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Mayo Clinic Researchers Identify Potential PGx Markers for Radiation Therapy

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Originally published Oct. 11.

Mayo Clinic researchers published a genome-wide association study in Genome Research earlier this month in which they identified several gene alterations in cell lines that may prove to be pharmacogenomic markers for guiding cancer radiation therapy.

In the study, Liewei Wang and colleagues used a combination of genome-wide association, gene expression, radiation response, and gene-knockdown studies to identify five genes that appear to be associated with radiation response in lymphoblastoid cell lines.

"Radiation therapy is used to treat more than half of all cancer cases, but patient response to therapy can vary greatly," the study authors said in a statement. "Genetics is increasingly being recognized as a significant contributor to inter-individual response to radiation, but the biology underlying response remains poorly understood."

In the study, the researchers first assessed genotypes and gene expression levels for 277 ethnically defined human lymphoblastoid cell lines. They then ran radiation cytotoxicity assays on the cell lines to obtain area under the curve, or AUC, which they used as a radiation response phenotype.

A total of 27 loci, "each containing at least two SNPs within 50 kb with P-values less than 10-4" were associated with radiation AUC. Additionally, the authors identified 270 expression probe sets associated with radiation AUC with P-value less than 10-3.

After conducting an integrated analysis of the data, the researchers were able to hone in on 50 SNPs in 14 of the 27 loci that were associated with both AUC and the expression of 39 genes associated with radiation AUC.

Next, the Mayo team used siRNA knockdown in multiple tumor cell lines to further narrow that set down to five genes — C13orf34, MAD2L1, PLK4, TPD52, and DEPDC1B — that "significantly altered radiation sensitivity in at least two cancer cell lines."

Based on this data, the researchers concluded that "studies performed with LCLs can help identify novel biomarkers that might contribute to variation in response to radiation therapy and enhance our understanding of mechanisms underlying that variation"

Wang said in a statement that the study points toward the possibility of designing "novel combination therapy for selected patients based on these biomarkers to overcome resistance."

Although clinical factors like radiation dose and fraction are known to impact cancer patients' response to treatment, as much as 80 percent of the variability in how patients' normal tissues are impacted by radiation therapy can have genetic underpinnings, according to the Mayo Clinic.

"If genetic variants and biological mechanisms contributing to radiation response are identified, more personalized treatment strategies could be employed in the clinic," Mayo said in a statement.

The study was funded by the National Institutes of Health, an ASPET-Astellas award, and a Center of Excellence in Clinical Pharmacology Award from the PhRMA Foundation.

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