MOLECULAR EPIDEMIOLOGY OF NON-MELANOMA SKIN CANCER

非黑色素瘤皮肤癌的分子流行病学

• 批准号: 2884583
• 负责人: HEATHER Hammond NELSON
• 金额: $ 32.82万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-30 至 2003-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2884583
• 关键词: basal cell carcinoma; cancer risk; carcinogenesis; clinical research; gene environment interaction; gene mutation; genetic markers; genetic polymorphism; genetic susceptibility; genotype; glutathione transferase; human genetic material tag; human subject; keratinocyte; neoplasm /cancer genetics; nucleic acid sequence; p53 gene /protein; phosphoester ligase; single strand conformation polymorphism; skin neoplasms; squamous cell carcinoma; ultraviolet radiation

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.

非黑色素瘤皮肤癌是美国最常见的恶性肿瘤，导致高发病率和医疗费用。流行病学调查已确定暴露于紫外线辐射是这种疾病的主要危险因素；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长、男性和阳光敏感的皮肤类型。基底细胞癌和鳞状细胞癌已被证明包含 p53 基因的改变，最近的工作已经确定了染色体 9q22 上的一个基因 ptch，该基因被认为在基底细胞癌的肿瘤发生中至关重要。 这些发现虽然信息丰富，但来自相对较小的选定患者群体，反映了针对这种疾病的基于人群的分子流行病学的缺乏。 我们建议在新罕布什尔州扩大一项大型、完善的非黑色素瘤皮肤癌病例对照研究，包括遗传易感性调查。 该项目将重点关注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）的多态性以及新发现的 DNA 切除修复基因（ERCC2/XPD 和 XPF）的变体。 此外，我们将从病例中收集肿瘤样本，以表征 p53 和 9q22/ptch 的突变。 我们将确定突变谱，检查突变与致癌物质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了解，并通过识别基因失活模式推进当前的皮肤癌发生模型。