Genomic Sunlight Dosimeters for Melanoma Prevention

早期发现黑色素瘤的治愈率接近100%，但在晚期诊断的存活率不到20%。早期诊断的力量使其成为预防黑色素瘤死亡的主要方法。然而，几乎没有证据表明大规模的公共皮肤癌筛查可以预防黑色素瘤死亡。关注风险最大的人群，可以早期预测风险，帮助初级保健医生确定应该由皮肤科医生随访的患者。这种预防性测试需要测量黑色素瘤风险的两个方面：遗传风险和日晒风险。项目1关注的是暴露在阳光下的风险，因为大多数患有菲茨帕特里克型皮肤的人不会得黑色素瘤。然而，紫外线照射通常是通过患者回忆来确定的，而不是通过过去阳光照射的客观生物学指标来确定的。为了克服评估个人紫外线暴露和黑色素瘤风险的这一关键障碍，我们建议将两种新技术与下一代测序相结合，以创建长期阳光暴露的基因组替代生物标志物。一种剂量计利用基因组特殊区域DNA光产物的积累；另一个结合了我们关于皮肤细胞克隆扩增的知识。然后我们评估这些基因组剂量计读数与皮肤黑色素瘤的关系。具体目标是：目标1：绘制紫外线损伤热点或DNA修复慢点的人类基因组区域。目的2：定量体内皮肤中罕见的紫外线突变基因。目标3：使用对紫外线光产物和突变敏感的基因组区域作为剂量计，将正常皮肤的累积阳光照射与黑色素瘤风险联系起来。这些研究建立了使用现代测量技术客观确定暴露于癌症风险的方法。

Detecting melanoma early leads to a nearly 100% cure rate, but diagnosing it at an advanced stage results in less than 20% survival. The power of early diagnosis has made it the major approach to preventing death from melanoma. Yet there is little evidence that large public skin cancer screenings prevent melanoma deaths. Focusing on people at greatest risk would be possible with an early predictor of risk that helps the primary care physician identify patients who should be followed by a dermatologist. This preventive test needs to measure both aspects of melanoma risk: genetic risk and sun-exposure risk. Project 1 focuses on sun-exposure risk because most people with Fitzpatrick Type I skin do not get melanoma. Yet UV exposure is usually ascertained by patient recollections rather than by objective biological indicators of past sun exposure. To overcome this critical barrier to assessing personal UV exposure and thus melanoma risk, we propose to couple two new technologies with Next-Gen sequencing to create genomic surrogate biomarkers of long-term sun exposure. One dosimeter takes advantage of the accumulation of DNA photoproducts in special regions of the genome; the other incorporates our knowledge about clonal expansion of cells in skin. We then evaluate these genomic dosimeter readings in skin for association with melanoma. The Specific Aims are: Aim 1: Map human genomic regions that are UV damage hotspots or DNA repair slowspots. Aim 2: Quantitate rare UV-mutated genes in skin in vivo. Aim 3: Use genomic regions sensitive to UV photoproducts and mutations as dosimeters to correlate cumulative sunlight exposure in normal skin to risk for melanoma. These studies establish ways to objectively ascertain exposure to cancer risk using modern measurement technologies.