Abstract
Purpose: Despite reduced sensitivity to sun exposure, many Black patients treated with ionizing radiation appear to experience increased skin toxicity as compared to White patients. The cause is unknown, yet some studies have suggested that DNA repair is reduced in these patients. Therefore, we developed a technology to examine organ-specific differences in mutation rate after irradiation. In this study, we demonstrate the feasibility of personalized quantitative measurements of single base errors in DNA using a saline skin swab after irradiation. We believe this technology will have the potential to identify patients at higher risk for skin toxicity and, therefore, for whom preventative measures are most important. Methods/Results: We have developed a method for quantification of point mutations using xeno-DNA clamps. This method exceeds the theoretical limit for quantitation of base errors using standard deep-gene sequencing by several orders of magnitude. It can be performed on an organ-specific basis with less than 1 ng of DNA (≈100 cells). We have developed both a mouse and a human clamp set. Measurements of mouse organs, including the liver, brain, skin, spleen, and small bowel, were performed before and at various times after irradiation (0.5 to 10 Gy). Human cell culture studies parallel the mouse studies, and human clinical trials are underway using cotton swabs of skin and oral mucosa. The brain is highly efficient at damage repair, whereas mature lymphocytes repair poorly; epithelial cells (GI and skin) have intermediate accumulation of mutations after irradiation. Mutation accumulation can be higher at a low dose and does not monotonically increase with dose. Conclusions: Our xeno-DNA clamp methodology can easily, inexpensively, and quantitatively measure incremental point changes in the non-coding silent DNA that makes up 98.5% of the human genome. The test is ready for clinical application and a clinical trial is beginning in Black and White patients with head and neck cancers. Preliminary data will be presented.
Citation Format: Paul Okunieff, Steven B Zhang, Zhenhuan Zhang, Steven G Swarts, Natalie A Lockney, Katherine Casey-Sawicki, Sadasivan Vidyasagar. Detection of personalized oncogenic risk after genotoxic exposures [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr A083.
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