Abstract PR01: Genomic UV-hypersensitive sites as sentinels for personal UV exposure

Abstract

Abstract The largest risk factor for skin cancers such as melanoma is past sun exposure, so an objective measurement of traces of an individual’s sun history would allow a general practitioner to identify people who should be monitored for early cancer detection. If the genome contains outlier DNA sequences hypersensitive to environmental agents such as ultraviolet light (UV), these would be genomic dosimeters for monitoring personal carcinogen exposure and would facilitate noninvasive measurements on small skin samples. Such DNA sites might also allow UV to drive direct changes in cell physiology rather than acting through rare mutations. New methods, adductSeq and freqSeq, tagged rare UV-induced cyclobutane pyrimidine dimers (CPDs) and provided statistical resolution to quantify rare lesions at single-base resolution across the genome. Primary human melanocytes, but not fibroblasts, carried spontaneous apurinic sites and TG sequence lesions more frequent than UV-induced CPDs. UV exposure revealed hyperhotspots acquiring CPDs up to 200-fold more frequently than the genomic average; these were 20-fold more prevalent in melanocytes. Hyperhotspots were disproportionately located near genes, particularly for RNA-binding proteins, with the most-recurrent hyperhotspots at a fixed position within two motifs. One motif occurred at ETS1 transcription factor binding sites, known to be UV targets, and at sites of mTOR/TOP-tract translation regulation; the second occurred at a sequence that developed delayed CPDs after UV exposure, repaired CPDs slowly, and had accumulated CPDs prior to the experiment. Melanocyte CPD hyperhotspots aligned precisely with recurrent UV signature mutations in individual gene promoters of melanomas and with known cancer drivers. At sunburn levels of UV exposure, every cell would have a hyperhotspot CPD in each of the ~20 cell pathways targeted, rendering CPD hyperhotspots epigenetic marks. This abstract is also being presented as Poster A28. Citation Format: Sanjay Premi, Lynn Han, Sameet Mehta, James Knight, Dejian Zhao, Antonella Bacchiocchi, Ruth Halaban, Meg A. Palmatier, Karl Kornacker, Douglas E. Brash. Genomic UV-hypersensitive sites as sentinels for personal UV exposure [abstract]. In: Proceedings of the AACR Special Conference on Environmental Carcinogenesis: Potential Pathway to Cancer Prevention; 2019 Jun 22-24; Charlotte, NC. Philadelphia (PA): AACR; Can Prev Res 2020;13(7 Suppl): Abstract nr PR01.