Molecular Characterization of Stage I Lung Cancer

I 期肺癌的分子特征

• 批准号: 7466801
• 负责人: MING YOU
• 金额: $ 34.05万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-17 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7466801
• 关键词: Adjuvant; Adjuvant Chemotherapy; Adjuvant Therapy; Adverse effects; Apoptosis; BCL-2 Protein; BCL2 gene; BCL2-Interacting Killer; BIK gene; Biological Markers; CASP10 gene; CASP8 gene; Cancer Etiology; Cancer Patient; Cancer and Leukemia Group B; Cessation of life; Clinical; Curative Surgery; Custom; Data; Data Analyses; Data Set; Diagnostic; Excision; Facility Construction Funding Category; Freezing; Future; Gene Expression Profile; Genes; Goals; Histopathology; Human; IL8RB gene; INHA gene; International; Malignant neoplasm of lung; Messenger RNA; Meta-Analysis; Microarray Analysis; Molecular; NID gene; Neoplasm Metastasis; Non-Small-Cell Lung Carcinoma; Operative Surgical Procedures; Outcome; Paraffin Embedding; Pathologist; Patients; Population; Proteins; RNA; Recurrence; Recurrent disease; Relapse; Resected; Resources; Risk; Sampling; Series; Son; Staging; Subgroup; Testing; Tissue Microarray; Tissues; Tumor Tissue; United States; Validation; collaborative trial; design; improved; presenilin-1; tumor; validation studies

DESCRIPTION (provided by applicant): Lung cancer is the leading cause of cancer related deaths in the United States. Despite undergoing curative surgery, a majority of patients with resected (Stage I -III) non-small cell lung cancer (NSCLC) will die from recurrent disease within five years. Adjuvant chemotherapy in an unselected group of patients with resected stage l-lll produces only modest improvement in survival. It is critical to develop molecular predictors for recurrence. In a recent study, we applied a meta-analysis of data sets from seven different microarray studies on lung cancer for differentially expressed genes related to survival and identified a gene expression signature consisting of 64 genes that is highly predictive of recurrence. The central hypothesis is that this 64-gene signature can accurately predict survival of patients with stage I NSCLC. Two aims are proposed to test this hypothesis. In Aim 1, we will validate the 64-gene signature using a custom-designed array in 300 stage I NSCLC cases from the Cancer and Leukemia Group B (CALGB) lung cancer study 140202. The goal is to develop a diagnostic gene signature that can guide the treatment options for these patients. In Aim 2, we will validate the 64-gene signature using the Tissue Microarray (TMA) approach. We will determine whether the 64-gene signature of mRNA changes can be confirmed on the protein level using existing lung cancer TMA, and we will evaluate a subset of the 64-gene signature in a new TMA created from tumor tissues from the CALGB 140202 study. Using the newly identified 64-gene signature and the unique patient populations already developed by the CALGB lung cancer study (140202), the proposed studies will help clinicians in selecting the most effective treatment options for stage I lung cancer. Lung cancer is the leading cause of cancer related death in the United States. Nearly 50% of patients with stage I and II NSCLC will die from recurrent disease despite surgical resection. Adjuvant chemotherapy improves survival in patients with resected stage I-III NSCLC. There are no reliable clinical or molecular predictors for identifying those at high risk for developing recurrent disease. If developed, this high risk subgroup could be selected for adjuvant therapy. Future studies on adjuvant therapy would then focus on this high risk group. Conversely, the low risk group can be spared the side effects of adjuvant therapy. In a recent study, we applied a meta-analysis of data sets from seven different microarray studies on lung cancer for differentially expressed genes related to survival (less than 2 years and greater than 5 years) (Lu et al. 2006). We identified a 64 gene - molecular marker set that is highly predictive of which stage I lung cancer patients may benefit from more aggressive therapy. Our study has shown that the 64-gene molecular marker set clearly demonstrated that the high and low-risk groups are significantly different in their overall survival. The objective of this proposal is to systematically validate the 64-gene molecular marker set to predicting survival of patients with stage I NSCLC. One major resource for our proposal is direct and full access to more than 300 well- characterized human stage I lung cancer tissues from CALGB study 140202 with relevant clinical information. The central hypothesis is that the 64-gene molecular marker set can accurately predict survival of patients with stage I NSCLC. This proposal is organized into two specific aims. Aim 1 will conduct a validation study of the 64-gene molecular marker set using a custom-designed array in more than 300 stage I NSCLC from the CALGB lung cancer study (140202). Frozen samples from eligible patients will be used for RNA extraction and microarray analysis. All paraffin-embedded tumor samples from the same patients in the validation series will be examined by a pathologist to verify histopathology. Microarray analysis will be performed using a custom-designed array with the 64 genes in triplicate. Aim 2 will validate the 64-gene molecular marker set using Tissue Microarrays (TMAs). We will determine whether mRNA changes of the 64-gene molecular marker set genes can be confirmed on the protein level using multiple independent sets of lung cancer with a TMA approach. At least two independent sets of lung cancer including CALGAB 140202, and archival samples with clinical outcome data from RPCI will be used for TMA construction. We believe that the 64-gene molecular marker set are validated, adjuvant therapy could be selectively administered to those patients at high risk for relapse.

