New Study Explores the Use of Focused Ultradeep DNA Sequencing to Quantify Skin Cancer Risk
Recent research has shed new light on the carcinogenic effect of exposure to ultraviolet (UV) radiation, laying the groundwork for improvements in skin cancer risk stratification and prevention. A study published by Lei Wei, PhD, and colleagues in Science Advances detailed a method to measure the abundance of cancer-related early changes to skin tissue long before the damage becomes visible to the eye.
Led by a multidisciplinary team, the study used a precision-medicine approach—focused ultradeep DNA sequencing—to systematically compare clonal mutations between sun-exposed and non–sun-exposed skin areas.
Lei Wei, PhD
Gyorgy Paragh, MD
“We show[ed] that targeted ultradeep 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,” said Gyorgy Paragh, MD, a dermatologist, Interim Co-Chair of the Department of Dermatology, and Assistant Professor of Oncology at Roswell Park Comprehensive Cancer Center 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 outlined 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,” said the paper’s co-first and co-corresponding author Dr. Wei, Associate Professor of Oncology in the Department of Biostatistics and Bioinformatics and 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 reported 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 noted that many of their findings were unexpected. They reported, for example, a high quantity of low-frequency background mutations in both sun-exposed and non–sun-exposed areas. Additionally, 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 noted.
“Based on this work, we are pursuing further studies that will use mutation detection to enumerate skin cancer risk decades before cancers emerge,” said 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.”
Disclosure: This study was supported by donations to Roswell Park, the National Institutes of Health, and a Career Development Award from the Dermatology Foundation. For full disclosures of the study authors, visit advances.sciencemag.org.The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.