Prospective Study of the Associations between Cutaneous Papillomavirus and Polyo

皮肤鳞状细胞癌（SCC）和基底细胞癌（BCC）组成了非黑色素瘤皮肤癌（NMSC），这是白种人最常见的癌症，在美国每年有超过300万的新病例被诊断出来。虽然通常不致命，但鳞状细胞癌可能反复复发并导致一小部分患者死亡，而且鳞状细胞癌的病史一直与其他几种癌症的风险增加有关。尽管目前人们已经了解了阳光照射的危害，并且越来越多地使用防晒霜，但鳞状细胞癌的发病率仍在继续增加，这强调了这种高度流行的癌症对公共卫生的重要性，并强调了对其病因和控制的进一步了解的必要性。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，特别是SCC的危险因素。在免疫能力强的个体中，高达50%的鳞状细胞癌组织中检测到多属皮肤型HPV的DNA。此外，一些病例对照研究表明，SCC与皮肤HPV类型抗体、眉毛毛囊中HPV DNA的存在或正常皮肤样本中HPV DNA的存在之间存在统计学意义上的关联。基于肿瘤的HPV DNA检测和血清学测量被纳入我们自己的病例对照研究，其中皮肤HPV血清反应性与HPV DNA阳性SCC显著相关，检测到的抗体与肿瘤组织中存在的相同HPV类型。在同一项研究中，SCC还与另一种皮肤病毒默克尔细胞多瘤病毒（MCV）相关，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明确证明在发病前存在病毒感染，因此无法确定皮肤乳头瘤病毒和多瘤病毒感染之间的因果关系。我们建议对有鳞状细胞癌风险的个体进行前瞻性队列研究，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跟踪，进行全身皮肤检查以检测偶发鳞状细胞癌。拟议研究的目的是估计SCC与皮肤HPV和MCV感染相关的风险，并证明正常组织中的病毒感染与随后的NMSC病变之间的类型特异性一致性。该研究将为建立皮肤病毒感染与鳞状细胞癌之间的因果关系提供关键证据。

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. While not usually fatal, SCC may repeatedly recur and result in death in a small proportion of patients, and a history of SCC has been consistently associated with an increased risk of several other types of cancers. Despite the current knowledge about the harms of sun exposure, and increased use of sunscreen, SCC incidence rates continue to increase, emphasizing the public health importance of this highly prevalent cancer, and highlighting the need for an increased understanding of its etiology and control. Accumulating evidence suggests that cutaneous human papillomavirus (HPV) infection may be a risk factor for developing NMSC, particularly SCC. DNA from cutaneous HPV types in multiple genera has been detected in up to 50% of SCC tissues from immuno-competent individuals. In addition, several case-control studies have demonstrated statistically significant associations between SCC and antibodies against cutaneous HPV types, presence of HPV DNA in eyebrow hair follicles or HPV DNA in normal skin samples. Tumor-based HPV DNA detection and serology measurements were incorporated into our own case-control study, in which cutaneous HPV seroreactivity was significantly associated with HPV DNA-positive SCC, with antibodies detected for the same HPV types that were present in the tumor tissue. In the same study, SCC was also associated with 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 of the viral infections prior to the onset of disease. We propose to conduct a prospective cohort study of individuals at risk for SCC, 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 the detection of incident SCC. The goal of the proposed research is to estimate the risk of SCC associated with cutaneous HPV and MCV infections and to demonstrate type-specific concordance between viral infections in normal tissues and subsequent NMSC lesions. The proposed study would provide the critical evidence needed for establishing causality between cutaneous viral infections and SCC.