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

描述(申请人提供)：皮肤鳞状细胞癌(SCC)和基底细胞癌(BCC)包括非黑色素瘤皮肤癌(NMSC)，这是高加索人最常见的癌症，在美国每年有超过300万例新诊断病例。NMSC虽然不像其他癌症那样经常致命，但与国家一级的高昂治疗成本、显著的患者发病率以及发展为其他癌症的风险增加有关。暴露在紫外线辐射下是NMSC的既定风险因素，但尽管公众知道阳光照射的危害和防晒霜的保护作用，NMSC的发病率仍在继续上升，强调迫切需要确定NMSC的其他风险因素，这些因素可以更好地表征高危个人的特征，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发生的危险因素。来自多个属的皮肤HPV类型的DNA已在高达50%的来自具有免疫能力的个人的NMSC组织中被检测到。此外，一些病例对照研究，包括我们自己的研究，已经证明NMSC与抗皮肤HPV类型的抗体、眉毛毛囊中HPV DNA的存在或正常皮肤样本中的HPV DNA之间存在统计上的显著相关性。我们还观察到鳞状细胞癌与另一种皮肤病毒--默克尔细胞多瘤病毒(MCV)之间的关系，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有说服力，但如果没有前瞻性数据清楚地证明在NMSC肿瘤发病前对相同病毒类型呈阳性的病毒感染的存在和持久性，就不能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NMSC的高危个体进行前瞻性队列研究，获得多种生物检验剂来测量皮肤HPV和MCV感染，并对参与者进行长达四年的全身皮肤检查，以检测NMSC的发生。还将获得紫外线暴露的重复测量，以检查其作为病毒感染和NMSC之间联系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，NMSC的风险将会增加，并且在随后的NMSC肿瘤中将检测到在正常组织中持续存在的相同病毒类型。我们还假设，在紫外线暴露水平较高的人中，与皮肤病毒感染相关的NMSC的风险将更大。这项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中起到因果作用，未来可能会开发出NMSC初级预防的新策略。

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.