Early detection of lung cancer in veterans

描述（由申请人提供）： 非小细胞肺癌（NSCLC）是美国退伍军人的头号癌症杀手。吸烟是退伍军人中NSCLC的主要原因。同时，吸烟也是慢性阻塞性肺疾病（COPD）的主要原因，COPD是退伍军人常见的良性疾病。此外，患有COPD的退伍军人患NSCLC的可能性是健康人的4-6倍。考虑到晚期NSCLC的预后不良，在重度吸烟者和COPD退伍军人中早期发现NSCLC将降低NSCLC的死亡率。然而，目前的诊断技术要么是侵入性的，要么准确性差。在这里，我们建议开发基于肿瘤的非编码RNA（ncRNA）生物标志物，可以联合收割机与基因组探针用于退伍军人中重度吸烟者和COPD患者的NSCLC早期检测。在此之前，我们改进了痰液诱导方案，建立了富集技术，可以有效地收集深呼吸道上皮细胞用于痰液的分子分析。我们还开发了基于肺癌的基因组探针，与痰液细胞学相比，它可以以更高的灵敏度诊断NSCLC。然而，探针的灵敏度对于临床应用来说还不够高。NcRNA，特别是miRNA，正在成为癌症诊断中的潜在生物标志物。我们最近证明，ncRNA是稳定存在于痰液中，并在肺癌的诊断有潜在的用途。此外，我们鉴定了一组ncRNA特征，包括21种miRNA和5种小核仁RNA（snoRNA），其表达改变与早期非小细胞肺癌相关。由于肺癌是一种异质性疾病，并且从复杂的多步骤过程发展而来，因此使用多种类型的生物标志物而不是仅一类生物标志物应该具有以可接受的准确度诊断肺癌的潜力。因此，我们假设，用开发的基因组探针分析痰液中的ncRNA将为退伍军人NSCLC的早期检测提供一种准确和非侵入性的方法。三个目标是：1，从鉴定的ncRNA特征，优化一组用于早期NSCLC的高度特异性和敏感性的痰生物标志物，2，确定在我们现有的痰标本中使用ncRNA生物标志物与基因组探针用于NSCLC早期检测，3，在独立队列中验证用于NSCLC早期检测的组合策略。完成后，这项工作将为进一步验证生物标志物诊断价值的临床试验奠定坚实的基础。可以在早期阶段识别NSCLC的生物标志物的使用将为恶性肿瘤的有效治疗提供最佳机会，因此将为被诊断患有肺癌的退伍军人提供最好的医疗保健。 公共卫生相关性： 非小细胞肺癌（NSCLC）是美国退伍军人的头号癌症杀手。重度吸烟的退伍军人比非吸烟者患NSCLC的可能性高出75%。此外，患有慢性阻塞性肺疾病（COPD）的退伍军人患肺癌的可能性是健康人的4-6倍。鉴于晚期NSCLC预后不良，早期发现重度吸烟者和COPD退伍军人的癌症将降低NSCLC的死亡率。然而，目前的诊断技术要么是侵入性的，要么准确性低。在这里，我们建议开发痰生物标志物，可用于非侵入性识别肺癌早期从重度吸烟者和COPD患者的退伍军人。生物标志物在临床环境中的未来应用将通过显着降低死亡率为患有肺癌的退伍军人提供最好的医疗保健。

DESCRIPTION (provided by applicant): Non-small cell lung cancer (NSCLC) is the number one cancer killer of U.S. Veterans. Tobacco smoking is the major cause of NSCLC among Veterans. Meanwhile, tobacco smoking is also the primary cause of chronic obstructive pulmonary disease (COPD) that is a common benign disease in Veterans. Furthermore, Veterans with COPD are 4-6 times more likely to develop NSCLC than healthy individuals. Given the poor prognosis associated with advanced stage NSCLC, early detection of NSCLC in Veterans who are heavy smokers and have COPD will reduce the mortality from NSCLC. However, the current diagnostic techniques are either invasive or have poor accuracy. Here we propose to develop sputum-based non-coding RNA (ncRNA) biomarkers that can combine with the genomic probes for NSCLC early detection in heavy smokers and COPD patients among Veterans. Previously, we modified sputum induction protocol and established enrichment technique that can efficiently collect deep respiratory epithelial cells for molecular analysis of sputum. We also developed sputum-based genomic probes that can diagnose NSCLC with higher sensitivity compared with sputum cytology. However, the sensitivity of the probes is not high enough for clinical application. NcRNAs, particularly miRNAs, are emerging as potential biomarkers in cancer diagnosis. We recently demonstrated that ncRNAs are stably present in sputum and are potentially useful in diagnosis of lung cancer. Furthermore, we identified a set of ncRNA signatures including 21 miRNAs and five small nucleolar RNAs (snoRNAs) whose altered expressions are associated with early stage NSCLC. Because lung cancer is a heterogeneous disease and develops from a complex and multistep processes, the use of multiple types of biomarkers rather than only one class of biomarkers should have the potential to diagnose lung cancer with acceptable accuracy. Therefore, we hypothesize that analyzing the ncRNAs with the developed genomic probes in sputum will provide an accurate and noninvasive approach for early detection of NSCLC in Veterans. Three Aims are: 1, from the identified ncRNA signatures, optimizing a panel of highly specific and sensitive sputum biomarkers for early stage NSCLC, 2, determining the use of ncRNA biomarkers with genomic probes for NSCLC early detection in our existing sputum specimens, 3, validating the combined strategy for NSCLC early detection in an independent cohort. Upon completion, the work will lay a solid foundation for a clinical trial that will further validate the diagnostic value of the biomarkers. The use of the biomarkers that can identify NSCLC at its early stage will offer the best opportunity for effective treatments of the malignancy, and therefore will provide the best health care for Veterans diagnosed with lung cancer. PUBLIC HEALTH RELEVANCE: Non-small-cell lung cancer (NSCLC) is the number one cancer killer for U.S. Veterans. Veterans who are heavy smokers are up to 75 percent more likely to develop NSCLC than non-smokers. Furthermore, Veterans with chronic obstructive pulmonary disease (COPD) are 4-6 times more likely to develop lung cancer than healthy individuals. Given the poor prognosis associated with advanced stage NSCLC, early detection of the cancer in Veterans who are heavy smokers and have COPD will reduce the mortality from NSCLC. However, the current diagnostic techniques are either invasive or have low accuracy. Here we propose to develop sputum biomarkers that can be used for noninvasively identifying NSCLC earlier from heavy smokers and COPD patients among Veterans. Future application of the biomarkers in clinical settings will provide the best health care for Veterans with lung cancer by dramatically reducing the mortality.