Genetic Variants in Immunological Mediator Genes and Skin Cancer Risk

描述（由申请人提供）：免疫中介基因的遗传变异与皮肤癌风险大量生物学证据表明，免疫监测在预防皮肤癌中起着关键作用。然而，免疫监视基因中的常见遗传变异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中的重要性在很大程度上是未知的；存在稀疏数据。我们建议在护士健康研究（219例黑色素瘤，286例鳞状细胞癌，300例BCC和874例匹配对照）的巢式病例对照研究中，同时详细检查与黑色素瘤，鳞状细胞癌（SCC）和基底细胞癌（BCC）风险相关的9种免疫中介基因的遗传变异。这项创新工作将通过使用互补方法评估常见变异，即评估假定的功能snp，选择标签snp来测试未知常见功能变异与皮肤癌风险的关联，以及探索性途径分析，推动这一领域向前发展。此外，我们还将评估这些基因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。本研究将充分利用现有特征良好的队列研究机会，包括队列特征、设计质量、随访率高、样本量大、前瞻性宿主风险因素评估严谨、回顾性问卷回复率高。我们的研究还将利用先前确诊的三种皮肤癌病例，储存的血液和DNA样本，以及先前收集的宿主危险因素和紫外线暴露史的信息。本研究将为确定皮肤癌高危人群和提供个体化风险管理策略提供科学依据。我们建议对与黑色素瘤、鳞状细胞癌和基底细胞癌同时发生的风险相关的免疫中介基因的遗传变异进行详细评估。通过使用互补方法系统地评估常见变体，这项创新工作将推动这一领域向前发展。本研究将为识别皮肤癌高危人群和提供个体化风险管理策略提供科学依据。

DESCRIPTION (provided by applicant): Genetic variants in immunological mediator genes and skin cancer risk Substantial biologic evidence indicates that the immune surveillance plays a critical role in protecting against skin cancer. However, the importance of common inherited variants in the immune surveillance genes and their interactions with constitutional host factors and UV exposure history in causing skin cancer is largely unknown; sparse data exist. We propose to examine in detail the genetic variants in 9 immunological mediator genes with the risk 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 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. We propose a detailed evaluation of genetic variation in immunological mediator genes in relation to the risks of melanoma, squamous cell carcinoma, and basal cell carcinoma simultaneously. This innovative work will move this field forward, by systematically evaluating common variants using complementary approaches. This research will contribute to the scientific basis for identifying individuals at high-risk for skin cancer and providing individualized risk management strategies.