Mechanisms of cancer mutations

癌症突变机制

• 批准号: 10563024
• 负责人: Gerd P Pfeifer
• 金额: $ 48.25万
• 依托单位: VAN ANDEL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-01 至 2027-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10563024
• 关键词: 8-oxo-dGTP; Adenine; Aldehydes; Aromatic Polycyclic Hydrocarbons; Base Sequence; Carcinogens; Cell Culture System; Characteristics; Complement; Cytosine; DNA; DNA Adduction; DNA Adducts; DNA Damage; DNA Methylation; DNA Repair; DNA Sequence; DNA lesion; Dependence; Environmental Exposure; Enzymes; Esophageal Adenocarcinoma; Esophagus; Etiology; Event; Felis catus; Frequencies; Future; Genes; Genetic Transcription; Genome; Geography; Goals; Guanine; Human; Human Genome; Induced Mutation; Inflammation; Knowledge; Lesion; Link; Lipid Peroxidation; Lung; Malignant Neoplasms; Malignant neoplasm of esophagus; Malignant neoplasm of liver; Malignant neoplasm of lung; Maps; Measures; Methodology; Methods; Mutagenesis; Mutate; Mutation; Mutation Analysis; Names; Nucleotides; Oxidative Stress; Pathologic; Pathway interactions; Pattern; Play; Positioning Attribute; Procedures; Process; Rare Lesion; Resolution; Role; Science; Skin Carcinoma; Smoker; Smoking; Somatic Mutation; Source; Specificity; Technology; Testing; Tissues; Tobacco; Tobacco smoke; Tobacco-Associated Carcinogen; Tobacco-Related Carcinoma; Work; adduct; cancer genome; cancer type; dominant genetic mutation; environment related cancer; genome sequencing; genome-wide; insight; melanoma; method development; mouth squamous cell carcinoma; mutation assay; sunlight-induced; tobacco user; transversion mutation; tumor

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.

项目概要： 癌症基因组测序已经在不同类型的人类中发现了数千种体细胞突变， 癌这些突变为潜在的致突变事件提供了有价值的信息来源 发生并产生突变，有时在肿瘤发展之前几十年。对于某些 癌症，暴露和癌症突变之间的令人信服的联系已经建立，最好的 典型的阳光诱导突变（二嘧啶序列处的C至T突变）是典型的例子， 在黑色素瘤和非黑色素瘤皮肤癌中流行，并通过吸烟相关的G到T颠换 这些突变在吸烟者的肺癌中很常见，但在非吸烟者的肺癌中却不常见。的类型和频率 不同肿瘤类型中的突变称为突变标记。几个签名也有一个 与例如转录方向相关的特征性DNA链偏好。几种人 在癌症中，存在来源不明的不寻常和特征性突变特征。这些签名是 被认为是由特定的DNA损伤、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损伤图谱识别和重建诱变标记， 我们确定人类所有序列位置上特定类型的DNA损伤的程序 基因组，结合突变分析，目标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。的 一种方法需要有足够的灵敏度来检测罕见的DNA损伤，并且必须能够做到这一点 基因组的位置。我们开发了一种方法，我们称之为圆损伤测序 （CD-seq）。我们提出三个具体目标。在第一个目标中，我们将使用我们的新方法来表征和 绘制我们假设在肝癌中起关键作用的活性谷胱甘肽衍生的DNA加合物。在 第二个目的，我们将检验从核苷酸库中掺入的8-oxo-dG是负责 对于在人类中观察到的作为显性突变类型的序列特异性A至C颠换突变， 食管腺癌最后一个目标是了解有针对性的机制， PAH类烟草烟雾致癌物的致突变作用，以及这种靶向作用与肺和口腔 吸烟者的鳞状细胞癌。我们的DNA损伤研究将通过突变 这些试验证实相关途径诱导预期类型的突变。我们提出的工作将 为人类癌症突变的潜在起源提供了机制性的见解。我们预计， 方法将有助于许多未来的研究DNA损伤和修复，并将有助于确定其他诱变剂， 机制等