“Hyperhotspots” in the human genome are up to 170-times more sensitive to ultraviolet radiation from sunlight compared to the genome average, researchers report.

Exposure to UV radiation is the major cause of skin cancer. Screening the hyperhotspots could offer a new way to predict a person’s skin cancer risk.

Scientists knew of hotspots, but not of ultra-sensitive hotspots.

“These are 100 times more sensitive than other sites in the genome,” says Douglas Brash, a senior research scientist in therapeutic radiology and dermatology and a member of the  Cancer Center at Yale University who led the research.

Skin cancer ‘bullseyes’

Named “cyclobutane pyrimidine dimer (CPD) hyperhotspots” after the type of DNA damage ultraviolet light causes, hyperhotspots can be thought of as “bullseyes” that attract damaging radiation. In the study, they occurred most often in melanin-forming cells in human skin known as melanocytes—the cells in the skin where melanoma skin cancer originates.

“Why wouldn’t evolution want to get rid of these?”

“We had thought that DNA damage and mutations that cause cancer were rare events, and random,” says Brash. “But this reveals that, at least for skin cancer, there are specific targets in the genome that are waiting to be hit by UV radiation.”

To find them, researchers designed a method for tagging sites of CPDs and used high-throughput DNA sequencing to map tags across the genome. They also developed a set of statistical methods for quantifying an individual site’s overrepresentation of CPDs relative to the genome average.

The researchers were surprised to discover the hotspots were located near genes, acting as a direct pathway for UV radiation to damage the cell.

The sites where the researchers identified hyperhotspots are “the same DNA sequences that control the regulation of DNA into RNA and protein, which is how the cell regulates growth,” Brash says.

At sunburn levels of UV exposure, UV radiation would affect hyperhotspots in the pigment cells of a person’s skin. A person would experience specific cell growth distortions from UV radiation in real time, not randomly or unpredictably and not weeks or years later, as was previously thought.

“Why wouldn’t evolution want to get rid of these?” Brash says.

The fact that evolution has not eliminated these bullseyes may be a tipoff that the cell uses hyperhotspots for sensing its environment, he says.

The existence of hyperhotspots suggests that mutations that a carcinogen—UV radiation or other—spawns are also not entirely random. Mutations related to gene regulation in melanoma tumors were present at CPD hyperhotspots 20,000 times more often than elsewhere.

Spotting risk ahead of time

The study suggests new ways of assessing skin cancer risk, the researchers say.

The most important factor for evaluating the risk is prior UV exposure. But doctors currently lack an objective means of measuring it, relying typically on patients’ memories of former sunburns.

If doctors could take a small skin sample and examine the hyperhotspots, Brash says, they could get a true picture of the DNA damage from prior sunburn at these sites and have a much better understanding of a patient’s exposure history and skin cancer risk.

Dermatologists could watch high-risk individuals closely so that they can detect skin cancers early, when they are still curable.

The study appears in the Proceedings of the National Academy of Sciences.

Source: Brita Belli for Yale University

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