Cohort Study of Genetic Susceptibility to Cutaneous Malignant Melanoma

皮肤恶性黑色素瘤遗传易感性队列研究

• 批准号: 7926398
• 负责人: JIALI HAN
• 金额: $ 34.66万
• 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: 2009-09-15 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7926398
• 关键词: Animals; Base Excision Repairs; Bathing; Biological Process; Blood; Candidate Disease Gene; Caucasians; Caucasoid Race; Cells; Characteristics; Cheek structure; Chromatin; Code; Cohort Studies; Cutaneous Melanoma; DNA Damage; DNA photoproducts; Development; Devices; ERCC1 gene; ERCC2 gene; ERCC3 gene; ERCC4 gene; ERCC5 gene; Etiology; Follow-Up Studies; Genes; Genetic; Genetic Polymorphism; Genetic Predisposition to Disease; Genetic Variation; Health Professional; In Vitro; Individual; Inherited; Integration Host Factors; Nucleotide Excision Repair; Nurses' Health Study; OGG1 gene; Pathway interactions; Play; Questionnaires; Recording of previous events; Research; Risk; Risk Management; Role; Sample Size; Sampling; Skin tanning; Specimen; Sun Exposure; Surveys; Testing; UV Radiation Exposure; UV induced; UV induced DNA damage; UVA induced; UVB induced; Variant; Work; XPA gene; XRCC1 gene; base; case control; cohort; design; epidemiologic data; follow-up; gene environment interaction; gene interaction; genetic variant; high risk; innovation; melanoma; oxidative DNA damage; prospective; repaired; response

DESCRIPTION (provided by applicant): Biologic evidence indicates that the repair of ultraviolet-induced DNA damage plays a critical role in protecting against melanoma; however, epidemiologic data are limited due to a limited number of genes and polymorphisms examined in initial studies with small sample sizes. The importance of common inherited variants in the relevant pathways and their interactions with UV exposure history in causing melanoma is largely unknown. We propose to evaluate several new hypotheses and also to extend our previous work to examine in detail the genetic variants in nucleotide excision repair genes, candidate chromatin modifiers involved in nucleotide excision repair, and base excision repair genes in relation to melanoma risk in US Caucasians. Many of them have not been evaluated previously with melanoma risk. No previous studies examined the interactions of these genes with UV exposure history. Using a nested case-control design, we will include 1120 pathologically confirmed melanoma cases and 1120 matched controls who provided blood or cheek cell samples from three large well-characterized cohorts, the Nurses Health Study, Nurses Health Study II, and the Health Professional Follow-up Study. We will systematically survey common genetic variation at each locus using two complementary approaches; 1) evaluating SNPs with potential functional relevance and 2) choosing tag-SNPs to test for associations of unknown common functional variants with melanoma risk. We will also perform exploratory pathway analyses, potentially incorporating information on the biological function of the genes and polymorphisms. In addition, we will assess the interactions between these genetic variants and intermittent UV exposure history, i.e. sun exposure while wearing a bathing suit and indoor tanning device usage, on melanoma risk. This innovative work will move this field forward, by systematically evaluating these common variants using these complementary approaches. This proposal will take