Cohort Study of Genetic Susceptibility to Cutaneous Malignant Melanoma

描述（由申请人提供）：生物学证据表明，修复紫外线诱导的DNA损伤在预防黑色素瘤中起着关键作用；然而，流行病学数据是有限的，因为在小样本量的初步研究中检测的基因和多态性数量有限。常见遗传变异在相关途径中的重要性及其与紫外线暴露史在引起黑色素瘤中的相互作用在很大程度上是未知的。我们建议评估几个新的假设，并扩展我们之前的工作，以详细检查与美国高加索人黑色素瘤风险相关的核苷酸切除修复基因的遗传变异、核苷酸切除修复中涉及的候选染色质修饰因子和碱基切除修复基因。他们中的许多人之前没有被评估过患黑色素瘤的风险。以前没有研究检查这些基因与紫外线照射史的相互作用。采用嵌套病例-对照设计，我们将纳入1120例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护士健康研究、护士健康研究II和卫生专业人员随访研究三个特征明确的大型队列的血液或脸颊细胞样本。我们将使用两种互补的方法系统地调查每个位点的常见遗传变异；1)评估具有潜在功能相关性的snp； 2)选择标签snp来检测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，潜在地结合基因和多态性的生物学功能信息。此外，我们将评估这些基因变异与间歇性紫外线照射史之间的相互作用，即穿泳衣时的阳光照射和室内晒黑设备的使用，对黑色素瘤风险的影响。通过使用这些互补方法系统地评估这些常见变体，这项创新工作将推动这一领域向前发展。本研究将利用现有特征良好的队列的研究机会，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。我们的建议还将利用先前确定和确认的黑色素瘤病例以及储存的生物标本。本研究将为识别黑色素瘤高危人群和提供个体化风险管理策略提供科学依据。生物学证据表明，修复紫外线诱导的DNA损伤在预防黑色素瘤中起着关键作用；然而，流行病学数据是有限的，因为在小样本量的初步研究中检测的基因和多态性数量有限。我们建议详细检查与黑色素瘤风险相关的核苷酸切除修复基因的遗传变异、参与核苷酸切除修复的候选染色质修饰因子和碱基切除修复基因，这些基因来自于1120例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大的特征明确的队列的血液或脸颊细胞样本。本研究将为识别黑色素瘤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): 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.