Prospective study of cutaneous viral infections and non-melanoma skin cancer

描述（由申请人提供）：皮肤鳞状细胞癌（SCC），沿着基底细胞癌（BCC），包括非黑色素瘤皮肤癌（NMSC），这是高加索人最常见的癌症，在美国每年诊断出超过3，000，000例新病例. NMSC虽然不像其他癌症那样经常致命，但与国家一级的高治疗费用，显著的患者发病率以及发展其他癌症的风险增加有关。暴露于紫外线辐射是NMSC的一个既定风险因素，但尽管公众了解阳光照射的危害和防晒霜的保护作用，NMSC的发病率继续增加，强调迫切需要确定NMSC的其他风险因素，这些因素可能更好地表征高风险个体，并有助于制定新的预防策略。越来越多的证据表明，皮肤人乳头瘤病毒（HPV）感染可能是NMSC发展的一个危险因素。来自多个属的皮肤HPV类型的DNA已在来自免疫活性个体的高达50%的NMSC组织中检测到。此外，包括我们自己在内的几项病例对照研究已经证明了NMSC与皮肤HPV类型抗体、眉毛毛囊中HPV DNA或正常皮肤样本中HPV DNA的存在之间存在统计学显著相关性。我们还观察到SCC与另一种皮肤病毒默克尔细胞多瘤病毒（MCV）之间的相关性，MCV DNA阳性病例的MCV抗体水平显著高于对照组。虽然病例对照数据非常令人信服，但在缺乏前瞻性数据的情况下，无法建立皮肤乳头状瘤病毒和多瘤病毒感染之间的因果关系，这些前瞻性数据清楚地证明了在NMSC肿瘤发病前病毒感染的存在和持续性，这些NMSC肿瘤对相同的病毒类型呈阳性。我们建议对有NMSC风险的个体进行前瞻性队列研究，获得多个生物标本用于测量皮肤HPV和MCV感染，并跟踪参与者长达四年，进行全身皮肤检查以检测事件NMSC。还将获得UV暴露的重复测量，以检查其作为病毒感染和NMSC之间的关联的效应调节剂的作用。我们假设在感染皮肤HPV（BCC和SCC）和MCV（仅SCC）的个体中观察到NMSC风险增加，并且在正常组织中持续存在的相同病毒类型将在随后的NMSC肿瘤中检测到。我们还假设，与皮肤病毒感染相关的NMSC的风险在紫外线暴露水平较高的人群中更大。拟议的研究将提供关键的时间证据，以促进我们对这些病毒作为NMSC潜在病原体的理解。如果这些病毒感染在NMSC中起因果作用，那么将来可以开发NMSC一级预防的新策略。

DESCRIPTION (provided by applicant): Cutaneous squamous cell carcinoma (SCC), along with basal cell carcinoma (BCC), comprise the non- melanoma skin cancers (NMSC), the most common cancer in Caucasians, with more than 3,000,000 new cases diagnosed annually in the United States. NMSC, though not as often fatal as other cancers, is associated with high treatment costs at the national level, significant patient morbidity, and an increased risk of developing other cancers. Exposure to UV radiation is an established risk factor for NMSC, but despite public knowledge about the harms of sun exposure and protective effects of sunscreen, NMSC incidence rates continue to increase, emphasizing the critical need for identification of additional risk factors for NMSC that may better characterize individuals at high risk and aid in the development of novel prevention strategies. Accumulating evidence suggests that cutaneous human papillomavirus (HPV) infection may be a risk factor for developing NMSC. DNA from cutaneous HPV types in multiple genera has been detected in up to 50% of NMSC tissues from immuno-competent individuals. In addition, several case-control studies, including our own, have demonstrated statistically significant associations between NMSC and antibodies against cutaneous HPV types, presence of HPV DNA in eyebrow hair follicles or HPV DNA in normal skin samples. We also observed associations between SCC and another cutaneous virus, Merkel cell polyomavirus (MCV), with MCV DNA-positive cases having significantly higher MCV antibody levels than controls. Although the case-control data are highly compelling, causal associations between cutaneous papillomavirus and polyomavirus infections cannot be established in the absence of prospective data that clearly demonstrate the presence and persistence of the viral infections prior to the onset of NMSC tumors that are positive for the same virus types. We propose to conduct a prospective cohort study of individuals at risk for NMSC, obtaining multiple biospecimens for the measurement of cutaneous HPV and MCV infections, and following participants for up to four years, conducting full body skin exams for th detection of incident NMSC. Repeated measures of UV exposure will also be obtained to examine its role as an effect modifier of the association between viral infection and NMSC. We hypothesize that an increased risk of NMSC will be observed among individuals infected with cutaneous HPV (BCC and SCC) and MCV (SCC only), and that the same viral types persistent in normal tissues will be detected in the subsequent NMSC tumors. We also hypothesize that the risk of NMSC associated with cutaneous viral infections will be greater among those with higher levels of UV exposure. The proposed study would provide the critical temporal evidence needed to advance our understanding of these viruses as potential etiologic agents in NMSC. If these viral infections play a causal role in NMSC, novel strategies for NMSC primary prevention could be developed in the future.