City of Hope researchers discovered that some defects, or mutations, in genetic code happen rapidly and in clusters, raising the possibility that cancer can occur by a more aggressive mechanism than previously thought. Steve Sommer, M.D., Ph.D., professor of molecular medicine and director of the Division of Molecular Genetics at City of Hope, and his team dub the phenomenon a “mutation shower.”
Their findings recently were published in Proceedings of the National Academy of Sciences.
Scientists generally believe that cancer develops after single mutations accumulate over many years until a cell acquires the ability to grow uncontrollably. However, Sommer and his team believe that scattered “mutation showers” may occur in several locations in a short time and in sufficient number to prompt enough genetic defects to produce a cell capable of uncontrolled growth.
That cell would be destined to produce a clinically detected tumor years later. Sommer said that additional research is needed to test this hypothesis.
“We observed that at least 1 percent of mutations are not single mutations as normally thought but are clusters of multiple mutations,” said Sommer. “Some of the mechanisms that could cause a mutation shower could also generate scattered showers, and this, which remains to be shown in future experiments, can make it possible for cancer to occur in an instant.”
Sommer’s team observed mutation showers in mice on standard diets and not exposed to agents known to cause mutations, which leads them to believe mutation showers may occur by endogenous processes — that is, from within. It is not yet known whether any environmental factors such as cigarette smoke, the sun’s ultraviolet rays or diet might cause or exacerbate mutation showers. The mutation showers observed thus far do not have any unusual characteristics that would suggest the genetic signature of any particular trigger.
“Contrary to what we were expecting, we observed that mutations did not occur singly and were not distributed randomly along the DNA sequence,” said Ji-Cheng Wang, Ph.D., postdoctoral research fellow in Sommer’s lab and lead author of the paper. “It is possible that our observation represents the tip of the iceberg since mutation showers are not easy to detect.”
The research team observed mutations in a strain of mice genetically engineered to allow easy identification of DNA mutations and analyzed mutations in several gene segments. When a DNA segment contained more than one mutation, they noticed that segments in the neighborhood were likely to contain additional mutations. The research team is continuing their investigation of mutation showers and their possible role in cancer.
“The ultimate significance of the current findings remains to be determined,” said Sommer. “As with any new finding, it is important to study mutation showers in different systems and organisms.”
The research team included these members: Kelly D. Gonzalez, genetic counselor; William A. Scaringe, senior biomedical informatics specialist; Kimberly Tsai, research associate; Ning Liu, postdoctoral research fellow; Dongqing Gu, bioinformatics specialist; Wenyan Li, research associate; and Kathleen A. Hill, Ph.D., assistant professor, Department of Biology, The University of Western Ontario, Canada.