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Breast Cancer Outcomes Linked to Gene Mutation 'Hotspots'

NEW YORK (GenomeWeb) – Researchers from the University of California, San Diego's School of Medicine and Moores Cancer Center have determined that kataegis is a positive marker in breast cancer, meaning that patients with kataegis have less invasive tumors and better prognoses.

Kataegis is a phenomenon where multiple mutations cluster in a few "hotspots" in a genome. It occurs in approximately 55 percent of breast cancer cases, according to the researchers. Previous studies have shown that the anomaly is present in some cancers, but were unable to determine what role kataegis plays in tumor development and patient outcomes.

In the study published today in the journal Cell Reports, the researchers reported their findings on kataegis and suggest that its status could help clinicians determine specialized treatment plans for patients with this mutation pattern.

"We don't know what causes kataegis, and before this study not much was known about its functional importance at the molecular or clinical level," Kelly Frazer, senior author and professor of pediatrics and director of the Institute for Genomic Medicine at UCSD, said in a statement.

Frazer and her colleagues studied whole-genome sequencing data of 97 tumors from patients with breast cancer known to have kataegis. They used data available from the National Institutes of Health's The Cancer Genome Atlas (TCGA), a database of genomic information from over 15,000 human tumors representing many cancer types.

The researchers analyzed the distribution of kataegis loci. They found that these somatic mutations are overrepresented on chromosomes 8, 17, and 22, and that the loci are enriched in genic regions and have active chromatin elements. The research team also showed that tumors harboring kataegis are associated with transcriptome-wide expression changes consistent with low invasive potential.

To confirm their findings, Frazer and her colleagues also looked at an additional 412 human breast cancer cases and used the kataegis expression signature to predict kataegis status based on transcriptome data. Initially, they determined that kataegis "hotspots" were more common in breast cancer patients diagnosed at a later age and in patients with HER2-positive and high-grade tumors.

However, after the researchers fit the data to a linear model — which defined a bad prognosis as death before 55 and defined a good prognosis as death after 55 — they found that currently established clinical variables, such as tumor grade and HER2 status, were not good indicators for age of death. Based on additional analysis of the coefficients in the model, the researchers found that the only significant predictor of age of death for these patients was kataegis. Therefore, they determined that kataegis could make a better marker for good prognosis than established clinical variables.

The researchers found that kataegis on chromosome 17 and 22 in particular was associated with low tumor invasiveness, another indicator associated with better cancer prognosis.

The research team also noted that while causes of death for patients in the TCGA database are unknown, patients without kataegis tended to die younger, at a median age of 47, than patients with kataegis, at a median age of 78.

While the mechanics behind kataegis are still unclear, the researchers did note that genes located near the hotspots were less likely to behave abnormally than genes located further away in the genome.

"We think kataegis mutations are dampening the abnormal expression of neighboring genes that might otherwise contribute to tumor development and invasiveness," Matteo D'Antonio, a postdoctoral researcher in Frazer's lab and first author of the study, said in a statement.

Frazer, D'Antonio, and their colleagues believe that kataegis status might be helpful in determining a patient's treatment options. The researchers confirmed that tumors with kataegis have high levels of HER2. While HER2-positive breast tumors tend to be more aggressive, it is well established that there are therapies that specifically target HER2-positive breast cancers, such as Herceptin, and are so effective that the prognosis for HER2-positive breast cancer is actually quite good, according to the Mayo Clinic. 

In addition to kataegis' association with HER2, the researchers found that tumors with kataegis upregulate PLAC1, a gene that encodes a molecule that is an immunotherapy target in gastric cancer. Tumors with kataegis on chromosome 8 also tended to have lower gene activity involved in resistance to the anti-leukemia drug imatinib, also known as Gleevec.

While there is a long way to go before kataegis status could be used in the clinic, Frazer noted, clinicians at Moores Cancer Center at UC San Diego Health have already begun tailoring cancer treatments to individual patients using genomic data similar to that found in this study.