Genetic Variants in Mitochondrial Genome and Skin Cancer Risk

线粒体基因组的遗传变异与皮肤癌风险

• 批准号: 7886812
• 负责人: Hongmei Nan
• 金额: $ 8.9万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-06 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7886812
• 关键词: Apoptosis; Basal cell carcinoma; Base Pairing; Biological Markers; Blood; Caucasians; Caucasoid Race; Cells; Characteristics; Code; Collection; Constitutional; DNA; DNA Damage; Defect; Development; Diagnosis; Etiology; Eukaryotic Cell; European; Evaluation; Exhibits; Generations; Genes; Genetic Polymorphism; Genetic Variation; Haplogroup; Haploidy; Human; Individual; Inheritance Patterns; Integration Host Factors; Lead; Malignant Neoplasms; Melanins; Mitochondria; Mitochondrial DNA; Nested Case-Control Study; Nurses' Health Study; Organelles; Oxidative Phosphorylation; Play; Predisposition; Process; Production; Questionnaires; Reactive Oxygen Species; Recording of previous events; Regulation; Research; Resources; Ribosomal RNA; Risk; Risk Factors; Risk Management; Role; Sampling; Single Nucleotide Polymorphism; Skin; Skin Cancer; Skin Carcinoma; Squamous cell carcinoma; Sun Exposure; System; Testing; Transfer RNA; Variant; Work; abstracting; base; cancer risk; cohort; design; follow-up; genetic variant; high risk; human disease; innovation; melanoma; mitochondrial DNA mutation; mitochondrial dysfunction; mitochondrial genome; prospective; public health relevance; response; trait; tumorigenesis; ultraviolet

DESCRIPTION (provided by applicant): Project Abstract: Substantial biologic evidence indicates that mitochondria may play crucial role in development of skin cancer by their multiple functions in cellular progression. However, the importance of common variants and haplogroups in the mitochondrial genome in causing skin cancer is largely unknown. We propose to examine in detail the associations of genetic variants and haplogroups in the mitochondrial genome 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 (400 melanoma cases, 600 SCC cases, 600 BCC cases, and 1,670 matched controls). This innovative work will move this field forward by evaluating common variants using complementary approaches, i.e. to evaluate putative functional tag-SNPs that predict all coding-region variants in European mitochondrial genome to test for associations of common functional variants with skin cancer risk. We will also evaluate the associations between common haplogroups in European mitochondrial genome and skin cancer risk. Furthermore, we will assess the interactions between the common genetic variants and haplogroups in the mitochondrial genome and risk factors of skin cancer, such as constitutional host factors and UV exposure history, on skin cancer risk. This application will take advantage of the research opportunities nested within the existing well- characterized cohort, including cohort characteristics, quality of design, high follow-up rate, 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, and previously collected information on host risk factors and UV exposure history. This research will contribute to our understanding of the role of mitochondria in the etiology of skin cancer and provide the scientific basis to identify individuals at high-risk for skin cancer and to create individualized risk-management strategies. PUBLIC HEALTH RELEVANCE: Project Narrative: We propose a detailed evaluation of genetic variation in the mitochondrial genome 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 our understanding of the role of mitochondria in the etiology of skin cancer and provide the scientific basis to identify individuals at high-risk for skin cancer and to create individualized risk-management strategies.

描述（由申请人提供）： 项目摘要：大量生物学证据表明，线粒体通过其在细胞进展中的多种功能，可能在皮肤癌的发生过程中发挥着至关重要的作用。然而，线粒体基因组中常见变异和单倍群在引起皮肤癌中的重要性尚不清楚。我们建议在护士健康研究的嵌套病例对照研究中同时详细检查线粒体基因组中的遗传变异和单倍群与黑色素瘤、鳞状细胞癌（SCC）和基底细胞癌（BCC）风险的关联（400 例黑色素瘤病例、600 例鳞状细胞癌病例、600 例基底细胞癌病例和 1,670 例匹配对照）。这项创新工作将通过使用补充方法评估常见变异来推动这一领域向前发展，即评估预测欧洲线粒体基因组中所有编码区变异的推定功能标签 SNP，以测试常见功能变异与皮肤癌风险的关联。我们还将评估欧洲线粒体基因组中常见单倍群与皮肤癌风险之间的关联。此外，我们将评估线粒体基因组中常见遗传变异和单倍群与皮肤癌风险因素（例如体质宿主因素和紫外线暴露史）之间的相互作用对皮肤癌风险的影响。该应用程序将利用现有的特征明确的队列中的研究机会，包括队列特征、设计质量、高随访率、严格的前瞻性宿主危险因素评估以及回顾性问卷的高回复率。我们的研究还将利用之前确诊的三种皮肤癌病例、储存的血液和DNA样本，以及之前收集的宿主危险因素和紫外线暴露史的信息。这项研究将有助于我们了解线粒体在皮肤癌病因学中的作用，并为识别皮肤癌高危人群和制定个体化风险管理策略提供科学依据。 公共卫生相关性： 项目叙述：我们建议对线粒体基因组中的遗传变异与黑色素瘤、鳞状细胞癌和基底细胞癌风险的同时进行详细评估。这项创新工作将通过使用补充方法系统地评估常见变体，推动该领域向前发展。这项研究将有助于我们了解线粒体在皮肤癌病因学中的作用，并为识别皮肤癌高危人群和制定个体化风险管理策略提供科学依据。