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，每年确诊病例超过70万例，且发病率呈上升趋势。尽管受影响的人口众多，并由此产生疾病负担，但对SCC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。缺乏发表的结果可能部分是由于皮肤SCC不是可报告的恶性肿瘤，因此难以可靠地识别。Kaiser Permanente北方加州（KNPC）的电子病理学数据库克服了这一障碍，并已用于在经验证的SCC登记中收集1997年以来所有活检证实的皮肤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、特征良好的队列中超过675，000个SNP的现有遗传数据。生殖健康方案还收集了全面的数据，包括关于其群组成员的人口和环境变量的信息。利用RPGEH的独特资源结合SCC登记，我们的目标是进行GWAS，以确定与SCC风险相关的SNP序列变异77，578非西班牙裔白色RPGEH成员，其中5，953人继续发展至少一个登记后SCC。我们还将测试与确定的SCC风险因素的相互作用，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物）。此外，我们将确定我们确定的SNP关联是否在患有多个原发性SCC的受试者中更强。此外，我们将评估SNP效应是否因肿瘤特征而存在任何变化。最后，我们将比较我们的SNPs与先前从发表的GWAS中鉴定的BCC和黑色素瘤的SNPs，以尝试鉴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SCC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.