文章：

人类癌症的谱系依赖性和谱系存活癌基因

Lineage dependency and lineage-survival oncogenes in human cancer

原文发布日期：2006-08-01

DOI: 10.1038/nrc1947

类型: Review Article

开放获取: 否

要点：

1. The close association between cell lineage and cancer phenotype has long been recognized. This link raises the possibility that cellular mechanisms that govern lineage proliferation and survival during development might also underlie tumorigenic mechanisms.
2. Many somatic genetic alterations show lineage-restricted patterns across human tumours, which indicates that genetic changes in cancer might be conditioned by the lineage programmes that are embedded in tumour precursor cells.
3. A convergence of lineage-based and genetic observations gives rise to a lineage-dependency (or lineage-addiction) model of human cancer, wherein tumour cells depend crucially on survival mechanisms that are programmed into lineage precursor cells during development, which might be affected by acquired genetic alterations. Unlike oncogene addiction, which invokes a dependency on a tumour-specific gain-of-function event, lineage addiction involves the persistence and/or deregulation of crucial lineage-survival mechanisms during carcinogenesis or tumour progression.
4. Presumably, lineage-dependency mechanisms that promote tumour progression involve master regulatory genes that also exert key developmental survival roles. Such genes can be termed lineage-survival oncogenes.
5. MITF (microphthalmia-associated transcription factor) and the androgen receptor are prototype lineage-survival oncogenes in melanoma and prostate cancer, respectively. A review of the scientific literature readily identifies several more genes with presumptive or predicted lineage-survival functions in different cancers.
6. Recognition of the lineage-dependency model might expand existing paradigms for tumour biology by emphasizing the importance of lineage in shaping key oncogenic mechanisms, thereby offering an explanatory framework for the distribution of genetic alterations in cancer. Targeting lineage dependencies as well as classical gain-of-function events might require combinatorial or synthetic-lethal therapeutic approaches to cancer.

要点翻译：

1. 细胞谱系与癌症表型之间的密切关联早已得到认可。这一联系提出了一种可能性：在发育过程中控制谱系增殖与存活的细胞机制，或许同样是肿瘤发生机制的基础。
2. 许多体细胞基因突变在人类肿瘤中呈现出谱系限制性分布模式，这表明癌症中的遗传变化可能受到肿瘤前体细胞内嵌的谱系程序的调控。
3. 基于谱系的观察与遗传学研究的融合，催生了人类癌症的"谱系依赖性"模型。该模型认为，肿瘤细胞本质上依赖于发育过程中谱系前体细胞编程设定的生存机制，这些机制可能受到后天获得性遗传改变的影响。与致癌基因成瘾性依赖肿瘤特异性功能获得性事件不同，谱系成瘾性涉及致癌过程或肿瘤进展中关键谱系生存机制的持续存在和/或失调。
4. 促进肿瘤进展的谱系依赖机制很可能涉及主调控基因，这些基因同时承担关键发育存活功能。此类基因可被称为"谱系生存致癌基因"。
5. MITF（小眼畸形相关转录因子）和雄激素受体分别是黑色素瘤和前列腺癌中的典型谱系生存致癌基因。通过系统梳理科学文献，我们不难发现更多在不同癌症中具有推定或预测性谱系生存功能的基因。
6. 对谱系依赖性模型的认知，可通过强调谱系在塑造关键致癌机制中的重要性来拓展现有肿瘤生物学范式，从而为癌症基因改变的分布规律提供解释框架。针对谱系依赖性及经典功能获得性事件的靶向治疗，可能需要采用组合疗法或合成致死策略。

英文摘要：

Although cell-lineage and differentiation models dominate tumour classification and treatment, the recognition that cancer is also a genomic disease has prompted a reconfiguration of cancer taxonomies according to molecular criteria. Recent evidence indicates that a synthesis of lineage-based and genetic paradigms might offer new insights into crucial and therapeutically pliable tumour dependencies. For example, MITF (microphthalmia-associated transcription factor), which is a master regulator of the melanocyte lineage, might become a melanoma oncogene when deregulated in certain genetic contexts. MITF and other lineage-survival genes therefore implicate lineage dependency (or lineage addiction) as a newly recognized mechanism that is affected by tumour genetic alterations.

摘要翻译： 

尽管细胞谱系和分化模型主导着肿瘤分类与治疗，但癌症本质上也是一种基因组疾病的认识，已促使人们依据分子标准重新构建癌症分类体系。最新证据表明，将谱系模型与遗传范式相结合，可能为揭示关键且可靶向的肿瘤依赖性提供新视角。例如，小眼畸形相关转录因子（MITF）作为黑色素细胞谱系的主调控因子，在特定遗传背景下失调时可能成为黑色素瘤的致癌基因。因此，MITF及其他谱系生存基因提示，“谱系依赖性”（或称“谱系成瘾”）是一种受肿瘤遗传改变影响的新机制。

原文链接：

Lineage dependency and lineage-survival oncogenes in human cancer