Cancer driver mutations (CDMs) are necessary and causal for carcinogenesis and have advantages as reporters of carcinogenic risk. However, little progress has been made toward developing measurements of CDMs as biomarkers for use in cancer risk assessment. Impediments for using a CDM-based metric to inform cancer risk include the complexity and stochastic nature of carcinogenesis, technical difficulty in quantifying low-frequency CDMs, and lack of established relationships between cancer driver mutant fractions and tumor incidence. Through literature review and database analyses, this review identifies the most promising targets to investigate as biomarkers of cancer risk. Mutational hotspots were discerned within the 20 most mutated genes across the 10 deadliest cancers. Forty genes were identified that encompass 108 mutational hotspot codons overrepresented in the COSMIC database; 424 different mutations within these hotspot codons account for approximately 63,000 tumors and their prevalence across tumor types is described. The review summarizes literature on the prevalence of CDMs in normal tissues and suggests such mutations are direct and indirect substrates for chemical carcinogenesis, which occurs in a spatially stochastic manner. Evidence that hotspot CDMs (hCDMs) frequently occur as tumor subpopulations is presented, indicating COSMIC data may underestimate mutation prevalence. Analyses of online databases show that genes containing hCDMs are enriched in functions related to intercellular communication. In its totality, the review provides a roadmap for the development of tissue-specific, CDM-based biomarkers of carcinogenic potential, comprised of batteries of hCDMs and can be measured by error-correct next-generation sequencing. Environ. Mol. Mutagen. 61:152-175, 2020. Published 2019. This article is a U.S. Government work and is in the public domain in the USA. Environmental and Molecular Mutagenesis published by Wiley Periodicals, Inc. on behalf of Environmental Mutagen Society.

中文翻译：

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开发热点癌症驱动基因突变作为癌症风险生物标记物的原理和路线图。

癌症驱动基因突变（CDM）是致癌作用所必需和因果的，具有作为致癌风险报告者的优势。然而，在开发作为癌症风险评估中使用的生物标志物的CDM的测量方面进展甚微。使用基于CDM的度量标准来告知癌症风险的障碍包括致癌作用的复杂性和随机性，量化低频CDM的技术难度以及癌症驱动突变体级分与肿瘤发生率之间缺乏已建立的关系。通过文献综述和数据库分析，该综述确定了最有希望的靶标，以作为癌症风险的生物标记物进行研究。在10个最致命的癌症中，有20个突变程度最高的基因中发现了突变热点。鉴定了40个基因，其中包含COSMIC数据库中过量表达的108个突变热点密码子。这些热点密码子中的424个不同突变约占63,000个肿瘤，并描述了它们在肿瘤类型中的普遍性。该综述总结了有关正常组织中CDM患病率的文献，并表明此类突变是化学致癌作用的直接和间接底物，其以空间随机方式发生。有证据表明，随着肿瘤亚群的出现，热点CDM（hCDM）经常发生，这表明COSMIC数据可能低估了突变发生率。在线数据库的分析表明，含有hCDM的基因富含与细胞间通讯有关的功能。总体而言，该评价为特定组织的发展提供了路线图，基于CDM的致癌潜力生物标志物，由hCDM电池组成，可以通过错误校正的下一代测序方法进行测量。环境。大声笑 诱变剂。61：152-175，2020年。于2019年发布。本文是美国政府的工作，在美国属于公共领域。Wiley Periodicals，Inc.代表环境诱变学会出版的《环境和分子诱变》。