Genome-wide association study of cutaneous squamous cell carincoma

描述(申请人提供)：皮肤鳞状细胞癌(SCC)是美国第二常见的癌症，每年诊断超过70万例，其发病率还在上升。尽管有大量人群受到影响并由此造成疾病负担，但对鳞状细胞癌的遗传决定因素知之甚少。目前尚无已发表的全基因组关联研究(Gwas)检测与鳞癌风险相关的单核苷酸多态(SNP)变异。缺乏发表的研究结果可能部分是由于皮肤鳞状细胞癌不是可报告的恶性肿瘤，因此很难可靠地识别。Kaiser Permanente North California(KNPC)的电子病理数据库克服了这一障碍，并已用于从1997年起在经过验证的SCC注册表中捕获所有经活检证实的皮肤SCC。该项目利用了来自基因、环境和健康研究计划(RPGEH)的一个大型、特征明确的队列的超过675,000个SNP的现有遗传数据。RPGEH还收集了全面的数据，包括关于其队列成员的人口和环境变量的信息。利用RPGEH的独特资源和鳞状细胞癌注册中心，我们的目标是在77,578名非西班牙裔白人RPGEH成员中识别与鳞癌风险相关的SNP序列变异，其中5,953人继续发展为至少一种登记后的鳞状细胞癌。我们还将测试与已确定的鳞状细胞癌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(慢性紫外线暴露的临床标志)。此外，我们将确定在患有多个原发鳞癌的受试者中，我们识别的SNP关联性是否更强。此外，我们将评估SNP效应是否会因肿瘤特征而发生变化。最后，我们将把我们的SNPs与之前发表的GWAs中发现的BCC和黑色素瘤的SNPs进行比较，试图确定与皮肤癌风险相关的基因位点。最终，我们寻求提高我们对皮肤鳞状细胞癌的理解，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.