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Study IDs Potential Radiation Biomarkers in Cell Lines

By a GenomeWeb staff reporter

NEW YORK (GenomeWeb News) – A group of researchers from the Mayo Clinic in Rochester reported in the early, online edition of Genome Research today that they have uncovered a handful of genes that appear to be associated with radiation response in cell lines.

Using a combination of genome-wide association, gene expression, radiation response, and gene knockdown studies, the team narrowed in on five genes that seem to be associated with radiation response in both lymphoblastoid cell lines and specific cancer cell lines. Those involved in the study say the work may ultimately lead to biomarkers for improving cancer treatment strategies.

"These studies will provide a foundation for future translational studies to individualize radiation therapy based on the expression of these candidate genes and may make it possible to design novel combination therapy for selected patients based on these biomarkers to overcome resistance," senior author Liewei Wang, a genomics researcher at the Mayo Clinic, said in a statement.

Although about half of individuals with cancer are treated with radiation, the researchers explained, response to such treatments varies dramatically from one individual to the next. Consequently, the group was keen to find genetic variants for guiding the way radiation treatment is used.

"The therapeutic efficacy of radiation is determined mainly by total dose, but the use of high doses has been limited because of the severity of side effects in normal tissue," the authors wrote. "[U]nderstanding the biology underlying the variation in response to radiation might help us to maximize radiation efficiency in the tumor while minimizing side effects in normal tissues."

To track down such SNPs, the researchers used Illumina HumanHap 550K and 510S BeadChip arrays to genotype 277 lymphoblastoid cell lines. The cell lines were generated from individuals from a variety of ethnic backgrounds and characterized for radiation response using a cytotoxicity assay.

After incorporating their own data with publicly available Affymetrix SNP 6.0 data, the team had genotype information at about 1.3 million SNPs. They also assessed gene expression patterns in the cell lines using Affymetrix U133 plus 2.0 GeneChips.

Overall, the team noted that sensitivity to radiation was greater for cell lines generated from individuals of Han Chinese descent than for cell lines from those of Caucasian descent.

When they combined their SNP, expression, and radiation response data, the researchers found a few hundred genes that seemed to have potential ties to radiation response.

From there, they focused in on 23 genes that they tested by knockdown in pancreatic cancer, cervical cancer, and non-small cell lung cancer cell lines. The team found that small interfering RNA-based knockdown of five of the genes — C13irf34 (BORA), MAD2L1, PLK4, TPD52, and DEPDC1B — altered radiation treatment response in at least two of the cancer cell lines.

Given their findings so far, the researchers argue that such studies may yield clues for learning more about the genes involved in radiation response and their functions and for applying radiation therapy more efficiently.

"[A]lthough variation in radiation response might result from multiple gene effects and, possibly, gene-environment interactions, our results provide important insights into novel genes and mechanisms that may contribute to variation in response to radiation therapy," the researchers concluded.

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