Defining critical aspects of environmental ultraviolet exposure in melanogenesis

描述(申请人提供)：阳光暴露一直与非黑色素瘤皮肤癌的发生有关，但其在黑色素瘤病因学中的作用仍存在争议，并因鲜为人知的遗传和行为因素而变得复杂。黑色素瘤的发病率继续上升(它现在是加州男性中第四种最常见的癌症)。通过避免阳光暴晒来减少黑色素瘤发病率的努力成效有限，这突显了我们对黑素生成的真实机制缺乏了解。黑色素瘤流行病学基于回溯性研究：回忆偏差可能解释了晒伤(几乎总是自我报告)与黑色素瘤之间的联系。此外，晒伤只是过度暴露在太阳辐射下，而阳光诱导的DNA损伤可能发生在所有强度的水平：在流行病学研究中，没有被接受的直接测量太阳暴露的方法。为了更好地了解黑色素瘤的病因(特别是日晒的作用)，需要有效的方法来评估当前和以往的日晒。虽然遗传因素可能在黑色素生成中发挥了一些作用，但还没有研究设法区分遗传和阳光暴露相关的风险。我们将在一项关于同卵双胞胎的病例对照研究中解决这两个问题(嵌套在加利福尼亚州已建立的基于人群的52,000对双胞胎队列中)，评估在没有遗传影响的情况下阳光暴露在黑色素瘤病因中的作用。历史的太阳暴露量将通过结合住宅历史和使用地理信息系统的新的细层内插太阳辐射水平来评估：我们已经表明，这种方法显着减少了错误分类和回忆偏差。我们将测量太阳辐射对皮肤的实际影响，测量肿瘤标本中紫外线诱导的表皮损伤，并注意到不同紫外线强度和波长的风险差异。这些结果有可能改善对黑色素瘤和其他皮肤癌的初级预防，并指导研究小组未来在与黑素生成相关的基因-环境相互作用方面的工作。我们将测量太阳辐射对皮肤的实际影响，测量肿瘤标本中紫外线(UV)诱导的表皮损伤，注意不同紫外线强度和波长的风险差异，并估计特定年龄段和终身暴露于特定波长紫外线的黑色素瘤风险。这些结果有可能通过指出避免有害紫外线暴露的适当方法来改善黑色素瘤和其他皮肤癌的初级预防，并指导研究小组未来在与黑素生成相关的基因-环境相互作用方面的工作。

DESCRIPTION (provided by applicant): Sun exposure has been consistently implicated in the development of non-melanoma skin cancers, but its role in melanoma etiology remains controversial, and is complicated by poorly understood genetic and behavioral factors. Melanoma incidence continues to increase (it is now the 4th most common cancer among males in California). Efforts to reduce melanoma incidence through sun exposure avoidance have had limited success, underscoring our lack of understanding of the true mechanisms of melanogenesis. Melanoma epidemiology is based on retrospective studies: recall bias probably explains associations between sunburn (almost always self-reported) and melanoma. Moreover, sun burn represents only excessive exposure to solar radiation, while sun-induced DNA damage potentially occurs across all levels of intensity: there is no accepted method for directly measuring sun exposure in epidemiological studies. In order to better understand the etiology of melanoma (particularly the role of sun exposure), valid methods of assessing both current and historical sun exposure are needed. While genetic factors probably play some role in melanogenesis, no study has yet managed to distinguish genetic from sun exposure-related risks. We will address both these issues in a case-control study of identical twins (nested in an established population-based cohort of 52,000 twins in California) assessing the role of sun exposure in melanoma etiology in the absence of genetic effects. Historical sun exposure will be assessed by combining residential history with novel fine-layer interpolated solar radiation level using GIS: we have already shown this method significantly reduces misclassification and recall bias. We will measure the actual impact of solar radiation on the skin, measuring UV- induced epidermal damage in tumor specimens noting differences in risk with varying UV intensity and wavelength. These results have the potential to improve primary prevention of melanoma and other skin cancers, and to direct the research team's future work on gene-environment interactions relevant to melanogenesis. We will measure the actual impact of solar radiation on the skin, measuring ultra-violet (UV)-induced epidermal damage in tumor specimens noting differences in risk with varying UV intensity and wavelength, and estimating the risk of melanoma with lifetime and age- specific exposures to specific wavelengths of UV. These results have the potential to improve primary prevention of melanoma and other skin cancers by indicating the appropriate means of avoiding harmful UV exposure, and to direct the research team's future work on gene-environment interactions relevant to melanogenesis.