Molecular origins and impact of APOBEC3 mutagenesis in cancer

APOBEC3 突变的分子起源和对癌症的影响

基本信息

批准号：
10693177
负责人：
JOHN MACIEJOWSKI
金额：
$ 40.94万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10693177
关键词：
Address B-Cell Lymphomas Bioinformatics Biological Assay Biological Markers Biological Models Breast Cancer cell line Cancer Etiology Cancer Model Cancer cell line Cell Line Cell model Cells Characteristics Clinical Cytidine Cytosine deaminase Data Deaminase Detection Dimensions Disease Engineering Enzymes Etiology Evolution Exposure to Family Gene Mutation Genome Goals High Prevalence Human Immune Individual Knock-out Link Lung Adenocarcinoma Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of urinary bladder Measures Metastatic Carcinoma Modeling Molecular Monitor Mus Mutagenesis Mutation Mutation Analysis Neoplasm Metastasis Outcome Patient Selection Pattern Physiological Play Polymerase Process RNA Viruses Reagent Regulation Resistance Retroelements Rodent Role Sensitivity and Specificity Single base substitution Single-Stranded DNA Site Source Surrogate Markers System Testing Therapeutic Transgenes Treatment Efficacy Tyrosine Kinase Inhibitor Xenograft procedure biomarker validation cancer cell cancer genome cancer prevention cancer therapy cancer type carcinogenesis experimental study genome sequencing human disease imprint insight lung cancer cell malignant breast neoplasm member mutant novel strategies overexpression paralogous gene preference prognostic reconstitution recruit scaffold targeted treatment therapeutic target therapy resistant tumorigenesis whole genome

项目摘要

PROJECT SUMMARY Mutations arise as a result of exogenous and endogenous processes that leave characteristic imprints or signatures upon the genome. Systematic analysis of these mutational signatures led to the identification of >50 distinct types of single base substitutions (SBS) in human cancer genomes. Revealing the origins of individual signatures is critical for understanding cancer etiology, with potential implications for cancer prevention and therapy. Two of the most prevalent mutational signatures in cancer, termed SBS2 and SBS13, are present in >78% of cancer types and 56% of all cancer genomes, with a particular prominence in breast, bladder, and lung cancers. SBS2 and SBS13 are proposed to be caused by the endogenous APOBEC3 (A3) enzymes, which target ssDNA and RNA of viruses and retroelements as part of the innate immune defense. Correlations between A3 expression, driver gene mutations in A3-preferred contexts, and clinical outcomes suggest that A3 mutagenesis may play important roles in cancer etiology and evolution. Thus, there is strong rationale to understand the mechanisms of A3 activity. However, reliance on engineered model systems and correlative data have caused links between A3 enzymes, mutations in cancer, and cancer etiology to be poorly understood. We have identified human cancer cell lines with endogenous A3 mutagenesis and developed a workflow that enables us to quantify contributions of individual A3 members to mutations. Here, we propose to leverage this workflow to accomplish the following goals: 1) Identify A3 mutator enzymes in cancer types where A3 mutagenesis is prevalent and find biomarkers of their activity; 2) Investigate mechanisms modulating A3 mutagenesis; 3) Determine the functional relevance of A3 mutagenesis in therapy resistance and metastasis. Aim 1 will expand upon our characterization of human cancer cells with active A3 mutagenesis to identify A3 mutators in breast, bladder, and lung cancers. In parallel, we will directly assess the unknown specificity and sensitivity of assays to measure activities of individual A3 enzymes. These experiments may further confirm the speculative A3-etiology of a large number of cancer mutations and quantify contributions of individual A3 enzymes, thus nominating them as putative targets for therapeutic pursuit. Aim 2 builds on our preliminary data to investigate proposed modulators of A3 mutagenesis. These experiments have the potential to broaden the scope of therapeutic opportunities focused on cancer cell evolution. Aim 3 will assess the links between A3 enzymes, therapy resistance and metastasis in breast, bladder, and lung cancer cell lines. These experiments will test predictions from multi-dimensional associations that A3-mutagenesis is a disease-modifying process that can be therapeutically exploited at various stages of cancer evolution. Taken together, these studies will define the etiologies of highly prevalent mutational processes and identify strategies to elicit more durable clinical benefits to targeted therapies and curb metastasis.

项目概要突变是由于外源和内源过程而产生的，这些过程留下了特征印记或基因组上的签名。对这些突变特征的系统分析导致识别出> 50 人类癌症基因组中不同类型的单碱基替换（SBS）。揭示个体的起源特征对于了解癌症病因至关重要，对癌症预防和治疗具有潜在影响治疗。癌症中最常见的两种突变特征，称为 SBS2 和 SBS13，存在于 >78% 的癌症类型和 56% 的所有癌症基因组，其中在乳腺癌、膀胱癌和癌症中尤为突出肺癌。 SBS2 和 SBS13 被认为是由内源性 APOBEC3 (A3) 酶引起的，其目标是病毒和逆转录因子的 ssDNA 和 RNA，作为先天免疫防御的一部分。相关性 A3 表达、A3 偏好环境中的驱动基因突变和临床结果之间的关系表明，A3 诱变可能在癌症病因学和进化中发挥重要作用。因此，有充分的理由了解 A3 活性的机制。然而，依赖工程模型系统和相关数据导致 A3 酶、癌症突变和癌症病因之间的联系很差明白了。我们已经鉴定出具有内源性 A3 突变的人类癌细胞系，并开发了一种工作流程使我们能够量化单个 A3 成员对突变的贡献。在此，我们建议利用此工作流程来实现以下目标：1) 识别癌症类型中的 A3 突变酶，其中 A3 诱变很普遍，并找到其活性的生物标志物； 2) 研究A3的调节机制诱变； 3)确定A3突变在治疗抵抗和转移中的功能相关性。目标 1 将扩展我们对具有活性 A3 诱变的人类癌细胞的表征，以识别 A3 乳腺癌、膀胱癌和肺癌中的突变基因。同时，我们将直接评估未知的特异性和测量单个 A3 酶活性的测定的灵敏度。这些实验或许可以进一步证实大量癌症突变的推测 A3 病因学并量化个体 A3 的贡献酶，从而将它们指定为治疗追求的推定目标。目标 2 基于我们的初步数据研究提出的 A3 诱变调节剂。这些实验有可能拓宽治疗机会的范围集中在癌细胞的进化上。目标 3 将评估 A3 之间的联系乳腺癌、膀胱癌细胞系和肺癌细胞系中的酶、治疗耐药性和转移。这些实验将测试来自多维关联的预测，即 A3 突变是一种疾病缓解过程可以在癌症进化的各个阶段进行治疗。总的来说，这些研究将定义高度普遍的突变过程的病因并确定引发更持久突变的策略靶向治疗和抑制转移的临床益处。