AT occurs in fewer than 1 in 40,000 children, yet Cheung soon realized, as her lab grew, that radiosensitivity was a trait not confined to these rare patients. Gene-expression studies in her lab suggested that AT carriers, who have one nonworking copy of ATM (and represent fully 1 percent of the population), are also more sensitive to radiation. In fact, Cheung noted from the literature that more than 10 percent of all patients receiving radiation therapy for cancer showed signs of excessive damage or secondary cancers.

“That told me that ATM wasn't the only gene responsible for radiosensitivity,” she remembers.

Cheung still does some clinical consultation at Children's Hospital. But for the past several years, and with support from HHMI since early 2008, she and her colleagues have been trying to understand the genetic underpinnings of radiosensitivity in AT patients as well as in the wider population. In a study published in Nature in April, Cheung and her lab members looked at gene expression responses to irradiation in a large sample of human cells. They were able to link individual differences in these responses to DNA-sequence variations in more than a dozen master regulators of the radiation response, which were found throughout the genome.

“One goal of this is to develop a DNA-based test to determine how radiosensitive a person is likely to be,” she says, adding that such information is becoming more important, given the rapid increase in the use of radiation for CT scans and cancer therapies over the past two decades. Detailed knowledge about the molecular first responders to radiation damage could help, too, in the development of drugs to make tumors more sensitive to radiotherapy.

Cheung also has a deeper goal in mind, which broadly relates to the popular concept of personalized medicine: “We can apply the same tools developed for this study to see how people differ in their responses to drugs or environmental toxins that they are exposed to in their ordinary lives,” she says.

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