Molecular Biology of Lung Cancer among Puerto Ricans

波多黎各人肺癌的分子生物学

• 批准号: 8728618
• 负责人: Doug Cress
• 金额: $ 20.57万
• 依托单位: H. LEE MOFFITT CANCER CTR & RES INST
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8728618
• 关键词: Address; Adenocarcinoma; Adherens Junction; Adhesions; Adhesives; Affect; African American; American; Automobile Driving; Biology; CDKN1C gene; CDKN2A gene; Cadherins; Cancer Center; Cancer Patient; Cell Adhesion; Cell Communication; Cell Cycle; Cell membrane; Cells; Clinic; DNA; Data; Data Set; Databases; Epidermal Growth Factor Receptor; Etiology; Gene Expression; Gene Expression Profiling; Gene Rearrangement; Genes; Genetic Transcription; Genetic screening method; Human; Individual; Integrins; KRAS2 gene; Link; Lung Adenocarcinoma; Malignant Neoplasms; Malignant neoplasm of lung; Measures; Messenger RNA; Methylation; Molecular; Molecular Biology; Molecular Profiling; Monitor; Mutate; Mutation; Non-Small-Cell Lung Carcinoma; Nuclear; Outcome; Pathway interactions; Patients; Pattern; Play; Population; Positioning Attribute; Property; Proteins; Puerto Rican; RB1 gene; Recommendation; Regulation; Retinoblastoma; Role; Sampling; Structure; TP53 gene; Testing; Tissues; Tumor Suppressor Genes; Tumor Suppressor Proteins; Tumor-Derived; Woman; Work; base; functional status; interest; mRNA Expression; medical schools; men; novel; promoter; repository; research study; rho GTP-Binding Proteins

Differences in the mutations underiying 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 {EGFF^ mutations in Latin American populations is significantiy higher than V\/hites 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 KRAS, 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 importantiy, 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 {RBI) 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 predominantiy 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 (directiy 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 KFiAS, TP53, EFGR, RB1, 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 patients for microarray-based gene expression analysis. We will use clustering approaches to draw correlations between the mutation patterns (observed in Aim 1) with expression profileis (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 celi 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 Rac 1.

个体癌症的突变差异可能会极大地影响最佳效果 治疗选择”，而且越来越明显的是，不同种族人群在以下方面存在显着差异： 突变导致肺癌^' ^ 肺癌是波多黎各 (PR) 男性的主要癌症杀手。 公关女性的第二杀手*'^ 尽管如此，人们对其分子机制知之甚少。 例如，最近的研究表明，表皮生长因子的比例是导致肺癌的因素。 拉丁美洲人群中的受体 {EGFF^ 突变显着高于 V\/hites 和非洲人群 美国人^。这个信息很重要，因为 EGFR 突变是临床上的目标^'^¿ ^.本申请 提议建立约 100 名 PR 肺癌患者的肺癌分子数据库。 本文将具体阐述 PR 肺癌患者具有不同模式的假设 实验将发现美国大陆白人中最常见的基因突变。 如果这一假设得到验证，则可以评估 KRAS、TP53、EGFR、BFiAF、CDKN1C 和 RBI 的变化。 极大地影响 PR 肺癌患者的基因检测和治疗建议，因为许多 这些突变可以在临床上进行靶向治疗。也许最重要的是，这些努力将产生重大影响。 数据和组织存储库，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（RBI）途径在肺癌中的作用，这是第一个。 肿瘤抑制基因有待发现，但其作为肿瘤抑制因子的效力仅部分保留 在令人兴奋的新实验中，我们发现了 pRb（RB1 的蛋白质产物）的作用。 基因）在细胞间相互作用的调节中这是一个新颖的角色，因为 pRb 主要被称为 a 发现 pRb 是调节钙粘蛋白表达所必需的，钙粘蛋白是 参与细胞粘附的粘附连接结构的组成部分。 由于 pRb 损失导致细胞粘附连接破坏和粘附性能受损。 比较 Rb+/+ 和 Rb-/- 细胞的表达微阵列表明，pRb 影响广泛的转录 细胞粘附相关基因库，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与肺的总体存活率密切相关 腺癌 (AC) 这表明细胞粘附相关基因表达异常，可能是由于 pRb 所致。 失活（直接或由于 CDKN2A 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，第一个目标是创建分子数据库。 对应于 -100 PR NSCLC（非小细胞肺癌）患者，使用肿瘤来源的 DNA。 将识别 NSCLC 中常见突变基因（包括 KFiAS、TP53、 EFGR、RB1、B-RAF 和 ALK 融合；此外，我们将通过以下方式监测 RBI 途径的放松管制。 第二个目标将利用测量 CDKN2A 启动子甲基化和 CDKN2A 基因重排。 我们将使用来自相同-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。 聚类方法绘制突变模式（在目标 1 中观察到的）与表达之间的相关性 profileis（在目标 2 中观察到）。我们发现 CDKN2A/RB1 通路的遗传改变可能是 发现与 Rb 调节的细胞粘附基因的失调有很好的相关性。最后，第三个目标是。 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。 具体来说，该目标侧重于 pRb 促进的分子机制的表征 我们将在目标 3 中测试的假设是 pRb 撞击细胞。 通过以某种方式调节细胞膜上粘附连接的组装和稳定来实现粘附 涉及小型 Rho GTPase Rac 1。