explains a long-standing conundrum for how childhood cancers develop,” says MSK cancer biologist Alex Kentsis, who led the study. “It also sheds light on the way programmed gene rearrangements can cause cancer. We suspect additional, similar rearrangements and their targeted therapies will be identified by future research.”
“Despite years of sequencing and laboratory studies of childhood tumors, this is a novel mechanism of mutation that the world has missed,” says Andrew Kung, Chair of MSK’s Department of Pediatrics. “This paper represents a major advance in understanding human cancers in general and pediatric tumors in particular. And it underscores yet again that the genome still has features we are blind to that have major functions in biology that we’re just starting to appreciate.”