Advancing skin cancer prevention by tackling UV-induced clonogenic mutations

1鳞状细胞皮肤癌（SCC）是美国第二常见的癌症。有一些方法可以利用 2，以防止SCC，但没有适当使用，因为我们缺乏方法来评估其有效性， 三是及时。来自太阳的紫外线（UV）诱导基因组损伤，这是最重要的原因 4皮肤癌在癌症形成过程的早期，紫外线会导致细胞突变， 5个克隆，突变细胞的集群。导致这些克隆生长的早期突变被称为 6个克隆突变（CM）。CM是SCC形成过程中的早期变化，在SCC形成前几十年出现 7临床可检测的癌症根据以前的证据，CM可能是皮肤癌风险的信号，并评估皮肤癌的发生率。 8预防性治疗策略和防晒的功效。CM在皮肤中的丰度较低， 9、使其难以检测。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识别和定量皮肤中的CM。初步数据显示， CMS可以被准确地检测到并用于评估太阳损伤的皮肤区域。许多发现于 12正常的阳光暴露皮肤也常见于SCC。该应用的中心假设是CM是 13个生物标志物的太阳引起的皮肤损伤和CM可以衡量如何以及皮肤癌的策略 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 通过识别暴露于阳光的皮肤与非暴露于阳光的皮肤中最常见的CM，对15组阳光诱导的CM进行比较。 16随后的研究将研究紫外线照射对CM板变化的影响， 17皮肤癌这些研究将评估CM的模式和患皮肤癌的风险。接下来 18个改良的CM面板将用于检查设计用于预防皮肤癌的治疗方法在严重 19阳光损伤的皮肤区域减少CM和皮肤癌的形成。在最后一组研究中，CM将用于 20评估防晒策略的功效，如防晒霜。防晒系数（SPF）是一个广泛的 21用于评估防晒霜。然而，SPF测量皮肤发红的减少，而不是实际的 22 DNA损伤。基因组DNA损伤导致皮肤癌，而不是皮肤的“发红”。基因组损伤 23可能是由长期的阳光损害引起的，但不会引起晒伤。在最后一组研究中，使用CM 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癌的影响。 26癌症预防。这些研究有可能将重点从治疗癌症转移到预防癌症。 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策略，并最终改善个人的生活与历史的太阳损伤和癌前病变。 29这项工作的重点是皮肤癌，但由于CM在大多数人类癌症的癌症生长中起着关键的第一步， 我们的发现和这项研究的框架将对更广泛的预防性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.