advantage of the research opportunities nested within the existing well-characterized cohorts, including cohort characteristics, quality of design, high follow-up rate, large sample size, prospective host factor assessment, and high response rate of retrospective questionnaires. Our proposal will also take advantage of the previously identified and confirmed cases of melanoma as well as stored bio-specimens. This research will contribute to the scientific basis for identifying individuals at high risk for melanoma and providing individualized risk management strategies. Biologic evidence indicates that the repair of ultraviolet-induced DNA damage plays a critical role in protecting against melanoma; however, epidemiologic data are limited due to a limited number of genes and polymorphisms examined in initial studies with small sample sizes. We propose to examine in detail the genetic variants in nucleotide excision repair genes, candidate chromatin modifiers involved in nucleotide excision repair, and base excision repair genes in relation to melanoma risk in 1120 pathologically confirmed melanoma cases and 1120 matched controls who provided blood or cheek cell samples from three large well-characterized cohorts. This research will contribute to the scientific basis for identifying individuals at high risk for melanoma and providing individualized risk management strategies. Biologic evidence indicates that the repair of ultraviolet-induced DNA damage plays a critical role in protecting against melanoma; however, epidemiologic data are limited due to a limited number of genes and polymorphisms examined in initial studies with small sample sizes. The importance of common inherited variants in the relevant pathways and their interactions with UV exposure history in causing melanoma is largely unknown. We propose to evaluate several new hypotheses and also to extend our previous work to examine in detail the genetic variants in nucleotide excision repair genes, candidate chromatin modifiers involved in nucleotide excision repair, and base excision repair genes in relation to melanoma risk in US Caucasians. Many of them have not been evaluated previously with melanoma risk. No previous studies examined the interactions of these genes with UV exposure history. Using a nested case-control design, we will include 1120 pathologically confirmed melanoma cases and 1120 matched controls who provided blood or cheek cell samples from three large well-characterized cohorts, the Nurses Health Study, Nurses Health Study II, and the Health Professional Follow-up Study. We will systematically survey common genetic variation at each locus using two complementary approaches; 1) evaluating SNPs with potential functional relevance and 2) choosing tag-SNPs to test for associations of unknown common functional variants with melanoma risk. We will also perform exploratory pathway analyses, potentially incorporating information on the biological function of the genes and polymorphisms. In addition, we will assess the interactions between these genetic variants and intermittent UV exposure history, i.e. sun exposure while wearing a bathing suit and indoor tanning device usage, on melanoma risk. This innovative work will move this field forward, by systematically evaluating these common variants using these complementary approaches. This proposal will take advantage of the research opportunities