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。吸烟是退伍军人非小细胞肺癌的主要原因。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的退伍军人患非小细胞肺癌的可能性是健康人的4-6倍。鉴于晚期非小细胞肺癌预后较差，在重度吸烟者和慢性阻塞性肺疾病的退伍军人中及早发现非小细胞肺癌将降低非小细胞肺癌的死亡率。然而，目前的诊断技术要么是侵入性的，要么是准确性差的。在这里，我们建议开发基于痰的非编码RNA(NcRNA)生物标记物，该生物标记物可以与基因组探针相结合，用于早期检测重度吸烟者和退伍军人中的COPD患者的NSCLC。在此之前，我们对诱导痰方法进行了改进，建立了一种能够高效采集深部呼吸道上皮细胞进行痰分子分析的浓缩技术。我们还开发了以痰为基础的基因组探针，与痰细胞学相比，它可以更敏感地诊断NSCLC。然而，这些探针的灵敏度还不够高，不适合临床应用。NcRNAs，特别是miRNAs，正在成为癌症诊断的潜在生物标志物。我们最近证明，ncRNAs稳定存在于痰中，并有可能用于肺癌的诊断。此外，我们还鉴定了一组ncRNA特征，包括21个miRNAs和5个小核仁RNAs(SnoRNAs)，它们的表达变化与早期NSCLC有关。由于肺癌是一种异质性疾病，其发展是一个复杂和多步骤的过程，使用多种类型的生物标记物而不是只使用一类生物标记物应该有可能以可接受的准确性诊断肺癌。因此，我们推测，利用已开发的基因组探针分析痰中的ncRNAs将为退伍军人早期发现非小细胞肺癌提供一种准确和非侵入性的方法。三个目标是：1，从已识别的ncRNA签名中，优化一组用于早期NSCLC的高度特异和敏感的痰生物标记物；2，确定ncRNA生物标记物与基因组探针在我们现有的痰标本中用于NSCLC早期检测的使用；3，在独立队列中验证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的诊断价值的临床试验奠定坚实的基础。早期识别非小细胞肺癌的生物标志物的使用将为恶性肿瘤的有效治疗提供最好的机会，因此将为被诊断为肺癌的退伍军人提供最好的保健。 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。烟瘾大的退伍军人患非小细胞肺癌的可能性比不吸烟的人高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。鉴于晚期非小细胞肺癌的预后较差，对重度吸烟者和患有COPD的退伍军人及早发现癌症将降低非小细胞肺癌的死亡率。然而，目前的诊断技术要么是侵入性的，要么是准确性低的。在这里，我们建议开发痰生物标志物，可以用于从退伍军人中的重度吸烟者和慢性阻塞性肺病患者中早期无创性地识别非小细胞肺癌。未来生物标志物在临床环境中的应用将大大降低死亡率，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.