Development of circulating biomarker for lung cancer

项目摘要 肺癌是美国和世界范围内癌症死亡的最常见原因。有限的 有效的治疗、早期发现和手术切除仍然是治疗的首选。可惜 在确诊时仅有15%的肺癌患者具有可切除的局限性病灶。进展 低剂量计算机断层扫描（CT）筛查现在可以早期检测到肺结节，并且已经 生存率提高20%，但低剂量CT不能区分少量恶性结节和恶性结节。 大多数是良性的。因此，一个简单的，非侵入性的测试，可以准确地区分恶性 从良性结节中分离仍然是一个重要的临床目标。为了鉴定NSCLC的候选生物标志物，我们 分析来自患有以下疾病的患者的全血的外周血单核细胞（PBMC）级分的RNA： 非小细胞肺癌（NSCLC）和对照，使用无偏正向遗传筛查方法。我们 将AKAP 4鉴定为NSCLC存在的高度准确的血液生物标志物。接收器下的区域 工作特征曲线（AUC）为0.9714（敏感性和特异性分别为92.80%和92.59%， 当来自264名NSCLC患者的血液样本与135名对照进行比较时， 仅对136例I期NSCLC病例的分析将AUC提高至0.9790， 患者样本与来自27名具有高风险但经组织学证实的良性肺结节患者的样本进行比较 AUC为0.9845，表明AKAP 4在血液中的表达可能是一种极好的早期肿瘤生物标志物。 肺癌分期和良恶性结节鉴别。为了验证AKAP 4的准确性， 在更大的队列中作为NSCLC的血液生物标志物，为临床应用的进一步开发奠定了基础， 我们提出了以下具体目标：具体目标1：作为血液生物标志物的MAPKAP 4， 检测早期非小细胞肺癌;检测AKAP 4作为复发的标志物。A. AKAP4 将在来自500例1期和2期NSCLC和500例无疾病NSCLC的PBMC样品中测定表达。 吸烟者和戒烟者，以评估其检测早期NSCLC的准确性。B。扩大初步 研究中，将在来自374名NSCLC患者的PBMC样品中测定AKAP 4表达， 血液和CT数据，以确定其在评估缓解和预测复发方面的实用性和准确性。 特异性目的2：将AKAP 4作为恶性肺结节的标志物，并确定 AKAP 4表达的细胞来源。A.将在来自500名受试者的PBMC样品中测定AKAP 4表达。 NSCLC患者和500例良性肺结节患者，以评估AKAP 4表达是否可以 鉴别肺结节的良恶性。B。确定AKAP 4表达的细胞来源。 我们将确定AKAP 4在12种类型的人血细胞中的表达，因为AKAP 4可能来源于 循环肿瘤细胞或免疫细胞。

Project Summary Lung cancer is the most common cause of cancer mortality in the US and worldwide. With limited effective treatments, early detection and surgical resection remain the treatment of choice. Unfortunately, at the time of diagnosis only 15% of patients with lung cancer have localized resectable disease. Advances in low-dose computed tomography (CT) screening now allow lung nodules to be detected early, and have increased survival by 20%, but low dose CT cannot distinguish the small number of malignant nodules from the majority of benign ones. Therefore a simple, non-invasive test that can accurately distinguish the malignant from benign nodules remains an important clinical goal. To identify candidate biomarkers for NSCLC, , we analyzed RNA from the peripheral blood mononuclear cell (PBMC) fraction of whole blood from patients with non-small cell lung cancer (NSCLC) and controls, using unbiased forward genetic screening approaches. We identified AKAP4 as a highly accurate blood biomarker for the presence of NSCLC. The area under receiver operating characteristics curve (AUC) is 0.9714 (sensitivity and specificity are 92.80% and 92.59%, respectively) when blood samples from 264 NSCLC patients were compared with 135 controls A separate analysis of only the 136 Stage I NSCLC cases improved the AUC to 0.9790, and a comparison of NSCLC patient samples to samples from 27 patients with high risk but histologically confirmed benign lung nodules gave an AUC of 0.9845, showing that AKAP4 expression in blood may be an excellent biomarker for early stage lung cancer and differentiation of malignant from benign nodules. To validate the accuracy of AKAP4 as a blood biomarker for NSCLC in a larger cohort, laying the groundwork for further development for clinical use, we propose the following specific aims: Specific Aim 1: Validate AKAP4 as a blood biomarker for the detection of early stage non-small cell lung cancer; test AKAP4 as a marker of recurrence. A. AKAP4 expression will be determined in PBMC samples from 500 Stage 1 and 2 NSCLC and 500 disease-free smokers and ex-smokers to assess its accuracy in detecting early stage NSCLC. B. Expanding on preliminary studies, AKAP4 expression will be assayed in PBMC samples from 374 NSCLC patients with longitudinal blood and CT data to determine its utility and accuracy in assessing remission and predicting recurrence. Specific Aim 2: Validate AKAP4 as a marker for malignant pulmonary nodules and determine the cellular source of AKAP4 expression. A. AKAP4 expression will be determined in PBMC samples from 500 NSCLC patients and 500 patients with benign lung nodules to assess whether AKAP4 expression can distinguish malignant from benign pulmonary nodules. B. Determine the cellular source of AKAP4 expression. We will determine the AKAP4 expression in 12 types of human blood cells, as AKAP4 may derive from circulating tumor cells or from immune cells.