描述（由申请人提供）：肺癌是美国癌症相关死亡的主要原因。尽管接受了治愈性手术，大多数切除（I-III期）非小细胞肺癌（NSCLC）患者仍将在五年内死于复发性疾病。在未经选择的 l-III 期切除患者组中进行辅助化疗仅对生存产生适度的改善。开发复发的分子预测因子至关重要。在最近的一项研究中，我们对七个不同的肺癌微阵列研究的数据集进行了荟萃分析，以寻找与生存相关的差异表达基因，并确定了由 64 个基因组成的基因表达特征，该特征可以高度预测复发。中心假设是这个 64 基因特征可以准确预测 I 期 NSCLC 患者的生存率。提出了两个目标来检验这一假设。在目标 1 中，我们将使用定制设计的阵列在来自癌症和白血病 B 组 (CALGB) 肺癌研究 140202 的 300 例 I 期 NSCLC 病例中验证 64 个基因特征。目标是开发一种诊断基因特征，可以指导这些患者的治疗选择。在目标 2 中，我们将使用组织微阵列 (TMA) 方法验证 64 基因特征。我们将确定是否可以使用现有的肺癌 TMA 在蛋白质水平上确认 mRNA 变化的 64 基因特征，并且我们将评估从 CALGB 140202 研究的肿瘤组织创建的新 TMA 中的 64 基因特征的子集。利用新确定的 64 基因特征和 CALGB 肺癌研究 (140202) 已经开发的独特患者群体，拟议的研究将帮助临床医生为 I 期肺癌选择最有效的治疗方案。肺癌是美国癌症相关死亡的主要原因。尽管进行了手术切除，仍有近 50% 的 I 期和 II 期 NSCLC 患者将死于复发性疾病。辅助化疗可提高已切除的 I-III 期 NSCLC 患者的生存率。没有可靠的临床或分子预测因子来识别那些患有复发性疾病的高风险人群。如果开发出来，可以选择这个高风险亚组进行辅助治疗。未来的辅助治疗研究将集中于这一高危人群。相反，低风险组可以免受辅助治疗的副作用。在最近的一项研究中，我们对七项不同的肺癌微阵列研究的数据集进行了荟萃分析，以寻找与生存（小于 2 年和大于 5 年）相关的差异表达基因（Lu et al. 2006）。我们确定了 64 个基因 - 分子标记集，可以高度预测哪些 I 期肺癌患者可能受益于更积极的治疗。我们的研究表明，64个基因分子标记集清楚地表明高风险组和低风险组的总体生存率存在显着差异。该提案的目的是系统地验证 64 个基因分子标记集，以预测 I 期 NSCLC 患者的生存情况。我们提案的一个主要资源是直接、全面地访问来自 CALGB 研究 140202 的 300 多个特征明确的人类 I 期肺癌组织以及相关临床信息。中心假设是 64 个基因分子标记集可以准确预测 I 期 NSCLC 患者的生存率。该提案分为两个具体目标。 Aim 1 将使用定制设计的阵列对来自 CALGB 肺癌研究 (140202) 的 300 多个 I 期 NSCLC 进行 64 基因分子标记集的验证研究。来自符合条件的患者的冷冻样本将用于 RNA 提取和微阵列分析。验证系列中来自同一患者的所有石蜡包埋肿瘤样本将由病理学家检查以验证组织病理学。将使用定制设计的阵列进行微阵列分析，其中 64 个基因一式三份。目标 2 将使用组织微阵列 (TMA) 验证 64 个基因分子标记集。我们将通过 TMA 方法使用多个独立的肺癌组来确定是否可以在蛋白质水平上确认 64 个基因分子标记组基因的 mRNA 变化。至少两组独立的肺癌（包括 CALGAB 140202）和来自 RPCI 的具有临床结果数据的档案样本将用于 TMA 构建。我们相信，64个基因分子标记集经过验证，可以选择性地对那些复发高风险的患者进行辅助治疗。