Image courtesy of Dr. David Hockenbery
A suspected marker for tumor development may not be what it seems, according to research by a Hutch scientist.
Studies by Basic Sciences Division postdoctoral fellow Dr. Hilary Coller, as part of her graduate work at the Massachusetts Institute of Technology, predict that accumulated mutations in the DNA of a cellular compartment called the mitochondria might not give tumors the growth advantage once suspected.
The results of the study, a collaboration with Dr. William Thilly's laboratory at MIT, appeared in the June issue of Nature Genetics.
Coller's results suggest that random events may be sufficient to explain the accumulation of particular mitochondrial mutations in each cell of a tumor.
Selective growth advantage
Such mutations, because they exist throughout an entire tumor, were believed to arise because they provide a selective growth advantage to the malignant cells.
"We found that random events can explain the accumulation of these mutations based on reasonable assumptions of the mutation rate of mitochondrial DNA and the number of cell divisions experienced by a tumor," said Coller, now a postdoctoral fellow in Dr. Jim Roberts laboratory. "But there is still a lot to learn about this process. There may be some non-random events occurring that we don't yet understand."
Mitochondria are small, membrane-bound compartments present in tens to hundreds of copies in the cells of most organisms. They carry out key metabolic reactions to generate energy for the cell.
Mitochondria contain their own DNA, which, like human chromosomes, can undergo mutation.
Each time a cell divides, the mitochondrial DNA copies are distributed between the two daughter cells, followed by DNA duplication necessary to restore the number of copies to roughly the original level. In rare cases, over the course of many cell divisions, the same mutation will be present in many copies of mitochondrial DNA in a single cell. Given enough cell doublings, cells in which all of the copies contain the same mutation will arise.
In a study published in 1998, researchers at Johns Hopkins University examined a number of tumors and found that every cell within a tumor contained the same mutation in every copy of mitochondrial DNA, a condition called homoplasmy.
"We wanted to know whether you expect that to happen by chance, given the large number of cell divisions, or alternatively, are those mutations present because they confer a growth advantage on the mitochondrial DNA or the cells?"
About 600 doublings
Coller and colleagues predicted that by the time a cell becomes the founder of a tumor, it already has gone through about 600 doublings.
"According to our model, that is enough time for random forces to explain the accumulation of that mutation uniformly within a cell," she said. The mathematical predictions are supported by analysis of healthy tissue.
Dr. Konstantin Khrapko, a assistant professor at Harvard Medical School and co-author of the paper, found homoplasmic mutations in healthy cheek cells from two individuals, demonstrating that this property is not unique to tumors.
Coller's research in the Roberts lab focuses on understanding the regulation of the cell division cycle in human cells.