Molecular Biology of Lung Cancer among Puerto Ricans

波多黎各人肺癌的分子生物学

基本信息

批准号：
8551283
负责人：
Warren Jackson Pledger
金额：
$ 19.17万
依托单位：
PONCE SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-01 至 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8551283
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 Expression Profiling 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

项目摘要

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：个体癌症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，不同种族人群导致肺癌的突变差异显着，肺癌是波多黎各 (PR) 男性的主要癌症杀手。尽管如此，人们对于导致 PR 女性患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) 突变率明显较高。比白人和非洲人美国人^。这一信息很重要，因为 EGFR 突变在临床上是可靶向的。本文描述的工作将具体解决 PR 肺癌患者患有肺癌的假设。美国大陆白人中最常见的基因突变的不同模式将通过实验评估 KFiAS、TP53、EGFR、BFiAF、CDKN1C 和 RBI 的变化。影响 PR 肺癌患者的基因检测和治疗建议，因为其中许多突变可以在临床上进行靶向治疗。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，这将有利于未来对 PR 男性主要癌症杀手的研究。该提案还将探讨视网膜母细胞瘤 (RB1) 通路在肺癌中的作用。肿瘤抑制基因有待发现，但其作为肿瘤抑制基因的效力仍仅得到部分解释。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）在调节肿瘤中的作用。这是一个新的作用，因为 pRb 主要被认为是细胞周期调节剂，是钙粘蛋白的调节表达所必需的，钙粘蛋白是参与细胞粘附的粘附连接结构的组成部分。 pRb 丢失导致细胞粘附连接破坏和粘附特性受损，表达微阵列显示 pRb 影响 Rb+/+ 和 Rb-/- 细胞的转录。广泛的细胞粘附相关基因，包括各种整合素和钙粘蛋白，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 调节的细胞粘附基因的子集的表达水平与肺腺癌的总体存活率相关。 (AC)。这表明细胞粘附相关基因表达异常，可能是由于 pRb 失活（直接或作为 CDKN2A 的结果）所致。沉默），可能与 AC 的分子病因学有关。该应用程序有三个具体目标，第一个目标是使用肿瘤来源的材料创建与约 100 名 PR NSCLC（非小细胞肺癌）患者相对应的分子数据库。首先，我们将鉴定 NSCLC 中常见突变基因（包括 KRAS、TP53、EFGR、RBI、B-RAF- 和 ALK 融合^）中存在的突变。此外，我们将监测基因的放松管制。通过测量 CDKN2A 启动子甲基化和 CDKN2A 基因重排来研究 RBI 通路的第二个目标是利用来自同一约 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。目标 1）和表达谱（目标 2 中观察到）我们发现 CDKN2A/RB1 途径的遗传改变可能与最后，第三个目标将重点关注 pRb 如何在细胞和分子水平上影响细胞间粘附的基础生物学。 pRb 从其核位置促进细胞粘附的机制我们将在目标 3 中测试的假设是，pRb 通过调节细胞膜上粘附连接的组装和稳定来影响细胞粘附。一种涉及小型 Rho GTPase Rae 1 的方式。