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。有一些人支持这样一种模型，即一些常见的遗传变异的影响很弱，这些变异加起来就构成了一个显著的可归因遗传风险。另一方面，有可能是许多不同的罕见基因突变，每一种都有很强的影响，总的来说是很大一部分人患病的原因。一项由耶鲁皮肤癌孢子基金支持的正在进行的项目涉及遗传和环境因素的作用分析以及这些因素在早发性皮肤基底细胞癌（40岁以下）风险中的相互作用。SPORE支持收集广泛的人口统计、种族和环境风险因素数据，以及来自500个病例和500个对照的DNA样本。MC1R，一个小的（单外显子）皮肤色素基因的测序也在所有受试者中得到支持。在构思这项研究的时候，分析额外基因的成本高得令人望而却步。最近引入的高通量DNA测序平台将允许查询许多可能与皮肤癌风险相关的基因突变。本应用程序的目的是使用高通量平台对100例病例和100例对照的体质DNA进行测序。该项目将广泛研究所有已知的主要皮肤色素基因，所有与紫外线诱导的DNA损伤修复密切相关的基因，以及可能与癌症风险相关的昼夜节律基因。我们的目的是从这部分研究对象中获得初步数据，以支持未来大笔拨款的申请，这将使我们能够对所有研究对象进行有希望的候选基因测试，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作用已得到证实，这为将我们的分析转化为更好地预防皮肤癌的公共卫生方法提供了一条途径。理论上，具有这种癌症遗传易感性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.