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: 7371846
• 负责人: JIALI HAN
• 金额: $ 36.07万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7371846
• 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; Data; 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; Invasive; Nucleotide Excision Repair; Numbers; Nurses' Health Study; OGG1 gene; Pathway interactions; Play; Questionnaires; Rate; Recording of previous events; Research; Risk; Risk Management; Role; Sample Size; Sampling; Skin tanning; Specimen; Sun Exposure; Surveys; Testing; UV Radiation Exposure; UV induced DNA damage; UVA induced; UVB induced; Variant; Work; XPA gene; XRCC1 gene; base; case control; cohort; design; follow-up; gene environment interaction; gene interaction; gene repair; genetic variant; innovation; melanoma; oxidative DNA damage; prospective; repaired; response; ultraviolet

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方面发挥着关键作用；然而，由于样本量较小的初步研究中检测的基因和多态性数量有限，流行病学数据有限。相关途径中常见遗传变异的重要性以及它们与紫外线暴露史的相互作用在导致黑色素瘤中的重要性尚不清楚。我们建议评估几个新的假设，并扩展我们之前的工作，以详细检查核苷酸切除修复基因、参与核苷酸切除修复的候选染色质修饰剂以及与美国白种人黑色素瘤风险相关的碱基切除修复基因的遗传变异。其中许多人之前没有接受过黑色素瘤风险评估。之前没有研究检查这些基因与紫外线暴露史的相互作用。使用嵌套病例对照设计，我们将纳入 1120 例经病理证实的黑色素瘤病例和 1120 例匹配的对照，这些对照提供了来自三个特征明确的大型队列（护士健康研究、护士健康研究 II 和健康专业跟踪）的血液或颊细胞样本向上研究。我们将使用两种互补的方法系统地调查每个基因座的常见遗传变异； 1) 评估具有潜在功能相关性的 SNP，2) 选择标签 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，可能会纳入有关基因生物学功能和多态性的信息。此外，我们将评估这些遗传变异与间歇性紫外线暴露史（即穿着泳衣时暴露在阳光下和使用室内晒黑设备）之间的相互作用对黑色素瘤风险的影响。这项创新工作将通过使用这些补充方法系统地评估这些常见变体，从而推动该领域向前发展。该提案将利用现有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、大样本量、前瞻性宿主因素评估和回顾性问卷的高回复率。我们的提案还将利用之前发现和确认的黑色素瘤病例以及存储的生物样本。这项研究将为识别黑色素瘤高风险个体并提供个性化风险管理策略奠定科学基础。生物学证据表明，修复紫外线引起的 DNA 损伤在预防黑色素瘤方面发挥着关键作用；然而，由于样本量较小的初步研究中检测的基因和多态性数量有限，流行病学数据有限。我们建议在 1120 例经病理证实的黑色素瘤病例和 1120 名提供血液或颊细胞的匹配对照中详细检查核苷酸切除修复基因、参与核苷酸切除修复的候选染色质修饰剂以及与黑色素瘤风险相关的碱基切除修复基因的遗传变异。来自三个特征明确的大型群体的样本。这项研究将为识别黑色素瘤高风险个体并提供个性化风险管理策略奠定科学基础。 生物学证据表明，修复紫外线引起的 DNA 损伤在预防黑色素瘤方面发挥着关键作用；然而，由于样本量较小的初步研究中检测的基因和多态性数量有限，流行病学数据有限。相关途径中常见遗传变异的重要性以及它们与紫外线暴露史的相互作用在导致黑色素瘤中的重要性尚不清楚。我们建议评估几个新的假设，并扩展我们之前的工作，以详细检查核苷酸切除修复基因、参与核苷酸切除修复的候选染色质修饰剂以及与美国白种人黑色素瘤风险相关的碱基切除修复基因的遗传变异。其中许多人之前没有接受过黑色素瘤风险评估。之前没有研究检查这些基因与紫外线暴露史的相互作用。使用嵌套病例对照设计，我们将纳入 1120 例经病理证实的黑色素瘤病例和 1120 例匹配的对照，这些对照提供了来自三个特征明确的大型队列（护士健康研究、护士健康研究 II 和健康专业跟踪）的血液或颊细胞样本向上研究。我们将使用两种互补的方法系统地调查每个基因座的常见遗传变异； 1) 评估具有潜在功能相关性的 SNP，2) 选择标签 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，可能会纳入有关基因生物学功能和多态性的信息。此外，我们将评估这些遗传变异与间歇性紫外线暴露史（即穿着泳衣时暴露在阳光下和使用室内晒黑设备）之间的相互作用对黑色素瘤风险的影响。这项创新工作将通过使用这些补充方法系统地评估这些常见变体，从而推动该领域向前发展。该提案将利用现有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、大样本量、前瞻性宿主因素评估和回顾性问卷的高回复率。我们的提案还将利用之前发现和确认的黑色素瘤病例以及存储的生物样本。这项研究将为识别黑色素瘤高风险个体并提供个性化风险管理策略奠定科学基础。项目叙述： 生物学证据表明，修复紫外线引起的 DNA 损伤在预防黑色素瘤方面发挥着关键作用；然而，由于样本量较小的初步研究中检测的基因和多态性数量有限，流行病学数据有限。我们建议在 1120 例经病理证实的黑色素瘤病例和 1120 名提供血液或颊细胞的匹配对照中详细检查核苷酸切除修复基因、参与核苷酸切除修复的候选染色质修饰剂以及与黑色素瘤风险相关的碱基切除修复基因的遗传变异。来自三个特征明确的大型群体的样本。这项研究将为识别黑色素瘤高风险个体并提供个性化风险管理策略奠定科学基础。