Genetic Variants in Pigmentation Genes and Skin Cancer Risk

描述（由申请人提供）： 大量的生物学证据表明，色素沉着途径在预防皮肤癌方面起着关键作用。然而，色素沉着途径中常见遗传变异的重要性及其与体质宿主因子和紫外线暴露史的相互作用在导致皮肤癌方面的重要性在很大程度上是未知的。除了黑皮质素1受体（MC 1 R）遗传变异外，存在稀疏的数据。我们建议在护士健康研究（219例黑色素瘤病例，286例鳞状细胞癌病例，300例基底细胞癌病例和874例匹配对照）的巢式病例对照研究中同时详细检查色素沉着途径中的遗传变异与黑色素瘤，鳞状细胞癌（SCC）和基底细胞癌（BCC）的风险。这项创新性工作将通过使用互补方法评估色素沉着途径中的常见变异来推动这一领域的发展，即评估推定的功能性SNP并选择标签-SNP来测试未知的常见功能性变异与皮肤癌风险的关联，沿着探索性途径分析。此外，我们还将评估这些基因中的遗传变异与体质宿主因素和紫外线暴露史对皮肤癌风险的相互作用。该提案将利用现有特征良好的队列中嵌套的研究机会，包括队列特征、设计质量、高随访率、大样本量、前瞻性宿主风险因素评估的严格性以及回顾性问卷的高应答率。我们的研究还将利用先前确认的三种皮肤癌病例、储存的血液和DNA样本，以及先前收集的关于宿主风险因素和紫外线暴露史的信息。这项研究将有助于确定皮肤癌高危人群的科学依据，并提供个性化的风险管理策略。

DESCRIPTION (provided by applicant): Substantial biologic evidence indicates that the pigmentation pathway plays a critical role in protecting against skin cancer. However, the importance of common inherited variants in the pigmentation pathway and their interactions with constitutional host factors and UV exposure history in causing skin cancer is largely unknown. Sparse data exist except for the melanocortin 1 receptor (MC1R) genetic variants. We propose to examine in detail the genetic variants in the pigmentation pathway with the risks of melanoma, squamous cell carcinoma (SCC), and basal cell carcinoma (BCC) simultaneously in a nested case- control study within the Nurses Health Study (219 melanoma cases, 286 SCC cases, 300 BCC cases, and 874 matched controls). This innovative work will move this field forward, by evaluating common variants in the pigmentation pathway using complementary approaches, i.e. to evaluate putative functional SNPs and to choose tag- SNPs to test for associations of unknown common functional variants with skin cancer risk, along with exploratory pathway analyses. In addition, we will also assess the interactions between genetic variants in these genes and constitutional host factors and UV exposure history on skin cancer risk. This proposal will take advantage of the research opportunities nested within the existing well-characterized cohort, including cohort characteristics, quality of design, high follow-up rate, large sample size, rigor in prospective host risk factor assessment, and high response rate of retrospective questionnaires. Our study will also take advantage of the previously confirmed cases of the three types of skin cancers, stored blood and DNA samples, as well as previously collected information on host risk factors and UV exposure history. This research will contribute to the scientific basis for identifying high-risk individuals for skin cancer and providing individualized risk management strategies.