Melanoma susceptibility as a complex trait: genetic variation controls all stages of tumor progression
Melanoma susceptibility as a complex trait: genetic variation controls all stages of tumor progression
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DOI：
10.1038/onc.2014.227
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发表时间：
2015-05-28
期刊：
影响因子：
8
通讯作者：
Walker, G. J.
中科院分区：
文献类型：
--
作者：
Ferguson, B.;Ram, R.;Walker, G. J.
对大多数常见癌症的易感性可能涉及多种低风险遗传变异之间的相互作用。虽然在鉴定这些变异方面取得了很大进展，但它们对表型的影响以及它们导致疾病的机制在很大程度上仍然未知。我们已经开发了一种小鼠黑色素瘤模型，该模型含有与人黑色素瘤有关的两种突变癌基因，CDK4（R24C）和NRAS（Q61K）。在这些小鼠中，肿瘤来自良性前驱病变，这是人类肿瘤的公认的强风险因素。为了定义参与黑色素瘤通路的分子事件，我们首次将协作交叉（CC）应用于癌症研究。CC是一个强大的资源，旨在加快发现复杂性状的基因。我们在50多个CC株中描述了黑色素瘤的发生，并观察到所有性状的巨大变化，包括痣和黑色素瘤的发病年龄和多样性，解剖部位偏好，痣转化为黑色素瘤的时间和转移。有趣的是，新生儿紫外线辐射暴露加剧了痣和黑色素瘤的形成，在大多数，但不是所有的CC株背景，这表明CC内的遗传变异将有助于解释个人对阳光照射的敏感性，主要的环境皮肤致癌物。由于遗传变异在单个小鼠模型中带来了显着的表型多样性，黑色素瘤相关的内表型比较为我们提供了有关致癌机制的信息，例如黑色素瘤的发病率是否取决于预先存在的痣细胞的密度。小鼠模型已被用于研究基因突变在肿瘤发生中的功能作用。这项工作代表了他们的下一个发展阶段，即研究生物变异如何极大地影响病变的发生和侵袭性，即使在已知的体细胞驱动突变的情况下。
Susceptibility to most common cancers is likely to involve interaction between multiple low risk genetic variants. Although there has been great progress in identifying such variants, their effect on phenotype and the mechanisms by which they contribute to disease remain largely unknown. We have developed a mouse melanoma model harboring two mutant oncogenes implicated in human melanoma, CDK4(R24C) and NRAS(Q61K). In these mice, tumors arise from benign precursor lesions that are a recognized strong risk factor for this neoplasm in humans. To define molecular events involved in the pathway to melanoma, we have for the first time applied the Collaborative Cross (CC) to cancer research. The CC is a powerful resource designed to expedite discovery of genes for complex traits. We characterized melanoma genesis in more than 50 CC strains and observed tremendous variation in all traits, including nevus and melanoma age of onset and multiplicity, anatomical site predilection, time for conversion of nevi to melanoma and metastases. Intriguingly, neonatal ultraviolet radiation exposure exacerbated nevus and melanoma formation in most, but not all CC strain backgrounds, suggesting that genetic variation within the CC will help explain individual sensitivity to sun exposure, the major environmental skin carcinogen. As genetic variation brings about dramatic phenotypic diversity in a single mouse model, melanoma-related endophenotype comparisons provide us with information about mechanisms of carcinogenesis, such as whether melanoma incidence is dependent upon the density of pre-existing nevus cells. Mouse models have been used to examine the functional role of gene mutations in tumorigenesis. This work represents their next phase of development to study how biological variation greatly influences lesion onset and aggressiveness even in the setting of known somatic driver mutations.