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.

项目摘要/摘要 在美国和全球，肺癌仍然是与癌症有关的主要原因。非小细胞 肺癌（NSCLC）约占所有肺癌的85％。早期发现不确定 具有胸部低剂量计算机断层扫描（LDCT）筛查的肺结节（IPN），然后有效 相对于胸部射线照相，治疗可以将死亡率降低20％。但是，高误报率 查找AS> 95％限制了该应用程序。早期诊断的未满足的临床需求是缺乏无创的 可以应用于具有CT检测肺结节的个体的测试，并可靠地区分 恶性或良性结节。液体活检着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介绍实体瘤的分子景观。 但是，ctDNA的生物学浓度低，体细胞突变的低频和混杂 克隆造血相关变体在早期肺癌中的影响限制了基于CTDNA的敏感性 液体活检测定法。如果可以包括其他无细胞生物标志物以允许 开发更灵敏的分子诊断方法，用于早期评估肺癌。 我们发现了具有不同的超短链单链单链的无细胞DNA（USCF/ctDNA）的种群 健康和NSCLC等离子体的40-70NT尺寸。我们的初步数据表明，片段特征， 包括功能元素轮廓，碎裂模式和USCFDNA分子的结束基序，可以 将NSCLC患者与健康捐助者区分开。此R21应用程序是探索和检验我们的假设 USCFDNA分子的片段特征可以用作区分NSCLC患者的新型生物标志物 来自具有IPN的非癌症受试者，并允许早期更敏感的液体活检分子诊断。 NSCLC检测。假设检验有两个具体的目标。目标1是开发一个预测模型 使用USCFDNA-SEQ分析进行NSCLC的液体活检进行USCFDNA片段分析。目标2是预验证 USCFDNA-SEQ测试NSCLC的早期检测。共同的翻译和预验证，定位 USCFDNA早期检测NSCLC可以破坏新的地面，并将以前的发现扩展到有影响力的 新的方向和临床应用。