The 1986 Chernobyl nuclear power plant disaster in Ukraine exposed millions of people in the region to ionizing radiation, leading to an increased rate of papillary thyroid cancer. Researchers have taken an in-depth look at the molecular profile of these cancers—revealing, among other things, the presence of DNA double-strand breaks that correlate with greater and earlier exposure to radiation.

The 1986 Chernobyl nuclear power plant explosion in Ukraine exposed millions in the region to ionizing radiation, leading to an increased rate of papillary thyroid cancer. A recent in-depth look at the molecular profile of these cancers revealed, among other things, the presence of DNA double-strand breaks that correlate with greater and earlier exposure to radiation (Science 2021;372:eabg2538).

In 1998, researchers started the Chernobyl Tissue Bank to collect tumor and normal tissue samples from people who developed papillary thyroid cancer after the disaster and to combine them with estimates of radiation exposure. “This provided a unique opportunity to conduct a large-scale molecular profiling of tumors where we actually could correlate the molecular characteristics of those tumors with the known potential carcinogenic exposure,” explains lead author Lindsay Morton, PhD, of the NCI.

She and her team performed genomic, transcriptomic, and epigenomic profiling of tumor tissue, normal tissue, and/or blood taken from 440 patients with papillary thyroid cancer from Ukraine: 359 patients had been exposed to Chernobyl's ionizing radiation as children, and the other 81 patients, born after 1986, had no exposure.

The analysis revealed that tumors from patients with greater radiation exposure and exposure at a younger age had a higher rate of DNA double-strand breaks. Additionally, those breaks tended to be clonal in nature and had signs of nonhomologous end joining as a DNA repair mechanism. There was no association between radiation dose and transcriptomic or epigenomic characteristics, but such characteristics were strongly related to cancer driver genes. Most alterations in driver genes occurred along the MAPK pathway—including RET, NTRK, and BRAF—and the ratio of fusions to point mutations rose with increasing radiation exposure.

The results suggest “that radiation-induced damage occurs very early in the process of thyroid carcinogenesis, and once the driver gene has been mutated, it really seems to take over and shape the entire subsequent profile of the tumor,” Morton explains. Additionally, the alterations in driver genes were highly consistent with those seen in papillary thyroid cancers not caused by radiation—indicating that the cancers may respond to similar treatments.

Morton and her team want to know if their results can be generalized across radiation and tumor types. They also want to further investigate the molecular basis of the higher cancer risk in people with earlier radiation exposure. In addition, they hope their work will motivate researchers to conduct detailed molecular profiling of tumors caused by other carcinogens. “We really hope that we've opened that door and provided that template,” Morton says.

“What's new about it and somewhat exciting is not so much the scope, but the depth of this story,” says Jochen Lorch, MD, of Dana-Farber/Brigham and Women's Cancer Center in Boston, MA, who wasn't involved in the research. “It's a huge sample size and it's very thoroughly sequenced and analyzed.”

For him, the most compelling finding is the relationship between the level of DNA damage and age and degree of radiation exposure. “You could clearly distinguish these radiation signatures among patients who had been very young but had also only been hit with quite a small dose,” he says. He says this reinforces the importance of protecting young people from even low levels of radiation.

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Destruction caused by the 1986 Chernobyl nuclear power plant explosion in Ukraine.

The results also quantify molecular aspects of the cancers, including the relative rates of driver alterations. “It's not a breakthrough in the sense that it's all novel,” he says, “but it's very definitive with the answers that it provides.” –Catherine Caruso

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