Autoantibodies Define Scleroderma Subgroups with Distinct Relationships to Cancer

自身抗体定义了与癌症具有独特关系的硬皮病亚群

• 批准号: 10132986
• 负责人: LIVIA A CASCIOLA-ROSEN
• 金额: $ 61.68万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-09 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10132986
• 关键词: Antibodies; Antibody Specificity; Antigen Targeting; Antigens; Autoantibodies; Autoantigens; Autoimmune Responses; Autoimmunity; Biological; Biological Assay; Cancer Detection; Centromere; Chronic; Clinical; Cohort Analysis; Complex; Computer Analysis; Control Groups; Custom; Data; Development; Differentiation Antigens; Disease; Drug Exposure; Epitopes; General Population; Genes; Genetic; High-Risk Cancer; Histology; Immune response; Immunologic Factors; Immunoprecipitation; Incidence; Inflammation; Kinetics; Link; Malignant Neoplasms; Matched Group; Methods; Mutate; Mutation; Myositis; Onset of illness; Pathogenesis; Patients; Pattern; Phenotype; Population; Proteomics; RNA Polymerase III; Registries; Rheumatism; SEER Program; Scleroderma; Screening for cancer; Serology; Site; Somatic Mutation; Specificity; Standardization; Stratification; Subgroup; Testing; Therapeutic; Time; Tissues; Topoisomerase; Universities; Validation; Work; anti-cancer; autoimmune rheumatologic disease; cancer risk; cancer type; clinically relevant; cohort; evidence base; high risk population; innovation; insight; novel; novel marker; patient subsets; population based; response; screening; screening guidelines; tool; tumor; validation studies

PROJECT SUMMARY Although an understanding of the biological mechanisms causing scleroderma (SSc) remains incomplete, emerging data underscore important connections linking cancer, autoimmunity and SSc. It is an important priority to identify SSc subgroups at high risk of cancer at SSc onset, as this may inform therapeutic approaches and provide insights into SSc pathogenesis. Our recent studies show that autoantibodies are useful to define biologically relevant subgroups. Among SSc patients with cancer, those with anti-RNA polymerase III (POLR3) antibodies are more likely to have cancer close to SSc onset (3, 4). However, >25% of patients with a short cancer-SSc interval currently have undefined autoantibodies. We have created an innovative autoantibody discovery pipeline, and demonstrate that multiple, additional autoantibodies (known and novel) are associated with coincident cancer at SSc onset. We also describe a novel antibody specificity that is enriched in anti-POLR3-positive patients who do not get cancer, suggesting that some immune responses might be protective against cancer. Lastly, we demonstrate that autoantibody subsets can aid in defining the magnitude and timing of cancer risk in SSc, and in predicting the types of tumors observed. The proposed studies will use a large population of SSc patients from two well-characterized SSc cohorts to define and validate autoantibodies associated with increased or decreased cancer risk, and to assess their utility, together with distinct phenotypic features, in quantifying cancer risk at SSc onset. We will accomplish this through the following specific aims: Aim 1 will use an innovative antibody discovery pipeline and a rich cohort of SSc patients with cancer to identify known and novel autoantibody markers of a short cancer-SSc interval in patients lacking the 3 major SSc antibody specificities. The studies will also use the defined autoantibodies to search for evidence of somatic mutations of relevant autoantigens in matched cancers. Since ~80% of patients with POLR3 antibodies do not have cancer, and our preliminary data shows novel antibodies in this group, we will also identify autoantibodies associated with protection against cancer. These may be important markers of low cancer risk. Aim 2 will define time-dependent overall and site-specific cancer risk in patients with SSc relative to the general population, based on autoantibody and phenotypic subsets, to develop an evidence-based approach to cancer screening in patients with new onset SSc. Findings will be validated in a second large SSc cohort. This work will allow the development of a clinically relevant approach to cancer detection at SSc onset and establish a framework of more homogeneous serologic subgroups in whom the mechanistic relationships between cancer and autoimmunity can be interrogated. This approach is also relevant to other autoimmune rheumatic diseases (e.g. inflammatory myopathies) in which cancer and rheumatic disease onset are temporally linked.

项目摘要 虽然对引起硬皮病（SSc）的生物学机制的理解仍然不完全， 新出现的数据强调了癌症、自身免疫和SSc之间的重要联系。这是一个重要 优先确定SSc发作时癌症高风险的SSc亚组，因为这可能会为治疗提供信息。 方法，并提供深入了解SSc发病机制。我们最近的研究表明，自身抗体 用于定义生物学相关亚组。在患有癌症的SSc患者中， 聚合酶III（POLR 3）抗体更可能在接近SSc发作时具有癌症（3，4）。然而，>25%的 具有短的癌症-SSc间隔的患者目前具有不确定的自身抗体。我们已创建了一个 创新的自身抗体发现管道，并证明了多种额外的自身抗体（已知的， 新的）与SSc发作时的并发癌症相关。我们还描述了一种新的抗体特异性， 在未患癌症的抗POLR 3阳性患者中富集，这表明一些免疫反应可能 可以预防癌症。最后，我们证明了自身抗体亚群可以帮助定义 和SSc中癌症风险的时间，以及预测观察到的肿瘤类型。拟议的研究将使用 来自两个充分表征的SSc队列的大量SSc患者人群，以定义和验证自身抗体 与癌症风险增加或降低相关，并评估其效用，以及不同的表型 特征，在SSc发作时量化癌症风险。我们将通过以下具体目标实现这一目标： Aim 1将使用创新的抗体发现管道和丰富的SSc癌症患者队列， 在缺乏3种主要SSc的患者中，已知的和新的短癌症-SSc间隔的自身抗体标志物 抗体特异性。这些研究还将使用定义的自身抗体来寻找体细胞免疫的证据。 匹配癌症中相关自身抗原的突变。由于约80%的POLR 3抗体患者没有 我们的初步数据显示，在这一组中有新的抗体，我们还将鉴定自身抗体。 与预防癌症有关。这些可能是低癌症风险的重要标志。目标2将定义 SSc患者相对于一般人群的时间依赖性总体和部位特异性癌症风险，基于 自身抗体和表型亚群，以发展一种循证的癌症筛查方法， 新发SSc患者。将在第二个大型SSc队列中验证结果。这项工作将使 开发临床相关的方法，在SSc发作时进行癌症检测，并建立 更同质的血清学亚组的框架，其中， 癌症和自身免疫可以被询问。这种方法也与其他自身免疫性疾病有关。 风湿性疾病（例如炎性肌病），其中癌症和风湿性疾病发作是 时间上的联系。