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Researchers ID Genetic Signature for Chemotherapy, Radiation Resistance

NEW YORK (GenomeWeb News) – An international team of researchers has identified a genetic signature that can help predict whether some breast cancers will be resistant to chemotherapy and/or radiation treatments.
In a paper published online this week in the Proceedings of the National Academy of Sciences, researchers from the US, the Netherlands, and Sweden describe a genetic signature made up of seven interferon-related genes. The study suggests that the seven genes, which they call the interferon-related DNA damage resistance signature, or IRDS, can be used to classify many cancer cell lines and, when used in conjunction with other markers, improve the accuracy of chemotherapy and radiation resistance predictions for breast cancer patients.
“[T]hese results suggest that the IRDS is a therapy predictive marker that performs across patient populations that may differ in baseline characteristics and treatment,” senior author Andy Minn, a radiation and cellular oncology researcher at the University of Chicago, and his colleagues wrote.
At the moment, adjuvant chemotherapy and radiation therapy after breast cancer surgery increase survival by just five to ten percent. That’s because only about 20 percent to 30 percent of patients have metastases that are targeted by such follow-up therapy. And of these, less than a third of patients have cancers that are sensitive to existing chemotherapy and radiation.
“[T]o optimally tailor adjuvant therapy for a heterogeneous group of patients, we need to identify a priori which patients are at risk for occult metastasis before adjuvant therapy, and which at-risk patients have disease that is sensitive to the treatment,” the authors noted.
In a previous study, the researchers identified the IRDS genes, which are related to the interferon pathway, part of the immune system. The IRDS gene expression profiles appeared to be associated with resistance to DNA damage from radiation, mediated by genes such as STAT1, ISG15, and IFIT1 that are associated with the interferon-signaling pathway.
For the latest study, Minn and his team looked at whether classifying human cancers as IRDS-positive or –negative could improve predictions about resistance following either chemotherapy or radiation.
First, the researchers looked at the IRDS expression patterns in several cell lines, including a radiation- and chemotherapy-resistant human squamous cell carcinoma cell line called Nu61, which differentially expressed 49 IRDS genes, and a panel of 34 cancer cell lines from the NCI60 panel, which contained 36 IRDS genes in the top quarter of the hits associated with radiation survival.
Based on these results as well as those from knockdown experiments, the team concluded that IRDS genes seem to regulate DNA damage resistance rather than cancer metastasis.
Next, the team compared the microarray profiles of breast, head and neck, prostate, lung, and glioma cancer samples in available databases to determine whether they were similar to those of the sensitive or resistant squamous cell carcinoma cells. Again, they found that IRDS genes could divide the cancer samples into those resembling typically sensitive human squamous cell carcinoma cells, termed IRDS(-) and those resembling the resistant Nu61 cells, termed IRDS(+).
Unsupervised clustering experiments indicated that 37 percent of head and neck cancers, 48 percent of lung cancers, 29 percent of prostate cancers, 46 percent of breast cancers, and half of high-grade glioma cases tested fell into the IRDS(+) category — the more resistant group.
Because IRDS seems to forecast chemotherapy and radiation resistance in the lab, the researchers speculated that it might be a useful predictive marker for the effectiveness of chemotherapy and radiation treatments.
The team then used the IRDS status from 78 breast cancer patients to train an IRDS predictive classifier with a top-scoring pairs method. When the researchers tested that TSP-IRDS signature in 295 early-stage breast cancer patients, they found that it could increase the accuracy of therapy predictions when combined with other markers and genomic classifiers.
The team validated these initial findings independently in three different cohorts: 292 breast cancer patients who had undergone chemotherapy and/or radiation therapy, 277 patients who had received endocrine therapy alone rather than chemotherapy or radiation, and a third cohort involved 286 patients who hadn’t received any adjuvant therapy following surgery.
The researchers’ results suggest that IRDS is not predictive for patients receiving endocrine therapy. Nor does it appear to be prognostic for those who don’t receive any follow-up therapy. Instead, the researchers suggested that the IRDS classifier improves prediction accuracy specifically for those receiving chemotherapy or radiation therapy.
The researchers still aren’t sure how IRDS relates to chemotherapy and/or radiation resistance and are doing more research to delve deeper into the process. “The mechanism that the IRDS confers resistance to chemo and radiation is actively being explored,” Minn told GenomeWeb Daily News in an e-mail message. “One clue may be that the DNA damage response can result in activation of interferon-related genes, and interferon-related genes are often growth inhibitory and/or promote cell death.”
And, Minn noted, “We are very intrigued by the presence of the IRDS among such a wide variety of common human cancers. We believe that it is possible that the IRDS may mark and mediate treatment resistance across different cancer types.” The team is currently testing that possibility.  
“We envision that predictive markers like the IRDS will help individualize treatment for breast cancer patients by helping them decide whether they want adjuvant treatment and help physicians decide how aggressive this treatment should be,” Minn said. In addition, he noted, experiments in model systems suggest that targeting IRDS genes could potentially reverse such resistance.

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