Nucleotide Excision Repair Gene Variants and Skin Cancer

描述（由申请人提供）： 我们建议评估遗传多态性和单倍型的核苷酸切除修复（NER）基因与黑色素瘤和非黑色素细胞皮肤癌（鳞状细胞癌，SCC;基底细胞癌，BCC）的风险在护士的健康研究中的妇女。由于紫外线（UV）直接诱导的DNA光产物主要由NER清除，因此NER是减轻UV遗传毒性效应的主要DNA修复途径。尽管广泛的证据表明NER在修复紫外线诱导的DNA损伤中的作用，但NER的常见遗传变异及其与阳光照射的相互作用在导致皮肤癌中的重要性相对未知。我们假设NER基因的遗传变异赋予个体对皮肤癌的易感性，这些遗传变异改变了阳光暴露与皮肤癌风险之间的关联。将从NIEHS环境基因组计划的系统重测序数据中鉴定具有潜在功能相关性的SNP和单倍型标记SNP。我们将评估NER基因的这些遗传变异与皮肤癌风险的关系，并评估这些多态性和单倍型之间潜在的基因-环境相互作用，体质易感性和阳光相关的风险因素。本申请是基于先前建立的巢式皮肤癌病例对照研究与护士健康研究，由219例黑素瘤、286例SCC、300例BCC和874例匹配对照组成。我们期望在本申请中识别出约60个以上的偶发性黑色素瘤病例（在2000-2002疾病随访周期中）和约160个以上的偶发性SCC病例（在1998-2002疾病随访周期中）。对于大多数感兴趣的基因型的主效应，我们将有>90%的把握度来检测1.5或更大的相对风险。我们也将有相当大的力量来检测这些基因型和阳光照射之间的相互作用。 这项研究将是候选NER基因多态性与三种主要类型皮肤癌相关性的首批研究之一，还将评估基因型和单倍型与阳光暴露对皮肤癌风险之间的潜在相互作用。

DESCRIPTION (provided by applicant): We propose to evaluate genetic polymorphisms and haplotypes in nucleotide excision repair (NER) genes in relation to the risk for melanoma and non-melanocytic skin cancers (squamous cell carcinoma, SCC; basal cell carcinoma, BCC) among women in the Nurses' Health Study. Because DNA photoproducts directly induced by ultraviolet (UV) are predominantly removed by NER, NER is a major DNA repair pathway mitigating UV genotoxic effects. Despite extensive evidence for the role of NER in the repair of UV-induced DNA damage, the importance of common inherited variations in NER and their interaction with sun exposure in causing skin cancer is relatively unknown. We hypothesize that genetic variations in NER genes confer individual susceptibility to skin cancer, and these genetic variations modify the association between sunlight exposure and the risk of skin cancer. SNPs with potential functional relevance and haplotype-tagging SNPs will be identified from the systematic resequencing data of the NIEHS Environmental Genome Project. We will evaluate these genetic variations in NER genes in relation to skin cancer risk, and assess the potential gene-environment interactions between these polymorphisms and haplotypes, constitutional susceptibility, and sunlight related risk factors. The present application is based on the previously established nested skin cancer case-control study with the Nurses' Health Study, consisting of 219 cases of melanoma, 286 SCC, 300 BCC, and 874 matched controls. We expect to identify about 60 more incident melanoma cases (in the 2000-2002 disease follow-up cycle) and about 160 more incident SCC cases (in the 1998-2002 disease follow-up cycle) in this application. We will have >90% power to detect relative risks of 1.5 or greater for the main effects of most of the genotypes of interest. We will also have substantial power to detect interactions between these genotypes and sunlight exposure. This study will be among the first studies of the association of polymorphisms in candidate NER genes with three major types of skin cancer, and will also assess potential interactions between genotypes and haplotypes and sunlight exposure on skin cancer risk.