Mechanisms of cancer mutations

项目总结： 癌症基因组测序在不同类型的人类中发现了数千个体细胞突变 癌症。这些突变提供了关于潜在诱变事件的有价值的信息来源 这些突变已经发生并造成了突变，有时是在肿瘤发展之前几十年。当然可以肯定 癌症，令人信服的暴露和癌症突变之间的联系已经被确立，最好的 以典型的阳光诱导的突变(双嘧啶序列的C到T突变)为例 常见于黑色素瘤和非黑色素瘤皮肤癌以及吸烟相关的G-T转换 在吸烟者肺癌中常见的突变，但不吸烟者则不是。的类型和频率 不同肿瘤类型的突变称为突变特征。几个签名也有一个 例如，与转录方向有关的特征DNA链偏向。在几个人类中 对于癌症，有不寻常的和特征的未知来源的突变特征。这些签名是 被认为是由特定的DNA损伤、有缺陷的DNA修复或内源性过程引起的。我们 假设我们可以使用DNA损伤图谱识别和重新创建突变特征，一个 我们确定人类所有序列位置上特定类型的DNA损伤的过程 基因组，结合突变分析，目的是将突变特征分配给病因学 与特定人类癌症相关的药物。这一领域的一个关键挑战是方法开发。这个 方法需要足够灵敏来检测罕见的DNA损伤，并且必须完全能够做到这一点 基因组的位置。我们已经开发了这样一种方法，我们称之为圆损伤排序 (CD-seq)。我们提出了三个具体目标。在第一个目标中，我们将使用我们的新方法来表征和 MAP反应醛衍生的DNA加合物，我们推测在肝癌中起着关键作用。在 第二个目的，我们将检验从核苷酸池中结合的8-oxo-dg是负责的假设。 在人类中观察到的作为显性突变类型的序列特异性A到C颠换突变 食管腺癌。最后一个目标将是理解有针对性的机制。 烟草烟雾多环芳烃类致癌物的致突变作用及其与肺和口腔的关系 烟草使用者的鳞状细胞癌。我们的DNA损伤研究将得到突变的补充 检测以确认相关途径会导致预期类型的突变。我们提议的工作将 提供对人类癌症突变的潜在来源的机械论见解。我们预计我们的 这些方法将有助于未来对DNA损伤和修复的许多研究，并将有助于识别其他诱变剂 机械装置。

PROJECT SUMMARY: Cancer genome sequencing has identified thousands of somatic mutations in different types of human cancer. These mutations provide a valuable source of information as to the potential mutagenic events that have occurred and created the mutations, sometimes decades before the tumor develops. For certain cancers, convincing links between an exposure and cancer mutations have been established, best exemplified by typical sunlight-induced mutations (C to T mutations at dipyrimidine sequences) that are prevalent in melanoma and in non-melanoma skin cancers and by smoking- related G to T transversion mutations that are common in lung cancers from smokers but not nonsmokers. The types and frequencies of mutations in different tumor types is called the mutational signature. Several signatures also have a characteristic DNA strand bias related to, for example, the direction of transcription. In several human cancers, there are unusual and characteristic mutational signatures of unknown origin. These signatures are thought to arise from specific DNA damage, defective DNA repair or from endogenous processes. We hypothesize that we can identify and recreate mutagenic signatures using DNA damage mapping, a procedure in which we determine DNA lesions of a specific type at all sequence positions of the human genome, combined with mutational analysis, with the goal of assigning mutational signatures to etiological agents relevant for specific human cancers. One key challenge in this field is method development. The method needs to be sufficiently sensitive to detect rare DNA lesions and must be capable of doing so at all positions of the genome. We have developed such a method, which we named circle-damage-sequencing (CD-seq). We propose three Specific Aims. In the first Aim, we will use our new method to characterize and map reactive aldehyde-derived DNA adducts that we hypothesize play a crucial role in liver cancer. In the second Aim, we will test the hypothesis that 8-oxo-dG incorporated from the nucleotide pool is responsible for sequence-specific A to C transversion mutations observed as a dominant mutation type in human esophageal adenocarcinomas. The last Aim will have the goal of understanding the mechanisms of targeted mutagenesis by tobacco smoke carcinogens of the PAH class and how this targeting relates to lung and oral squamous cell carcinomas in tobacco users. Our DNA damage studies will be complemented by mutation assays to confirm that the relevant pathways induce the expected types of mutations. Our proposed work will provide mechanistic insights into the potential origin of human cancer mutations. We anticipate that our methods will aid in many future studies of DNA damage and repair and will help identify other mutagenic mechanisms.