Genetic epidemiology of early-onset basal cell carcinoma

描述（由申请人提供）：大多数人类疾病是遗传和环境因素相互作用的结果。常见疾病中遗传成分的性质是一个有争议的话题。有人支持一种模型，其中一些常见的遗传变异具有微弱的影响，这些影响加起来就构成了一个重大的可归因遗传风险。另一方面，可能是许多不同的罕见基因突变，每一种都有很强的影响，总的来说，在很大一部分人中造成了疾病。由耶鲁皮肤癌孢子补助金支持的一个正在进行的项目涉及遗传和环境因素的作用以及这些因素在皮肤早发性基底细胞癌（40岁以下）风险中的相互作用的分析。SPORE支持收集广泛的人口统计学，种族和环境风险因素数据以及来自500例病例和500例对照的DNA样本。还支持所有受试者中的小（单外显子）皮肤色素基因MC1R的测序。在这项研究构思的时候，分析额外基因的成本高得令人望而却步。最近引入的用于DNA测序的高通量平台将允许查询许多基因中可能与皮肤癌风险相关的突变。本申请的目的是使用高通量平台对来自100例病例和100例对照的宪法DNA进行测序。该项目将广泛撒网，检查所有已知的主要皮肤色素基因，所有与修复紫外线诱导的DNA损伤密切相关的基因，以及可能与癌症风险相关的昼夜节律基因。我们的目的是从这个研究对象的子集中生成初步数据，以支持未来的大型赠款申请，这将使我们能够测试我们所有的受试者，以寻找有希望的候选基因，并与其他小组合作，在其他皮肤癌病例中检查这些基因。发现潜在的遗传易感性可能有助于制定预防措施和“个性化”医疗。紫外线暴露作为皮肤癌的环境风险因素的既定作用提供了一条途径，将我们的分析转化为公共卫生方法，以更好地预防皮肤癌。从理论上讲，具有这种癌症遗传倾向的个体可以成为行为矫正的目标。 公共卫生相关性：发现皮肤癌的潜在遗传易感性可能有助于制定预防措施和“个性化”医疗。紫外线暴露作为皮肤癌的环境风险因素的既定作用提供了一条途径，将我们的分析转化为公共卫生方法，以更好地预防皮肤癌。从理论上讲，具有这种癌症遗传倾向的个体可以成为行为矫正的目标。

DESCRIPTION (provided by applicant): Most human diseases result from the interplay of hereditary and environmental factors. The nature of the genetic component in common disorders is a subject of some debate. There are proponents for a model in which a few common genetic variants have weak effects, which add up to a significant attributable genetic risk. On the other hand it is possible that many different rare genetic mutations, each with a strong effect, in aggregate account for disease in a high proportion of people. An ongoing project supported by the Yale Skin Cancer SPORE Grant involves analysis of the roles of hereditary and environmental factors and the interaction between these factors in the risk for early-onset basal cell carcinoma of the skin (below age 40). The SPORE supports collection of broad demographic, ethnic, and environmental risk factor data as well as DNA samples from 500 cases and 500 controls. Sequencing of MC1R, a small (one-exon) skin pigment gene in all subjects is also supported. At the time the study was conceived, the cost of analysis of additional genes was prohibitively expensive. More recent introduction of high- throughput platforms for DNA sequencing will allow for querying many genes for mutations that may be associated with skin cancer risk. The aim of this application is use high-throughput platforms for sequencing constitutional DNA from 100 cases and 100 controls. This project will cast a wide net, examining all known major skin pigment genes, all genes closely associated with repair of UV-induced DNA damage, and circadian rhythm genes that may be associated with cancer risk. The intention is to generate preliminary data from this subset of study subjects to support applications for future large grants that would allow us to test all of our subjects for promising candidate genes and, in collaboration with other groups, examine these genes in additional skin cancer cases. Discovering an underlying genetic predisposition may help tailor preventive measures and "personalize" medical treatment. The well established role of UV exposure as an environmental risk factor for skin cancer provides a route to translate our analyses into public health approaches to better prevent skin cancer. In theory, individuals with a genetic predisposition to this cancer type could be targeted for behavior modification. PUBLIC HEALTH RELEVANCE: Discovering an underlying genetic predisposition to skin cancer may help tailor preventive measures and "personalize" medical treatment. The well established role of UV exposure as an environmental risk factor for skin cancer provides a route to translate our analyses into public health approaches to better prevent skin cancer. In theory, individuals with a genetic predisposition to this cancer type could be targeted for behavior modification.