MOLECULAR EPIDEMIOLOGY OF NON-MELANOMA SKIN CANCER

非黑色素瘤皮肤癌是美国最常见的恶性肿瘤，发病率高，医疗费用高。流行病学调查已确定紫外线辐射暴露是该病的主要危险因素；其他导致风险的环境暴露包括电离辐射、砷、多环芳烃和慢性免疫抑制。与非黑色素瘤皮肤癌风险增加相关的宿主因素包括年龄增加、男性性别和对阳光敏感的皮肤类型。基底细胞癌和鳞状细胞癌已被证明含有p53基因的改变，最近的工作发现了位于染色体9q22上的一个基因ptch，该基因被认为在基底细胞癌的发生发展中起着关键作用。这些发现虽然提供了信息，但来自相对较小的精选患者群体，反映了这种疾病基于人群的分子流行病学的匮乏。我们建议在新罕布夏州扩大一项大型、成熟的非黑色素瘤皮肤癌病例对照研究，以包括遗传易感性的研究。该项目将专注于可能改变紫外线辐射暴露的基因，包括谷胱甘肽S转移酶(GSTM1、GSTT1和GSTP1)的多态以及新发现的DNA切除修复基因的变种(ERCC2/XPD和XPf)。此外，我们将从病例中收集肿瘤标本，以确定p53和9q22/ptch突变的特征。我们将确定突变谱，检查突变与致癌暴露和患者特征的关联，并完善皮肤肿瘤发生的新模型。这些研究将增加我们对宿主对非黑色素瘤皮肤癌易感性的理解，并通过鉴定基因失活模式来推进皮肤癌发生的现有模型。

Non-melanoma skin cancer is the most prevalent malignancy in the US, resulting in significant morbidity and health-care expense. Epidemiologic investigations have identified exposure to ultraviolet radiation as the primary risk factor for this disease; other environmental exposures that contribute to risk include ionizing radiation, arsenic, polycyclic aromatic hydrocarbons, and chronic immunosuppression. Host factors associated with increased risk for non-melanoma skin cancer include increasing age, male gender, and sun sensitive skin type. Basal cell and squamous cell carcinomas have been shown to contain alterations in the p53 gene, and recent work has identified a gene on chromosome 9q22, ptch, that is hypothesized to be critical in basal cell carcinoma tumorigenesis. These findings, while informative, are derived from relatively small, selected groups of patients and reflects the paucity of population-based molecular epidemiology for this disease. We propose to expand a large, well-established case-control study of non-melanoma skin cancer in New Hampshire to include investigation of genetic susceptibility. The project will focus on genes that potentially modify ultraviolet radiation exposure, including polymorphisms in the glutathione S-transferases (GSTM1, GSTT1, and GSTP1) and the newly identified variants in DNA excision repair genes (ERCC2/XPD, and XPF). In addition, we will collect tumor specimens from cases for characterization of mutations at p53 and 9q22/ptch. We will determine mutation spectra examine associations of mutation with carcinogenic exposures and patient traits, and refine a novel model of skin tumorigenesis. These studies will increase our understanding of host susceptibility to non-melanoma skin cancer and advance current models of skin carcinogenesis through identification of patterns of gene inactivation.