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Predicting DNA Damage

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Researchers led by Rebecca Fry at MIT, who is now at the University of North Carolina School of Public Health, have discovered a gene expression signature that can predict how well cells will respond to a DNA damaging agent. Extending this basic work to the clinic could mean better predicting how patients will respond to chemotherapy. The scientists published their findings in the September 19 online edition of the Journal Genes and Development.

Fry and her team assayed 24 bone marrow cell lines from healthy people, dosing the cells with MNNG to examine how they grew when exposed to this DNA-damaging compound that's similar to toxic chemicals found in tobacco smoke and in common chemotherapy agents. "One of the first questions we had was, what's the range of differential response across the healthy human population when exposed to [a] DNA-damaging agent," Fry says, "and one of the first findings that was surprising was how massive the range was in response."

She and her colleagues followed up the cell screens with microarrays to look at gene expression on a genome-wide scale in those cell lines. They used expression patterns to create a detection algorithm for genes associated with drug sensitivity. One goal, Fry says, was to determine whether they could use genomic information to predict how cells would respond to this kind of toxic compound. "If we didn't know their sensitivity score, could we predict it based on their gene expression levels?" she says. Looking at the extreme responding populations, the team found 48 genes that were very different between cells that are resistant to the damaging agent and cells that are sensitive.
 
Next, the researchers looked at how well the expression of those genes could predict resistance or sensitivity. "We looked only at the gene expression levels of those 48 genes, and we could predict 94 percent of the time how a cell would respond when hit with this DNA damaging agent," Fry says.

Taking a closer look at that panel of 48 genes, the scientists weren't surprised to find MGMT among them. "MGMT is currently used in the clinic as a diagnostic indicator of how tumor cells will respond to chemotherapeutics," Fry says. Another gene that they found was C21ORF56, which is located on chromosome 21 and encodes for a protein whose function is still unknown. When they knocked down C21ORF56, they were able to make the cells more sensitive to the MNNG agent. A third gene, MYH, showed the opposite effect: when it was knocked down, it made cells more resistant. "By controlling their expression, we actually show that not only can their expression be used as an indicator — a biomarker of how cells respond to exposure — but by changing their expression you can change cell responses to this DNA-damaging agent," Fry says.

In terms of clinical application, this signature panel could be used as a better way to predict who will or won't respond to chemotherapy. Moreover, it could be applied to the level of tumor. If a tumor's gene expression profile shows a resistant pattern, "that tumor wouldn't respond well to treatment with a chemotherapeutic that generates this type of DNA damage," Fry says. Additionally, a signature like this could be used in more subtle ways. "Depending on how [a person] is expressing this panel of genes, [it] could be [an] indicator of potential susceptible populations to various environmental exposures," she says.

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