Peripheral Blood Gene Expression for the Diagnosis of Indeterminate Lung Nodules

描述（由申请人提供）：非小细胞肺癌（NSCLC）是西方国家恶性疾病导致过早死亡的最常见原因。早期发现后进行手术仍然是最有效的治疗方法。对于内科医生、外科医生和肺科医生来说，在胸部x线或CT扫描中发现病因不明的肺结节的诊断是一个非常常见和重要的临床问题。通过减少不必要的手术、活检、正电子发射断层扫描（PET）和/或重复的CT扫描，能够更准确地确定肺结节患者恶性疾病风险的血液检查将是非常有价值的，并且具有非常重要的经济意义。我们先前假设可以在肺癌患者的外周血中确定诊断性基因表达谱。为了支持这一假设，我们最近发表的一项研究表明，与高危吸烟者和戒烟者组成的适当对照组相比，血液基因表达谱的差异可以准确地识别非小细胞肺癌患者。使用从137名NSCLC受试者和91名对照中采集的外周血单个核细胞（PBMC），我们确定了一个29个基因的标记，其总体识别准确率为86%。非小细胞肺癌组受影响的特异性免疫功能通路包括t细胞受体信号传导和凋亡、巨噬细胞和单核细胞吞噬的改变。该提案的目标是将这些初步研究扩展到Paxgene血液采集系统，该系统提供更大的mRNA稳定性和更容易用于常规临床应用的平台。我们将专注于利用Paxgene系统开发外周血基因表达标记（目标1），以及评估外周血基因表达与多种新型血清生物标志物的结合（目标2）。如果成功，这些检测可以整合到不确定肺结节患者的诊断算法中，并用于防止不必要的手术和重复的CT扫描。如果具有足够的敏感性和特异性，则有可能将该测试扩展到筛查其他高危人群（接触石棉的吸烟者、重度吸烟者等）。

DESCRIPTION (provided by applicant): Non-small cell lung cancer (NSCLC) is the most common cause of premature death from malignant disease in western countries. Early detection followed by surgery remains the most effective treatment. The diagnosis of patients who have lung nodules of unknown etiology identified on screening chest X-rays or computerized axial tomography (CT) scans, is a very common and important clinical problem for internists, surgeons, and pulmonologists. A blood test that could more accurately determine the risk of malignant disease in patients with lung nodules would be extremely valuable and have very important economic implications by reducing unnecessary surgery, biopsies, Positron Emission Tomography (PET) scans, and/or repeated CT scans. We previously hypothesized that a diagnostic gene expression profile can be identified in the peripheral blood of lung cancer patients. In support of this hypothesis, we recently published a study showing that differences in blood gene expression profiles can be identified that accurately identify patients with NSCLC when compared to the appropriate control group of high-risk smokers and ex-smokers. Using peripheral blood mononuclear cells (PBMC) harvested from 137 NSCLC subjects and 91 controls, we identified a 29-gene signature that provides an overall discrimination accuracy of 86%. Specific immune function pathways that were affected in the NSCLC group included alterations in T-cell receptor signaling and apoptosis, and macrophage and monocyte phagocytosis. The goal of this proposal is to expand these preliminary studies to the Paxgene blood collection system, which provides greater mRNA stability and a platform more easily adopted for routine clinical use. We will focus our work on developing a peripheral blood gene expression signature from peripheral blood with the Paxgene system (Aim 1) and on evaluating the combination of peripheral blood gene expression with multiple novel serum biomarkers (Aim 2). If successful, these assays could be integrated into a diagnostic algorithm for patients with indeterminate lung nodules and used to prevent needless surgery and repetitive CT scans. If sufficiently sensitive and specific, it is possible that this test could be extended to screening of other high-risk populations (smokers with asbestos exposure, heavy smokers, etc). PUBLIC HEALTH RELEVANCE: Lung nodules of unknown etiology are discovered frequently on chest x-rays or CT scans but only a small fraction of these lung nodules are found to be lung cancers. Currently, the only way to differentiate benign from malignant nodules is an invasive biopsy, surgery, or prolonged observation with repeated scanning. Given these facts, the development of a blood test that could more accurately determine the risk of malignant disease in patients with lung nodules would be extremely valuable and have very important economic implications by reducing unnecessary surgery, biopsies, Positron Emission Tomography (PET) imaging, and/or repeated CT scans.