Melanoma genes in high-risk twins

大而多的痣(葡萄胎)是黑色素瘤发生的最重要的预测因子。虽然雀斑的频率随着年龄的增长而增加，这意味着他们在发育过程中暴露在阳光下，但加性遗传因素似乎解释了雀斑大小和数量的大部分个体间差异。英国和澳大利亚青春期双胞胎研究的数据显示，60%到70%的雀斑数量变异是由遗传因素解释的，尽管导致这种变异的基因尚不清楚。我们以前的工作已经证明，在没有遗传变异的情况下，与大或许多痣相关的黑色素瘤风险似乎不会增加，这意味着在有大痣的个体中，只有遗传易感者才会患上黑色素瘤。关于家族性黑色素瘤中候选基因的发生已经做了很多工作，但还没有一个突出的具有足够渗透性和普遍性的候选基因可能导致大多数黑色素瘤。有充分的证据表明，由于阳光暴晒，环境因素导致了黑色素瘤。为了进一步了解基因在黑色素瘤病因学中的作用，我们在加利福尼亚州开展了一项关于基因-环境相互作用的研究，该队列由52,000对双胞胎组成，加州是世界上黑色素瘤发病率最高的州之一。在接下来的几年里，这个队列中将有超过1000例黑色素瘤被诊断出来，使其成为黑色素瘤病因学中识别基因-环境相互作用的关键资源，通过使用传统的双胞胎方法来区分加性遗传效应和共享环境所产生的影响。在这项申请中，我们的目标是进行一项可行性研究，这将极大地提高加州双胞胎计划(CTP)未来黑色素瘤病因研究的成功。我们的具体目标是：1.确定对黑色素瘤的多种遗传和环境决定因素进行大规模双胞胎研究的可行性：(A)从基于人群的加州双胞胎计划队列中选择并联系具有不同水平黑色素瘤风险基因的同卵双胞胎；(B)收集、分离、从每一个双胞胎的口腔拭子中扩增和存储DNA样本(C)表明，被认为具有黑色素瘤风险的关键基因的流行足以证明大规模研究的合理性2.基于黑色素瘤高风险基因的一致性，检查具有高黑色素瘤风险基因的双胞胎中导致黑色素瘤风险的关键基因的流行率是否高于那些低黑色素瘤风险基因3.验证这种双胞胎人群中痣数量(相对于医生的评估)和阳光暴露(针对重复的自我报告)的自我报告4.建立一个理论模型来研究导致黑色素瘤风险的关键基因、大的黑色素痣的存在和阳光暴露之间的关系，这可以在一项大规模的双胞胎研究中得到验证。 这项工作将为未来评估基因和环境在黑色素瘤风险中的相对重要性的研究奠定基础。

The presence of large and many nevi (moles) is the most important predictor of melanoma occurrence. While nevi frequency increases with age, implicating sun exposure in their development, additive genetic factors appear to explain the majority of inter-individual variation in nevus size and counts. Data from adolescent twins studies in the UK and in Australia show that between 60 and 70% of nevus count variation is explained by genetic factors, although the genes responsible for this variation are unknown. Our previous work has demonstrated that in the absence of genetic variation, there appears to be no increased risk of melanoma associated with large or many nevi, implying that among individuals with large nevi, only the genetically susceptible will develop melanoma. Much work has been done on the occurrence of candidate genes in familial melanomas, but none have stood out that are both sufficiently penetrant and prevalent that they could contribute to a majority of melanomas. There is ample evidence of environmental causation in melanoma, by virtue of sun exposure. To further our understanding of the role of genotype in melanoma etiology, we are developing a study of gene-environment interaction in a population-based cohort of 52,000 twins in California, a state with among the highest rates of melanoma in the world. In the next few years, over 1,000 melanomas will have been diagnosed in this cohort, making it a critical resource for identifying gene-environment interactions in melanoma etiology, by use of traditional twin methods to partition additive genetic effects and those borne of shared environment. In this application we aim to conduct a feasibility study that will greatly enhance the success of the future study of melanoma etiology in the California Twin Program (CTP). Our specific aims are: 1. determine the feasibility of conducting a large scale twin study of multiple genetic and environmental determinants of melanoma: (a) select and contact identical twins with varying levels of melanoma risk genotype from the population-based California Twin Program cohort (b) gather, isolate, amplify and store samples of DNA from buccal swabs from each twin (c) demonstrate that the prevalence of key genes thought to confer melanoma risk is sufficient to justify a large-scale study 2. examine whether or not the prevalence of key genes conferring melanoma risk is higher in twin pairs with high melanoma risk genotype based on their nevi concordance than among those with low melanoma risk genotype 3. validate self-report of nevus counts (against physician assessment) and sun exposure (against repeated self-report) in this twin population 4. construct a theoretical model for the relationship between key genes conferring melanoma risk, the presence of large nevi, and sun exposure, that can be tested in a large scale twin study. This work will set the scene for future studies assessing the relative importance of genes and environment in melanoma risk.