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New information about kataegis offers hope
SAN DIEGO—Researchers at the University of California, San Diego School of Medicine and Moores Cancer Center have recently discovered that an anomaly present in some cancers is in fact a marker for a good prognosis in breast cancer. Kataegis, named for the ancient Greek word for thunder, refers to instances where multiple mutations cluster in various spots within a genome. Detailed analysis of human tumor genetic data in breast cancer has shown that patients with such “mutation hotspots” have less-invasive tumors and better prognoses.
The full study, published June 30 in Cell Reports, indicates that kataegis occurs in nearly 55 percent of breast cancers. After analyzing data pulled from The Cancer Genome Atlas, the National Institutes of Health’s repository of tumor-related genomic information, the researchers found a strong correlation between the presence of these somatic gene mutations and lower tumor invasiveness.
The study paired mutation status with patient information such as age at diagnosis, treatment and outcome. Kataegis presented more frequently in patients diagnosed at a later age, and patients with HER2-positive and high-grade tumors. The data showed that kataegis, particularly on chromosome 17 and 22, corresponded with low tumor invasiveness.
“We need to understand the molecular mechanisms underlying this association,” says Dr. Matteo D’Antonio, a postdoctoral researcher at the Institute of Genomic Medicine at UC San Diego School of Medicine and first author of the study. “We need to understand if kataegis is the reason why these tumors are less invasive or if other mechanisms that result in less-invasive tumors facilitate the appearance of kataegis.”
The team also found that patients presenting with the mutation tended to survive significantly longer than those without it—median mortality age with kataegis was 78 years old vs. a median mortality age of 47 years without.
In addition to indicating a better prognosis, patients presenting with kataegis hotspots may allow physicians to better predict tumor invasiveness, and thus offer a widened portfolio of treatment options. One example of another potential clinical benefit, according to Dr. Kelly Frazer, professor of pediatrics and director of the Institute for Genomic Medicine, is that tumors with kataegis have high levels of human epidermal growth factor receptor 2 (HER2), which can then be treated with HER2-targeted therapies, improving prognosis.
The existence of kataegis was known prior to this study, but its cause and functional importance at the molecular or clinical level was not understood, according to Frazer. Other cancer types, including pancreas, lung, liver, leukemia and lymphoma, have shown evidence of kataegis. The UCSD study may well serve as a pilot for replication on other cancer types.
While kataegis status may not immediately be useful in creating new treatment modalities or in direct clinical use, there appear to be instances where kataegis co-presents with elevated levels of PLAC1, a gene that encodes a molecule that is an immunotherapy target in gastric cancer. Recent research and clinical success in immunotherapy trials show that careful targeting can stimulate a patient’s own immune system to better fight tumors while leaving healthy tissue alone. The potential for improved immunotherapy based on kataegis status promises to inform upcoming clinical trials.
“We have shown that kataegis is associated with a particular gene expression signature, which we may be able to exploit in a fashion similar to already-established assays ... to guide treatment decisions ... and in that respect have utility,” states D’Antonio.
The name kataegis originates from the “rainfall plots” that are typically drawn to show the mutations. The anomalies in the kataegis loci appear to be raining down when mapped.
The study was conducted in collaboration with Frazer, D’Antonio and Drs. Pablo Tamayo and Jill Mesirov, also of the UCSD Cancer Genomes and Networks Program at the Moores Cancer Center.