| Autor: |
Wei, Lei, Fitzgerald, Megan, Graham, James, Hutson, Nicholas, Zhang, Chi, Huang, Ziyun, Hu, Qiang, Zhan, Fenglin, Xie, Jun, Zhang, Jianmin, Liu, Song, Remenyik, Eva, Gellen, Emese, Colegio, Oscar R., Christensen, Sean, Lin, Haifan, Bax, Michael, Xu, Jinhui, Huss, Wendy J., Foster, Barbara A., Paragh, Gyorgy |
| Jazyk: |
angličtina |
| Rok vydání: |
2020 |
| Předmět: |
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| DOI: |
10.1101/2020.01.10.902098 |
| Popis: |
Exposure to ultraviolet (UV) radiation results in growth of clonal somatic mutation (CM) harboring cell groups in clinically normal appearing skin and can cause non-melanoma skin cancer (NMSC), the most common cancers in humans. CMs can be considered the earliest detectable manifestations of photocarcinogenesis. Systematic evaluation of CMs is crucial to understand early photo-carcinogenesis. Differences between CMs in sun-exposed (SE) and non-SE (NE) areas are unknown. To address these problems, we developed a robust method to quantitatively measure CMs in skin using targeted (5,500bp), ultra-deep (64,730X median coverage), high-throughput sequencing in 450 matched SE and NE epidermal punch biopsies obtained from clinically normal skin (n=13 individuals). In total we identified 638 mutations including 298 UV-signature mutations (USMs). SE samples showed 3-fold higher rate of USM and higher USM variant allele frequencies than NE. We identified areas in TP53, NOTCH1 and GRM3 where mutation burden was significantly associated with UV-exposure. Six mutations were almost exclusively present in SE epidermis and accounted for 42% of the overall difference between SE and NE mutation burden. Cumulative Relative Clonal Area (CRCA) was defined as the overall relative percentage of the sampled skin area affected by CM. UV-induced DNA damage is a clinically relevant criterion and CRCA is a single metric of UV-damage. CRCA was dramatically elevated (mean = 11.2 fold) in SE samples compared to NE. This study represents the first analysis of clonogenic mutations in SE and NE human skin. The findings unveiled previously unknown patterns of early mutations introduced by UV exposure. Significance statement In UV radiation exposed skin, mutations fuel clonal cell growth. We established a sequencing-based method to objectively assess the mutational differences between sun-exposed and non-sun-exposed areas of normal human skin. Striking differences, in both the numbers of mutations and variant allele frequencies, were found between sun-exposed and -protected areas. Furthermore, we identified specific genomic regions where mutation burden is significantly associated with UV-exposure status. These findings revealed previously unknown mutational patterns associated with UV-exposure, providing important insights into UV radiation’s early carcinogenic effects. The CRCA can be developed for quantitatively measuring subclinical skin UV damage and field carcinogenesis. Classification Biological Sciences, Genetics; Cancer risk; Early detection |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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