DNA damage and mutations across the genome (Environmental Factor, October 2018)

Saini’s research direction is rooted in questions such as, “Is having a thousand mutations bad or do I need to have a million mutations in order to get cancer?” (Photo courtesy of Steve McCaw)

Environmental exposures can lead to increased mutations in the genome, according to NIEHS postdoctoral fellow Natalie Saini, Ph.D. She opened the fall seminar series for Duke University’s Program in Environmental Health and Toxicology Sep. 7 with a discussion of “The Contributions of DNA Damage and Repair to Genome-wide Human Somatic Mutation Loads” in the Field Auditorium.

Environmental mutagens and cancer

Mutations, or changes in DNA, are linked to a wide range of diseases, such as Alzheimer’s and autism. Each person has a certain number of mutations, called mutation load, and more mutations arise throughout a person’s lifetime, Saini explained. Her research interest is about whether some mutations are due to environmental agents.

In general, cancers are considered to have a high mutation load, but there is a lot of variety in the number and types of mutations associated with specific cancers. Saini pointed to the example of skin cancer, which shows a specific pattern of mutations from ultra-violet (UV) damage.

The pattern involves a change from the DNA base cytosine to thymine, or C to T, in particular locations. Saini and her collaborators used this change as a signature for UV exposure when looking at the mutation loads in people.

The impact of UV damage on mutation load

Ed Levin, Ph.D., professor of psychiatry and behavioral sciences at Duke, introduced Saini. (Photo courtesy of Steve McCaw)

At the NIEHS Clinical Research Unit, volunteers provided skin samples from arms and hips. Because arms are exposed to more sunlight and are more likely to have UV damage, Saini hypothesized that the skin samples from arms would show more UV-caused mutations than the skin from hips.

Her hypothesis proved correct — the arm skin showed significantly more of the UV-specific C-to-T mutations. “We can clearly see an impact of UV in the forearms,” she said.

C-to-T changes can also occur due to a spontaneous change in cytosines to thymines in particular locations. This mutation occurs in all of us and gradually increases in our cells as we grow older. This C-to-T mutation signature is also prominent in cancers that have defects in the MBD4 gene, which is a gene that helps with DNA repair.

Using the NIEHS Environmental Polymorphisms Registry, Saini was able to look at samples from cancer-free individuals and see what mutations were in their MBD4 genes.

Although a few people had mutations known to be harmful, others had particular mutations associated with a higher cancer incidence. This research may lead to key insights regarding risk factors for high mutation loads or for developing cancer later in life.

Future goals

In the future, Saini hopes to develop ways to tie mutation signatures to specific causes of genome instability. She highlighted the Environmental Polymorphisms Registry as a great resource for studying the factors that influence mutation loads.

Saini would also like to define what levels of genome instability are normal and what levels are pathological, leading to disease. “We have so much data on cancers … but we don’t know what to compare it with,” she explained. “We don’t have a normal or baseline for healthy people.”