Melanoma genes in high-risk twins

大而多的痣（痣）的存在是黑色素瘤发生的最重要的预测因素。虽然痣的频率随着年龄的增长而增加，这表明阳光照射在其发展中，但加性遗传因素似乎可以解释痣大小和数量的大部分个体间变异。来自英国和澳大利亚青少年双胞胎研究的数据显示，60%至70%的痣计数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，似乎没有与大痣或多痣相关的黑色素瘤风险增加，这意味着在大痣患者中，只有遗传易感者才会发展为黑色素瘤。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，但是没有一个突出的是足够的渗透性和普遍性，它们可以导致大多数黑色素瘤。有充分的证据表明，由于阳光照射，黑色素瘤的环境原因。为了进一步了解基因型在黑色素瘤病因学中的作用，我们正在加州开展一项基于人群的52，000对双胞胎的基因-环境相互作用研究，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，在这个队列中将诊断出超过1,000例黑色素瘤，使其成为识别黑色素瘤病因学中基因-环境相互作用的关键资源，通过使用传统的双胞胎方法来划分加性遗传效应和共享环境所产生的遗传效应。 在本申请中，我们的目标是进行一项可行性研究，这将大大提高加州双胞胎计划（CTP）中黑色素瘤病因学未来研究的成功率。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接触具有不同水平的黑素瘤风险基因型的同卵双胞胎（B），扩增并储存来自双胞胎中每一个的口腔拭子的DNA样品（c）证明被认为赋予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。根据痣的一致性，检查赋予黑色素瘤风险的关键基因在具有高黑色素瘤风险基因型的双胞胎中的患病率是否高于具有低黑色素瘤风险基因型3的双胞胎。验证该双胞胎人群中痣计数的自我报告（对照医生评估）和日光暴露（对照重复的自我报告）4.构建一个理论模型，用于研究黑色素瘤风险的关键基因、大痣的存在和阳光照射之间的关系，该模型可以在大规模的双胞胎研究中进行测试。 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.