nested within the existing well-characterized cohorts, including cohort characteristics, quality of design, high follow-up rate, large sample size, prospective host factor assessment, and high response rate of retrospective questionnaires. Our proposal will also take advantage of the previously identified and confirmed cases of melanoma as well as stored bio-specimens. This research will contribute to the scientific basis for identifying individuals at high risk for melanoma and providing individualized risk management strategies. Project Narrative: Biologic evidence indicates that the repair of ultraviolet-induced DNA damage plays a critical role in protecting against melanoma; however, epidemiologic data are limited due to a limited number of genes and polymorphisms examined in initial studies with small sample sizes. We propose to examine in detail the genetic variants in nucleotide excision repair genes, candidate chromatin modifiers involved in nucleotide excision repair, and base excision repair genes in relation to melanoma risk in 1120 pathologically confirmed melanoma cases and 1120 matched controls who provided blood or cheek cell samples from three large well-characterized cohorts. This research will contribute to the scientific basis for identifying individuals at high risk for melanoma and providing individualized risk management strategies.

描述（由申请人提供）：生物学证据表明，紫外线诱导的DNA损伤的修复在预防黑色素瘤中起着至关重要的作用。然而，由于基因数量有限，并且在样本量较小的初始研究中检查了许多基因和多态性，因此流行病学数据受到限制。相关途径中共同的遗传变体的重要性及其与紫外线暴露历史的相互作用在引起黑色素瘤中的相互作用在很大程度上是未知的。我们建议评估几种新的假设，并扩展我们的先前工作，以详细检查核苷酸切除修复基因的遗传变异，涉及核苷酸切除修复的候选染色质修饰剂以及与美国高原危险中黑色素瘤风险有关的基本切除修复基因。其中许多人以前尚未对黑色素瘤风险进行评估。以前没有研究检查这些基因与紫外线暴露史的相互作用。使用嵌套的病例对照设计，我们将包括1120例病理确认的黑色素瘤病例和1120个匹配的对照，他们提供了来自三个大型特征良好的同类人群的血液或脸颊细胞样品，护士健康研究，护士健康研究II和《卫生专业人员》和《关注》 - up研究。我们将使用两种互补方法系统地在每个基因座进行系统的常见遗传变异。 1）评估具有潜在功能相关性的SNP和2）选择TAG-SNP来测试未知常见功能变异与黑色素瘤风险的关联。我们还将进行探索性途径分析，并有可能结合有关基因和多态性生物学功能的信息。此外，我们将评估这些遗传变异和间歇性紫外线暴露历史之间的相互作用，即穿着泳衣和室内晒黑装置在黑色素瘤风险方面的阳光暴露。这项创新的工作将通过系统地评估这些互补方法来系统地评估这些常见变体，从而推动这一领域的发展。该提案将利用嵌套在现有良好表征的队列中的研究机会，包括队列特征，设计质量，高后续率，样本量较大，预期宿主因素评估以及回顾性问卷的高回应率。我们的建议还将利用先前鉴定的和确认的黑色素瘤病例以及储存的生物特异性病例。这项研究将有助于科学依据，以确定黑色素瘤高风险的人并提供个性化的风险管理策略。生物学证据表明，紫外线诱导的DNA损伤的修复在预防黑色素瘤中起着至关重要的作用。然而，由于基因数量有限，并且在样本量较小的初始研究中检查了许多基因和多态性，因此流行病学数据受到限制。我们建议详细检查核苷酸切除修复基因中的遗传变异，涉及核苷酸切除修复的候选染色质修饰剂以及基础切除修复基因与1120个病理确认的黑色素瘤病例的黑色素瘤风险和1120例相匹配的对照组的黑色素瘤风险有关来自三个大型特征良好的队列的样品。这项研究将有助于科学依据，以确定黑色素瘤高风险的人并提供个性化的风险管理策略。 生物学证据表明，紫外线诱导的DNA损伤的修复在预防黑色素瘤中起着至关重要的作用。然而，由于基因数量有限，并且在样本量较小的初始研究中检查了许多基因和多态性，因此流行病学数据受到限制。相关途径中共同的遗传变体的重要性及其与紫外线暴露历史的相互作用在引起黑色素瘤中的相互作用在很大程度上是未知的。我们建议评估几种新的假设，并扩展我们的先前工作，以详细检查核苷酸切除修复基因的遗传变异，涉及核苷酸切除修复的候选染色质修饰剂以及与美国高原危险中黑色素瘤风险有关的基本切除修复基因。其中许多人以前尚未对黑色素瘤风险进行评估。以前没有研究检查这些基因与紫外线暴露史的相互作用。使用嵌套的病例对照设计，我们将包括1120例病理确认的黑色素瘤病例和1120个匹配的对照，他们提供了来自三个大型特征良好的大型群体的血液或脸颊细胞样品，护士健康研究，护士健康研究II和《健康专业人员》和《关注》 - up研究。我们将使用两种互补方法系统地在每个基因座进行系统的常见遗传变异。 1）评估具有潜在功能相关性的SNP和2）选择TAG-SNP来测试未知常见功能变异与黑色素瘤风险的关联。我们还将进行探索性途径分析，并有可能结合有关基因和多态性生物学功能的信息。此外，我们将评估这些遗传变异和间歇性紫外线暴露历史之间的相互作用，即穿着泳衣和室内晒黑装置在黑色素瘤风险方面的阳光暴露。这项创新的工作将通过系统地评估这些互补方法来系统地评估这些常见变体，从而推动这一领域的发展。该提案将利用嵌套在现有良好表征的队列中的研究机会，包括队列特征，设计质量，高后续率，样本量较大，预期宿主因素评估以及回顾性问卷的高回应率。我们的建议还将利用先前鉴定的和确认的黑色素瘤病例以及储存的生物特异性病例。这项研究将有助于科学依据，以确定黑色素瘤高风险的人并提供个性化的风险管理策略。项目叙述： 生物学证据表明，紫外线诱导的DNA损伤的修复在预防黑色素瘤中起着至关重要的作用。然而，由于基因数量有限，并且在样本量较小的初始研究中检查了许多基因和多态性，因此流行病学数据受到限制。我们建议详细检查核苷酸切除修复基因中的遗传变异，涉及核苷酸切除修复的候选染色质修饰剂以及基础切除修复基因与1120个病理确认的黑色素瘤病例的黑色素瘤风险和1120例相匹配的对照组的黑色素瘤风险有关来自三个大型特征良好的队列的样品。这项研究将有助于科学依据，以确定黑色素瘤高风险的人并提供个性化的风险管理策略。