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Roswell Park Experts Use Gene Sequencing to Quantify Risk of Skin Cancer Long Before Damage is Visible

From left, Drs. Wendy Huss, Lei Wei (on monitor), Barbara Foster and Gyorgy Paragh have developed an approach for assessing dangerous mutations in skin tissue long before damage becomes visible.


New findings could lead to better tools for the identification of at-risk individuals, earlier cancer prevention

BUFFALO, N.Y. — Research conducted by a team at Roswell Park Comprehensive Cancer sheds new light on the carcinogenic effect of exposure to ultraviolet (UV) radiation, laying the groundwork for improvements in skin cancer risk stratification and prevention. In a study published today in the journal Science Advances, the team details a method to measure the abundance of cancer-related early changes to skin tissue long before the damage becomes visible to the eye. 

With over 5 million cases diagnosed annually in the U.S., nonmelanoma skin cancers are the most common human malignancy. While these skin cancers are frequent in sun-exposed skin areas and are mostly caused by long-term cumulative sun damage, currently no clinical technique exists for measuring this early damage.

Led by a multidisciplinary team from Roswell Park’s Dermatology, Biostatistics and Bioinformatics and Pharmacology and Therapeutics departments — Lei Wei, PhDBarbara Foster, PhDWendy Huss, PhD, and Gyorgy Paragh, MD, PhD — this first-of-its-kind study used a precision-medicine approach, focused ultra-deep DNA sequencing, to systematically compare clonal mutations between sun-exposed and non-sun-exposed skin areas.

“We show that targeted ultra-deep sequencing of skin DNA samples is a tool that can effectively identify potentially cancer-causing cumulative skin damage before the appearance of visible skin changes,” says Dr. Paragh, a dermatologist, Interim Co-Chair of the Department of Dermatology and Assistant Professor of Oncology at Roswell Park and co-senior author on the new study. “Our work shows that sun exposure in the skin leads to specific patterns of UV-induced mutations. We also showed that the burden of mutations could be determined from clinically relevant small skin samples and that this information can be combined in a clinically meaningful way to compare individual skin mutation levels.”

The researchers outline a bioinformatics pipeline for accurately characterizing these low-frequency mutations.

“Our work not only confirms the existence of microscopic groups of cells in the normal skin with DNA alterations, but also allowed us to discover the systematic differences between the mutations caused by UV from the ones caused by aging or other environmental factors,” reports the paper’s co-first and co-corresponding author, Dr. Wei, who is an Associate Professor of Oncology from the Department of Biostatistics and Bioinformatics, and the Co-Director of Bioinformatics Core Resource at Roswell Park. “The UV-induced mutations often occur in specific sites or ‘hotspots’ of human genes, and, interestingly, some of these sites are rarely mutated in non-sun-exposed skin even with aging or other factors.”

The team uncovered several other patterns regarding UV-induced mutations. They report that these mutations tend to result in changes of genes that modify protein function and are associated with specific contexts of DNA sequence, and that the clones harboring the mutations are generally larger in sun-exposed skin areas than the ones in non-sun-exposed areas.

The investigators note that many of their findings were unexpected. They report, for example, a high quantity of low-frequency background mutations in both sun-exposed and non-sun-exposed areas. And while the existence of mutational hotspots has already been established, this study revealed that over one-third of the differences between the mutations in sun-exposed and non-sun exposed areas were due to mutations in just six codons.

Another novel finding was the existence of “mutation-exempt” genomic regions in non-sun-exposed skin. These genomic areas, which are never mutated in detectable clones during skin aging, can lose their mutation-exempt status when exposed to sun. Further exploration is required to fully understand the mechanisms behind this observation, the authors note.

“Based on this work, we are pursuing further studies that will use mutation detection to enumerate skin cancer risk decades before cancers emerge,” says Dr. Paragh. “We intend to use these preliminary results to comprehensively improve skin cancer prevention by better identifying at-risk individuals, improve early treatment strategies and develop better tools for evaluating the efficacy of sun-protection techniques.”

Another key contributor to this research is Sean Christensen, MD, PhD, of the Yale School of Medicine, co-first author on the new study.

This work was supported primarily by generous donations to Roswell Park. Additional funding came from two National Institutes of Health grants (project numbers P30CA016056 and U24ES026465) and a Career Development Award from the Dermatology Foundation.

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