文章：

恶性黑色素瘤的遗传学：来自老鼠和人类的经验教训

The genetics of malignant melanoma: lessons from mouse and man

原文发布日期：2003-08-01

DOI: 10.1038/nrc1145

类型: Review Article

开放获取: 否

要点：

1. Melanoma pathogenesis is driven by both genetic and environmental risk factors. Its incidence is influenced by skin pigmentation, sun-exposure history and geographical location.
2. About 10% of all melanoma cases are familial. Genetic analysis in familial melanoma patients has identified germline mutations in CDKN2A, which encodes INK4A and ARF, and CDK4. Human and mouse data indicate that inactivation of INK4A–CDK4–RB and ARF–p53 are two near-obligate events in melanoma genesis.
3. The red-hair colour (RHC) phenotype has long been associated with an increased risk for melanoma and is linked to specific variants of MC1R. These also increase the penetrance of CDKN2A mutants among germline carriers and are believed to be low-penetrance melanoma-predisposition mutations.
4. With the discovery of high-frequency BRAF mutations in melanocytic neoplasms, activation of the RAS–RAF–ERK signalling pathway seems to be yet another near-obligate event in melanoma development.
5. Cell-based functional studies, coupled with genetic data in engineered mouse models, have identified MET-HGF activation and loss of the PTEN tumour-suppressor pathway as causal events in melanoma genesis and/or progression.
6. Mouse models of melanoma have served as an in vivo genetic platform on which the role and molecular targets of ultraviolet (UV) radiation can be examined. They have provided genetic evidence in support of the epidemiological link between increased melanoma risk and childhood sunburn and have facilitated the identification of components of the RB pathway as specific UV-light targets.
7. The search for rational targets for the development of melanoma therapeutics will benefit from the use of inducible onco-transgene models for identification of melanoma-maintenance targets.

要点翻译：

1. 黑色素瘤的发病机制由遗传和环境风险因素共同驱动。其发病率受皮肤色素沉着、日照史和地理位置影响。
2. 约10%的黑色素瘤病例具有家族聚集性。对家族性黑色素瘤患者的遗传学分析发现，CDKN2A基因（编码INK4A和ARF）及CDK4基因存在胚系突变。人类与小鼠数据表明，INK4A–CDK4–RB通路失活和ARF–p53通路失活是黑色素瘤发生过程中两个近乎必经的环节。
3. 红发表型长期以来与黑色素瘤风险增加相关，该表型与MC1R基因特定变异体有关。这些变异同时会增强CDKN2A突变在胚系携带者中的外显率，被认为是低外显率的黑色素瘤易感突变。
4. 随着黑色素细胞肿瘤中高频BRAF突变的发现，RAS–RAF–ERK信号通路的激活被认为是黑色素瘤发展过程中另一个近乎必经的环节。
5. 基于细胞的功能学研究结合基因工程小鼠模型的遗传学数据，已确定MET-HGF激活与PTEN肿瘤抑制通路失活是黑色素瘤发生和/或进展的致病因素。
6. 黑色素瘤小鼠模型作为体内遗传学平台，可用于研究紫外线辐射的作用机制及分子靶点。这些模型为"儿童期晒伤增加黑色素瘤风险"的流行病学关联提供了遗传学证据，并证实RB通路组分是紫外线特异性作用靶点。
7. 通过诱导型癌基因转基因模型识别黑色素瘤维持靶点，将有助于寻找黑色素瘤靶向治疗的合理靶标。

英文摘要：

Therapeutic resistance and proclivity for metastasis are hallmarks of malignant melanoma. Genetic, epidemiological and genomic investigations are uncovering the spectrum of stereotypical mutations that are associated with melanoma and how these mutations relate to risk factors such as ultraviolet exposure. The ability to validate the pathogenetic relevance of these mutations in the mouse, coupled with advances in rational drug design, has generated optimism for the development of effective prevention programmes, diagnostic measures and targeted therapeutics in the near future.

摘要翻译： 

治疗抗性和转移倾向是恶性黑色素瘤的标志。遗传、流行病学和基因组学研究正在揭示与黑色素瘤相关的典型突变谱，以及这些突变如何与紫外线暴露等风险因素相关联。在小鼠中验证这些突变的致病相关性的能力，加上合理药物设计的进展，为不久的将来开发有效的预防方案、诊断措施和靶向治疗带来了希望。

原文链接：

The genetics of malignant melanoma: lessons from mouse and man