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)包括非黑色素瘤皮肤癌(NMSC)，NMSC是高加索人最常见的癌症，在美国每年有超过300万新诊断病例。虽然鳞状细胞癌通常不是致命的，但在一小部分患者中可能会反复复发并导致死亡，而且鳞状细胞癌的病史一直与几种其他类型癌症的风险增加有关。尽管目前人们对阳光暴晒的危害以及防晒霜的使用量有所增加，但鳞状细胞癌的发病率仍在继续上升，强调了这种高度流行的癌症对公共卫生的重要性，并强调了加强对其病因和控制的了解的必要性。越来越多的证据表明，皮肤人乳头瘤病毒(HPV)感染可能是NMSC，尤其是SCC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%的鳞状细胞癌组织中检测到，这些组织来自具有免疫能力的个人。此外，几项病例对照研究表明，鳞癌与针对皮肤HPV类型的抗体、眉毛毛囊中HPV DNA的存在或正常皮肤样本中HPV DNA的存在具有统计学意义的相关性。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，在该研究中，皮肤HPV血清反应性与HPV DNA阳性的鳞癌显著相关，检测到的抗体与肿瘤组织中存在的HPV类型相同。在同一项研究中，鳞癌还与另一种皮肤病毒--默克尔细胞多瘤病毒(MCV)有关，MCV DNA阳性病例的MCV抗体水平显著高于对照组。尽管病例对照数据具有很强的说服力，但在没有明确证明发病前存在病毒感染的前瞻性数据的情况下，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。我们建议对鳞癌高危个体进行前瞻性队列研究，获取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，以检测发生的鳞癌。这项拟议研究的目的是评估与皮肤HPV和MCV感染相关的鳞状细胞癌的风险，并证明正常组织中的病毒感染与随后的NMSC病变之间的特定类型的一致性。这项拟议的研究将为确定皮肤病毒感染和鳞癌之间的因果关系提供必要的关键证据。

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.