Molecular Biology of Lung Cancer among Puerto Ricans

波多黎各人肺癌的分子生物学

• 批准号: 8464841
• 负责人: Warren Jackson Pledger
• 金额: $ 19.04万
• 依托单位: PONCE SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-25 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8464841
• 关键词: Address; Adenocarcinoma; Adherens Junction; Adhesives; Affect; African American; American; Automobile Driving; Biology; Brassicaceae; CDKN1C gene; CDKN2A gene; Cadherins; Cancer Center; Cancer Etiology; Cancer Patient; Cell Adhesion; Cell Communication; Cell Cycle; Cell membrane; Cells; Clinic; DNA; Data; Data Set; Databases; Epidermal Growth Factor Receptor; Etiology; Event; Gene Expression; Gene Rearrangement; Genes; Genetic Transcription; Genetic screening method; Individual; Integrins; KRAS2 gene; Lung Adenocarcinoma; Malignant Neoplasms; Malignant neoplasm of lung; Measures; Messenger RNA; Methylation; Minority; Molecular; Molecular Biology; Molecular Profiling; Monitor; Mutate; Mutation; Non-Small-Cell Lung Carcinoma; Nuclear; Pathway interactions; Pattern; Pilot Projects; Population; Positioning Attribute; Property; Proteins; Puerto Rican; RB1 gene; Recommendation; Regulation; Retinoblastoma; Role; Structure; Supporting Cell; TP53 gene; Testing; Tissues; Tumor Suppressor Genes; Tumor Suppressor Proteins; Tumor-Derived; Woman; Work; abstracting; base; interest; medical schools; men; novel; promoter; repository; research study; rho GTP-Binding Proteins

Abstract: Differences in the mutations underlying an individual's cancer can dramatically affect the best treatment choice and it is becoming clear that different ethnic populations differ significantly in which mutations drive their lung cancers. Lung cancer is the leading cancer killer among Puerto Rican (PR) men and second killer among PR women. Despite this fact, little is known regarding the molecular mechanisms driving lung cancer among PRs. For example, recent work has shown that the rate of epidermal growth factor receptor (EGFR) mutations in Latin American populations is significantly higher than Whites and African Americans^. This information is important as EGFR mutations are targetable in the clinic. This application proposes to establish a lung cancer molecular database on ~100 PR lung cancer patients. The work described herein will specifically address the hypothesis that PR lung cancer patients have a different pattern of mutations in genes that are most commonly mutated in the White, mainland US population. Experiments will assess alterations in KFiAS, TP53, EGFR, BFiAF, CDKN1C and RBI. If this hypothesis is verified, it could dramatically affect genetic testing and treatment recommendations for PR lung cancer patients since many of these mutations can be targeted clinically¿. Perhaps most importantly, these efforts will create a significant data and tissue repository that will benefit future research on the leading cancer killer of PR men. This proposal will also probe the role of the retinoblastoma {RB1) pathway in lung cancer. RBI was the first tumor suppressor gene to be discovered, and yet its potency as a tumor suppressor remains only partially explained. In exciting new experiments, we have uncovered a role for pRb (the protein product of the RB1 gene) in the regulation of cell-to-cell interactions^. This is a novel role since pRb is predominantly known as a cell-cycle regulator. pRb is found to be required for the regulated expression of cadherins, which are components of the adherens junction structures involved in cellular adhesion. Abnormal cadherin expression due to pRb loss resulted in cells with disrupted adherens junctions and impaired adhesive properties. Expression microarrays comparing Rb+/+ and Rb-/- cells show that pRb impacts the transcription of a wide repertoire of cell adhesion-related genes, including various integrins and cadherins. Importantly, the examination of publically available gene expression datasets demonstrates that the expression levels of a subset of these pRb-regulated cell adhesion genes strongly correlates with overall survival in lung adenocarcinoma (AC). This suggests that aberrant cell adhesion-related gene expression, possibly due to pRb inactivation (directly or as a result of CDKN2A silencing), could be related to the molecular etiology of AC. This application has three specific aims. The first aim will focus on creating a molecular database corresponding to ~100 PR NSCLC (non-small-cell lung cancer) patients using tumor-derived DNA. First, we will identify the mutations present in genes commonly mutated genes in NSCLC (including KRAS, TP53, EFGR, RBI, B-RAF- and ALK fusions^. In addition, we will monitor deregulation of the RBI pathway by measuring CDKN2A promoter methylation and CDKN2A gene rearrangements. The second aim will utilize tumor-derived mRNA from the same ~100 patieints for microarray-based gene expression analysis. We will use clustering approaches to draw correlations between the mutation patterns (observed in Aim 1) with expression profiles (observed in Aim 2). We hypothesize that genetic alterations of the CDKN2A/RB1 pathway may be found to correlate well with the deregulation of Rb-regulated cell adhesion genes. Finally, the third aim will focus on the basic | biology of how pRb affects cell-to-cell adhesion at the cellular and molecular levels. Specifically, this aim is focused on the characterization of the molecular mechanisms by which pRb promotes cell adhesion from its nuclear position. The hypothesis that we will test in Aim 3 is that pRb impinges on cell adhesion by regulating the assembly and stabilization of adherens junctions at the cell membrane in a manner that involves the small Rho GTPase Rae 1.

