Genome-wide association study of cutaneous squamous cell carincoma

描述（由申请人提供）：皮肤鳞状细胞癌（SCC）是美国第二大常见癌症，每年诊断超过70万例，其发病率呈上升趋势。尽管受影响的人群众多，并由此带来疾病负担，但对SCCs的遗传决定因素知之甚少。目前还没有发表的全基因组关联研究（GWAS）检查与SCC风险相关的单核苷酸多态性（SNP）变异。缺乏发表的研究结果可能部分是由于皮肤SCCs不是可报告的恶性肿瘤，因此难以可靠地识别。Kaiser Permanente北加州（KNPC）的电子病理数据库克服了这一障碍，并已用于捕获自1997年以来所有经活检证实的皮肤SCC。该项目利用来自基因、环境和健康研究计划（RPGEH）的一个大型、特征良好的队列的超过675,000个snp的现有遗传数据。人口与环境研究所还收集了全面的数据，包括关于其同组成员的人口和环境变量的资料。利用RPGEH与SCC登记处的独特资源，我们的目标是对77,578名非西班牙裔白人RPGEH成员进行GWAS，以确定与SCC风险相关的SNP序列变异，其中5,953人在入组后继续发展至少一种SCC。我们还将测试与现有SCC危险因素的相互作用，包括色素沉着、性别、吸烟和光化性角化病（慢性紫外线照射的临床标志）。此外，我们将确定我们发现的SNP关联是否在多发原发性SCCs患者中更强。此外，我们将根据肿瘤特征评估SNP效应是否存在变化。最后，我们将把我们的snp与先前从已发表的GWAS中发现的bcc和黑素瘤的snp进行比较，试图确定与皮肤癌风险相关的遗传位点。最终，我们寻求提高我们对皮肤SCCs的理解，并确定遗传易感性增加的机制。

DESCRIPTION (provided by applicant): Cutaneous squamous cell carcinoma (SCC) is the second most common cancer in America, with over 700,000 cases diagnosed annually, and its incidence is on the rise. Despite the large population affected and resultant burden of disease, little is known about genetic determinants of SCCs. There are no published genome-wide association studies (GWAS) examining single nucleotide polymorphism (SNP) variants associated with SCC risk. The lack of published findings may be due, in part, to the fact that cutaneous SCCs are not reportable malignancies, and are therefore difficult to reliably identify. The electronic pathology databases at Kaiser Permanente Northern California (KNPC) overcome that barrier, and have been used to capture all biopsy-proven cutaneous SCCs from 1997 onward in a validated SCC registry. This project utilizes existing genetic data on over 675,000 SNPs from a large, well-characterized cohort of the Research Program on Genes, Environment and Health (RPGEH). The RPGEH has also collected comprehensive data including information on demographic and environmental variables on its cohort members. Using the unique resources of the RPGEH combined with the SCC Registry, we aim to perform a GWAS to identify SNP sequence variants associated with SCC risk on 77,578 non-Hispanic white RPGEH members, 5,953 of whom go on to develop at least one post-enrollment SCC. We will also test for interactions with established SCC risk factors, including pigmentation, gender, smoking, and actinic keratosis (a clinical marker for chronic ultraviolet light exposure). Furthermore, we will determine whether our identified SNP associations are stronger in subjects with multiple primary SCCs. In addition, we will evaluate whether there is any variation in SNP effects by tumor characteristics. Finally, we will compare our SNPs with those previously identified for BCCs and melanomas from published GWAS to attempt to identify genetic loci associated with skin cancer risk. Ultimately, we seek to improve our understanding of cutaneous SCCs and to identify mechanisms accounting for increased inherited susceptibility.