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：个体癌症突变的差异可以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的头号癌症杀手，也是波多黎各女性的第二号癌症杀手。尽管如此，对于 PR 中导致肺癌的分子机制仍知之甚少。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 突变在临床上是可靶向的。本申请拟建立约 100 名 PR 肺癌患者的肺癌分子数据库。本文描述的工作将具体解决这样的假设：PR 肺癌患者具有不同的基因突变模式，这些基因在美国大陆白人群体中最常见。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，这将有利于未来对公关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。 RBI 是第一个被发现的肿瘤抑制基因，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）在调节细胞间相互作用^中的作用^。这是一个新的角色，因为 pRb 主要被认为是细胞周期调节剂。研究发现 pRb 是钙粘蛋白调节表达所必需的，钙粘蛋白是参与细胞粘附的粘附连接结构的组成部分。 pRb 丢失导致钙粘蛋白表达异常，导致细胞粘附连接破坏和粘附特性受损。比较 Rb+/+ 和 Rb-/- 细胞的表达微阵列表明，pRb 影响多种细胞粘附相关基因的转录，包括各种整合素和钙粘蛋白。重要的是，对公开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 (AC) 的总体生存期密切相关。这表明异常的细胞粘附相关基因表达可能是由于 pRb 失活（直接或 CDKN2A 沉默的结果）所致，可能与 AC 的分子病因学有关。该应用程序具有三个具体目标。第一个目标将侧重于使用肿瘤来源的 DNA 创建一个与约 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 中常见突变基因中存在的突变（包括 KRAS、TP53、EFGR、RBI、B-RAF- 和 ALK 融合^。此外，我们将通过测量 CDKN2A 启动子甲基化和 CDKN2A 基因重排来监测 RBI 通路的失调。第二个目标将利用来自相同约 100 名患者的肿瘤来源的 mRNA 基于微阵列的基因表达分析。我们将使用聚类方法来绘制突变模式（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 调节的细胞粘附基因的失调密切相关。最后，第三个目标将侧重于基本| pRb 如何影响的生物学 细胞和分子水平上的细胞间粘附。具体来说，该目标集中于 pRb 从其核位置促进细胞粘附的分子机制的表征。我们将在目标 3 中测试的假设是，pRb 通过以涉及小型 Rho GTPase Rae 1 的方式调节细胞膜上粘附连接的组装和稳定来影响细胞粘附。