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）与基底细胞癌（BCC）共同构成非黑色素瘤皮肤癌（NMSC），是白种人中最常见的癌症，在美国每年有超过300万的新诊断病例。NMSC虽然不像其他癌症那样经常致命，但在国家层面上与高治疗费用、显著的患者发病率和发展为其他癌症的风险增加有关。暴露于紫外线辐射是NMSC的一个确定的危险因素，但是尽管公众知道阳光照射的危害和防晒霜的保护作用，NMSC的发病率仍在继续增加，强调了识别NMSC的其他危险因素的关键需要，这些因素可能更好地表征高危个体，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）感染可能是发生NMSC的危险因素。在免疫能力强的个体中，高达50%的NMSC组织中检测到多属皮肤型HPV的DNA。此外，一些病例对照研究，包括我们自己的研究，已经证明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上的显著关联。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）之间的关联，MCV dna阳性病例的MCV抗体水平明显高于对照组。尽管病例对照数据非常令人信服，但由于缺乏前瞻性数据，无法明确证明在相同病毒类型阳性的NMSC肿瘤发病之前病毒感染的存在和持续存在，因此无法建立皮肤乳头瘤病毒和多瘤病毒感染之间的因果关系。我们建议对有NMSC风险的个体进行一项前瞻性队列研究，获取多个生物标本用于测量皮肤HPV和MCV感染，并对参与者进行长达四年的随访，进行全身皮肤检查以检测NMSC事件。还将获得紫外线暴露的重复测量，以检验其作为病毒感染与NMSC之间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）的个体中会观察到NMSC的风险增加，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，在紫外线暴露水平较高的人群中，与皮肤病毒感染相关的NMSC风险更大。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潜在病原的理解。如果这些病毒感染在NMSC中起因果作用，那么未来可以开发出新的NMSC一级预防策略。

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.