摘要：个人癌症潜在突变的差异会极大地影响最佳治疗选择，而且越来越明显的是，不同种族人群在导致肺癌的突变方面存在显着差异。肺癌是波多黎各男性癌症的头号杀手，也是公关女性的第二大杀手。尽管如此，对PR中肺癌的分子机制知之甚少。例如，最近的研究表明，拉丁美洲人群的表皮生长因子受体(EGFR)突变率显著高于白人和非裔美国人。这一信息很重要，因为EGFR突变在临床上是有针对性的。本申请建议建立约100例PR肺癌患者的肺癌分子数据库。这里描述的工作将具体解决这样一个假设，即PR肺癌患者的基因突变模式不同，而这些基因突变在美国大陆的白人人群中最常见。实验将评估KFiAS、TP53、EGFR、BFiAF、CDKN1C和RBI的变化。如果这一假设得到证实，它可能会极大地影响PR肺癌患者的基因测试和治疗建议，因为这些突变中的许多都可以在临床上进行靶向。也许最重要的是，这些努力将创建一个重要的数据和组织存储库，这将有助于未来对公关男性头号癌症杀手的研究。该提案还将探讨视网膜母细胞瘤(RB1)通路在肺癌中的作用。RBI是第一个被发现的肿瘤抑制基因，然而它作为肿瘤抑制基因的效力仍然只有部分解释。在令人兴奋的新实验中，我们发现了pRb(RB1基因的蛋白质产物)在调节细胞间相互作用中的作用。这是一个新的角色，因为pRb主要是作为细胞周期调节因子而为人所知。研究发现，pRB是调节钙粘附素表达所必需的，钙粘附素是参与细胞黏附的黏附连接结构的组成部分。由于pRB缺失导致的钙粘附素异常表达导致细胞黏附连接中断和黏附特性受损。比较RB+/+和RB-/-细胞的表达芯片显示，pRB影响广泛的细胞黏附相关基因的转录，包括各种整合素和钙粘附素。重要的是，对公开可用的基因表达数据集的检查表明，这些pRB调节的细胞黏附基因的子集的表达水平与肺腺癌(AC)的总体生存密切相关。这表明细胞黏附相关基因的异常表达可能是由于pRB失活(直接或由于CDKN2A沉默)，可能与AC的分子病因学有关。这个应用程序有三个具体目标。第一个目标将集中在使用肿瘤衍生DNA创建与大约100名PR NSCLC(非小细胞肺癌)患者相对应的分子数据库。首先，我们将确定在NSCLC中常见的突变基因(包括KRAS、TP53、EFGR、RBI、B-RAF-和ALK融合)中存在的突变。此外，我们将通过检测CDKN2A启动子甲基化和CDKN2A基因重排来监测RBI途径的放松调控。第二个目标是利用同样来自约100名患者的肿瘤来源的mRNA进行基于微阵列的基因表达分析。我们将使用聚类方法来得出突变模式(在目标1中观察到)与表达谱(在目标2中观察到)之间的相关性。我们假设CDKN2A/RB1通路的遗传改变可能与RB调节的细胞黏附基因的解除调控有很好的相关性。最后，第三个目标将集中在PRB如何在细胞和分子水平上影响细胞与细胞间黏附的基础生物学上。具体地说，这个目标集中在描述pRB促进细胞从核位置黏附的分子机制。我们将在目标3中测试的假设是，pRB通过调节细胞膜上黏附连接的组装和稳定来影响细胞黏附，这种方式涉及到小的Rho GTP酶RAE 1。