Novel ultra-short cell free DNA biomarkers for early detection of non-small cell lung cancer.

用于早期检测非小细胞肺癌的新型超短无细胞 DNA 生物标志物。

• 批准号: 10730508
• 负责人: Feng Li
• 金额: $ 18.35万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-15 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10730508
• 关键词: Apoptotic; Benign; Bioinformatics; Biologic Characteristic; Biological; Biological Assay; Biological Markers; Biological Process; Blood; Cancer Detection; Cancer Etiology; Cancer Patient; Cells; Cessation of life; Chest; Clinical; DNA; DNA Library; DNA sequencing; Data; Development; Diagnosis; Disease; Drug resistance; Early Diagnosis; Early Intervention; Elements; Epidermal Growth Factor Receptor; Face; Frequencies; Generations; Hematopoiesis; Individual; Libraries; Lung Neoplasms; Lung nodule; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of lung; Medical center; Methods; Modeling; Molecular Profiling; Monitor; Morbidity - disease rate; Mutation; Names; Necrosis; Nodule; Non-Invasive Detection; Non-Small-Cell Lung Carcinoma; Nucleic Acids; Patients; Pattern; Performance; Plasma; Population; Preparation; Procedures; Publications; Research; Sensitivity and Specificity; Single-Stranded DNA; Solid Neoplasm; Somatic Mutation; Source; Statistical Data Interpretation; Testing; Therapeutic; Thoracic Radiography; Validation; Variant; Work; X-Ray Computed Tomography; actionable mutation; cell free DNA; clinical application; cohort; computed tomography screening; diagnostic strategy; direct application; early detection biomarkers; effective therapy; genome-wide; high risk population; improved; liquid biopsy; low dose computed tomography; lung basal segment; lung cancer screening; molecular diagnostics; molecular marker; mortality; neoplastic cell; new technology; novel; novel marker; predictive modeling; response; screening program; tumor; tumor DNA

PROJECT SUMMARY/ABSTRACT Lung cancer remains the leading cause of cancer-related deaths in the U.S. and worldwide. Non–small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancers. Early detection of indeterminate pulmonary nodules (IPNs) with chest low dose computed tomography (LDCT) screening followed by effective treatments can reduce mortality by 20% relative to chest radiography. However, the high false positive rate finding as >95% limits the application. The unmet clinical need for early diagnosis is the lack of a noninvasive test that can be applied to individuals with CT-detected lung nodules and reliably discriminates between malignant or benign nodules. Liquid biopsy focused on the characterization of tumor-associated genetic alterations in cell free circulating tumor DNA can non-invasively profile the molecular landscape of solid tumors. However, the low biological concentrations of ctDNA, low frequency of somatic mutations and the confounding impact of clonal hematopoiesis-related variants in early-stage lung cancer limit the sensitivity of ctDNA-based liquid biopsy assays. It would be essential if additional cell free DNA biomarkers could be included to allow the development of more sensitive molecular diagnostics approaches for the early assessment of lung cancer. We have discovered a distinct population of ultra-short single-stranded cell-free DNA (uscf/ctDNA) with a size of 40-70nt in healthy and NSCLC plasma. Our preliminary data showed that the fragmentomic features, including functional element profile, fragmentation patterns and end motifs of uscfDNA molecules, can distinguish NSCLC patients from healthy donors. This R21 application is to explore and test our hypothesis that the fragmentomic features of uscfDNA molecules can serve as novel biomarkers to differentiate NSCLC patients from non-cancer subjects with IPNs and allow more sensitive liquid biopsy molecular diagnostics for early NSCLC detection. Two specific aims are in place for hypothesis testing. Aim 1 is to develop a predictive model using uscfDNA-seq assay on uscfDNA fragmentomic analysis for liquid biopsy of NSCLC. Aim 2 is to pre-validate uscfDNA-Seq test for the early detection of NSCLC. Together, the translational and pre-validation, targeting uscfDNA for early detection of NSCLC can break new ground and extend previous discoveries towards impactful new directions and clinical applications.

项目概要/摘要 肺癌仍然是美国和全世界非小细胞癌症相关死亡的主要原因。 肺癌 (NSCLC) 约占所有肺癌的 85%，早期检测不确定。 通过胸部低剂量计算机断层扫描 (LDCT) 筛查肺结节 (IPN)，然后进行有效的筛查 相对于胸部X光检查，治疗可降低20%的死亡率，但假阳性率较高。 >95% 的发现限制了早期诊断的未满足的临床需求是缺乏无创性。 该测试可应用于 CT 检测到肺结节的个体，并可靠地区分 恶性或良性结节的液体活检侧重于肿瘤相关遗传的表征。 无细胞循环肿瘤 DNA 的改变可以非侵入性地描绘实体瘤的分子景观。 然而，ctDNA 的生物浓度低、体细胞突变频率低以及混杂因素 克隆造血相关变异对早期肺癌的影响限制了基于 ctDNA 的敏感性 如果可以包含额外的无细胞 DNA 生物标志物以允许进行液体活检，那将是至关重要的。 开发用于肺癌早期评估的更灵敏的分子诊断方法。 我们发现了一个独特的超短单链无细胞 DNA (uscf/ctDNA) 群体，其 我们的初步数据显示，健康和非小细胞肺癌血浆中的片段组特征为 40-70nt。 包括 uscfDNA 分子的功能元件概况、片段化模式和末端基序，可以 该 R21 应用程序旨在探索和检验我们的假设： uscfDNA分子的片段组学特征可以作为区分NSCLC患者的新型生物标志物 来自具有 IPN 的非癌症受试者，并允许更灵敏的液体活检分子诊断进行早期诊断 NSCLC 检测有两个具体目标：目标 1 是开发预测模型。 使用 uscfDNA-seq 分析进行 NSCLC 液体活检的 uscfDNA 片段组分析 目标 2 是预验证。 uscfDNA-Seq 测试用于 NSCLC 的早期检测、翻译和预验证、靶向。 用于 NSCLC 早期检测的 uscfDNA 可以开辟新天地，并将先前的发现扩展到具有影响力的领域 新方向和临床应用。