Advancing skin cancer prevention by tackling UV-induced clonogenic mutations

鳞状细胞皮肤癌(SCC)是美国第二常见的癌症。有多种方法可供选择 2预防鳞状细胞癌，但没有适当地使用，因为我们缺乏评估其有效性的方法 3及时处理。来自太阳的紫外线(UV)导致基因组损伤是最重要的原因 4皮肤癌。在癌症形成的早期，紫外线会在细胞中引起突变，从而导致小的 5个克隆，成簇的突变细胞。导致这些克隆生长的早期突变称为 6克隆性突变(CM)。CMS是鳞状细胞癌形成过程中的早期变化，在几十年前就出现了 7例临床可检出的癌症。根据以前的证据，CMS可能会发出皮肤癌风险的信号，并评估 8预防治疗策略和防晒的有效性。Cm在皮肤中的丰度较低 9使它们具有检测的挑战性。然而，基因组测序技术的最新进展和 10种计算工具可以准确地识别和定量皮肤中的CMS。初步数据显示 11 CMS可以被准确地检测出来，并用于评估阳光损伤的皮肤区域。中发现的许多不育系 12正常日晒皮肤在鳞状细胞癌中也很常见。这个应用的中心假设是CMS是 晒伤皮肤的13个生物标记物，CMS可以衡量皮肤癌的治疗策略 14预防和防治工作。在第一组研究中，我们将完善以前开发的 15组太阳照射诱导的CMS，通过鉴定阳光暴露与非太阳暴露皮肤中最常见的CMS。 16后续研究将研究紫外线照射对CM面板变化和发展的影响 皮肤癌17例。这些研究将评估CMS的类型和患皮肤癌的风险。接下来， 18个精制的CMS小组将被用来检查旨在预防重度皮肤癌的治疗效果如何 19阳光损伤的皮肤区域可减少CMS和皮肤癌的形成。在最后一组研究中，CMS将用于 20评估防晒策略的效果，例如防晒霜。防晒系数(SPF)被广泛使用 21项用于评估防晒霜。然而，SPF衡量的是皮肤红度的减少，而不是实际的 22 DNA损伤。基因组DNA损伤会导致皮肤癌，而不是皮肤“发红”。基因组损伤 23可能是由不会导致晒伤的长期日晒损伤引起的。在最后一组研究中，使用了CMS 24评估防晒霜对防止基因组损伤和皮肤癌的有效性。这些研究 25将改变我们如何评估患者患皮肤癌的风险，以及我们如何确定皮肤的影响 26.防癌。这些研究有可能将重点从治疗癌症转移到预防 27皮肤癌的发生。这将导致癌症护理结果的改善，改善治疗 28种策略，并最终改善有日光损伤和癌前病变病史的个人的生活。 29这项工作的重点是皮肤癌，但由于CMS在大多数人类癌症的癌症生长过程中起着关键的第一步作用 30我们的发现和这项研究的框架将对更广泛的预防肿瘤学领域产生影响。

1 Squamous cell skin cancer (SCC) is the second most common cancer in the US. There are methods available 2 to prevent SCC but are not appropriately used because we lack methods of evaluating their effectiveness in a 3 timely manner. Ultraviolet light (UV) from the sun induces genomic damage which is the most important cause 4 of skin cancer. Early in the process of cancer formation UV causes mutations in cells which result in small 5 clones, clusters of mutated cells. The early mutations that result in the growth of these clones are called 6 clonogenic mutations (CM). CMs are early changes during SCC formation, which appear decades before 7 clinically detectable cancer. Based on previous evidence CMs may signal skin cancer risk and evaluate the 8 efficacy of preventative treatment strategies and sun protection. CM are in low abundance in the skin which 9 make them challenging to detect. However, recent advances in genomic sequencing technology and 10 computational tools allow accurate identification and quantitation of CMs in the skin. Preliminary data has shown 11 that CMS can be accurately detected and used to evaluate sun damaged skin areas. Many of the CMs found in 12 normal sun exposed skin are also common in SCC. The central hypothesis for this application is that CMs are 13 biomarkers of sun induced skin damaged and that CMs can measure how well strategies for skin cancer 14 prevention and preventative treatment work. In the first set of studies we will refine the previously developed 15 panel of sun induced CMs by identifying the most common CMs in sun exposed versus non-sun exposed skin. 16 Subsequent studies will examine the impact of UV exposure on changes in the CM panel and development of 17 skin cancer. These studies will evaluate patterns of CMs and the risk of developing skin cancer. Next, the 18 refined panel of CMs will be used to examine how well treatments designed to prevent skin cancer in heavily 19 sun damaged skin areas reduce CMs and skin cancer formation. In the final set of studies, CMs will be used to 20 evaluate the efficacy of sun protection strategies, such as sunscreens. Sun protection factor (SPF) is widely 21 used to evaluate sunscreens. However, SPF measures reduction in redness of the skin instead of the actual 22 DNA damage. Genomic DNA damage contributes to skin cancer, not “redness” in the skin. Genomic damage 23 can be caused by long term sun damage that does not cause a sunburn. In the final set of studies, CMs are used 24 to evaluate the effectiveness of sunscreens to protect against genomic damage and skin cancer. These studies 25 will change how we evaluate a patient’s risk of developing skin cancer and how we determine the effect of skin 26 cancer prevention. These studies have the potential to shift the focus from treating cancer to preventing the 27 occurrence of skin cancer. This would result in an improvement in cancer care outcomes, improve treatment 28 strategies and ultimately improve the life of individual with a history of sun damage and pre-cancerous lesions. 29 This work focuses on skin cancer but as CMs play a crucial first step in cancer growth in most human cancers 30 our findings and the framework of this study will have implications for the wider field of preventative oncology.