Profiling genome-wide circulating ncRNAs for the early detection of lung cancer

分析全基因组循环 ncRNA 以早期检测肺癌

• 批准号: 10242187
• 负责人: Youping Deng
• 金额: $ 76.85万
• 依托单位: UNIVERSITY OF HAWAII AT MANOA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10242187
• 关键词: Adenocarcinoma; Advisory Committees; Age; Anxiety; Benign; Biological Markers; Blood; Blood specimen; Cancer Detection; Chest; Clinic; Clinical; Complement; Data; Development; Diagnosis; Diagnostic tests; Disease; Early Diagnosis; Expression Profiling; Gender; Genetic Transcription; Granuloma; Hamartoma; Hawaii; Health; Human; Human body; Individual; Inflammatory; International; Lesion; Lung; Lung Neoplasms; Lung nodule; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of lung; Measures; Methods; MicroRNAs; Monitor; Neoadjuvant Therapy; Non-Malignant; Non-Neoplastic Lung Disorder; Patients; Phenotype; Plasma; Play; Positioning Attribute; Predictive Value of Tests; Public Health; Publications; Publishing; Quantitative Reverse Transcriptase PCR; RNA marker; Race; Reporting; Reverse Transcription; Role; Sample Size; Sampling; Series; Serum; Small Nucleolar RNA; Small RNA; Smoking Status; Squamous cell carcinoma; Technology; Testing; Thoracic Radiography; Time; Transfer RNA; Untranslated RNA; Work; X-Ray Computed Tomography; base; blood-based biomarker; circulating microRNA; classification algorithm; cohort; companion diagnostics; computed tomography screening; cost; cost effective; diagnostic accuracy; differential expression; disease diagnosis; early detection biomarkers; genome-wide; high risk; improved; low dose computed tomography; lung cancer screening; molecular marker; mortality; next generation; novel; novel marker; patient response; prospective; screening; screening program; tool; transcriptome sequencing; whole genome

PROJECT SUMMARY The 5-year survival for patients with lung cancer remains dismal at approximately 15%. It has been estimated that early diagnosis of lung cancer can provide a 60-80% survival benefit. The National Lung Screening Trial (NLST) demonstrated a 20% relative reduction in lung cancer mortality with the use of annual low-dose computed tomography (LDCT) screening compared to annual chest x-ray. The difference in lung cancers identified was due to the identification of more early-stage lung cancers, as there was no difference in the number of stage IIB-IV cancers between groups. The authors concluded that LDCT screening reduced lung cancer mortality in appropriately selected high-risk patients. Unfortunately, nearly 40% of patients in the NLST had a positive screen at one point, with 96.4% of these being false positives. Accordingly, the International Association for the Study of Lung Cancer (IASLC) and the Strategic CT Screening Advisory Committee (SSAC) published a position statement calling for the increased use of blood-based biomarkers to augment the diagnostic accuracy of LDCT screening, so it is urgently necessary to develop new non-invasive methods, such as identifying blood molecular biomarkers, for early detection of lung cancer. Our immediate objective for this proposal is to identify circulating non-coding RNA (ncRNA) markers for the early detection of lung cancer using prospectively collected human blood samples. Very few studies have compared the expression profiles of circulating miRNA between benign lesions and lung cancer. Therefore, it is important to validate existing miRNA studies and identify potential novel circulating miRNA markers for early detection of lung cancer. In addition, recent studies have shown that other types of small ncRNAs such as small nucleolar RNAs (snoRNAs) and transfer RNAs (tRNAs) play important roles in cancer development and progression. However, there are no reports which use other types of circulating small ncRNAs as markers for lung cancer early detection. We hypothesize that circulating ncRNA could be used as biomarkers for early detection of lung cancer. Based on next generation small RNA sequencing, we have identified circulating plasma ncRNAs that are significantly differentiated in expression between non-malignant and lung cancer biospecimens. Moreover, although a series of publications have reported the potential circulating miRNA markers for early detection of lung cancer, they are quite inconsistent. In order to increase our sequencing power, evaluate our previous finding and other published biomarkers for early detection of lung cancer. Using prospectively collected plasma samples, in the proposed study, we would like to reach the following aims: 1. Measure the types and levels of ncRNA expression in human plasma from non-malignant and lung cancer biospecimens. 2. Evaluate ncRNA markers that vary reproducibly between non-malignant samples and lung cancer samples based on the real- time PCR platform. 3. Validate and test the predictive value of the ncRNA markers using independent samples.

项目概要 肺癌患者的 5 年生存率仍然很低，约为 15%。它一直 据估计，肺癌的早期诊断可以提供 60-80% 的生存获益。国家肺 筛查试验 (NLST) 表明，使用每年一次的筛查可使肺癌死亡率相对降低 20% 低剂量计算机断层扫描 (LDCT) 筛查与年度胸部 X 光检查相比。肺的区别 发现的癌症是由于发现了更多的早期肺癌，因为在肺癌中没有差异 组间 IIB-IV 期癌症的数量。作者得出结论，LDCT 筛查减少了肺 适当选择的高风险患者的癌症死亡率。不幸的是，近 40% 的 NLST 患者 曾一度筛查呈阳性，其中 96.4% 为误报。据此，国际 肺癌研究协会 (IASLC) 和战略 CT 筛查咨询委员会 (SSAC) 发表了一份立场声明，呼吁增加基于血液的生物标志物的使用，以增强 LDCT筛查的诊断准确性，因此迫切需要开发新的非侵入性方法， 例如识别血液分子生物标志物，以早期发现肺癌。 我们此提案的直接目标是确定循环非编码 RNA (ncRNA) 标记 使用前瞻性收集的人类血液样本早期检测肺癌。很少有研究表明 比较良性病变和肺癌之间循环 miRNA 的表达谱。因此，它 对于验证现有的 miRNA 研究并识别早期潜在的新型循环 miRNA 标记物非常重要 肺癌的检测。此外，最近的研究表明其他类型的小 ncRNA，例如 小核仁 RNA (snoRNA) 和转移 RNA (tRNA) 在癌症发生和发展中发挥重要作用 进展。然而，目前还没有使用其他类型的循环小 ncRNA 作为标记物的报道。 肺癌早期发现。 我们假设循环 ncRNA 可用作肺癌早期检测的生物标志物。 基于下一代小 RNA 测序，我们已经鉴定出循环血浆 ncRNA 非恶性和肺癌生物样本之间的表达存在显着差异。而且， 尽管一系列出版物报道了用于早期检测的潜在循环 miRNA 标记 肺癌，它们非常不一致。为了提高我们的测序能力，评估我们之前的 发现和其他已发表的用于早期检测肺癌的生物标志物。使用前瞻性收集的血浆 样本，在拟议的研究中，我们希望达到以下目标： 1. 测量 来自非恶性和肺癌生物样本的人血浆中的 ncRNA 表达。 2. 评估 ncRNA 基于实际情况，非恶性样本和肺癌样本之间可重复变化的标记物 时间PCR平台。 3. 使用独立样本验证和测试 ncRNA 标记的预测价值。