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.

个人癌症下的突变的差异会极大地影响最佳 待遇选择”，很明显，不同的种族人口有所不同 突变驱动其肺癌 ^' ^。肺癌是波多黎各人（PR）男性的主要癌症杀手 PR妇女中的第二个杀手*'^。尽管这一事实，关于分子机制知之甚少 在PR中驱动肺癌。例如，最近的工作表明表皮生长因子的速率 拉丁美洲人口中的接收器{egff^突变高于v \/hites和非洲人 美国人^。此信息很重要，因为EGFR突变在诊所^'^€^中是针对性的。此应用程序 提案以约100名PR肺癌患者建立肺癌分子数据库。描述的工作 此处将特别解决以下假设：PR肺癌患者具有不同的模式 在美国白人大陆种群中最常见的基因突变。实验会 评估KRAS，TP53，EGFR，BFIAF，CDKN1C和RBI的变化。如果该假设得到验证，则可以 龙对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靶向。也许最重要的是，这些努力将创造重要的 数据和组织存储库将有利于公关男性领先的癌症杀手的未来研究。 该提案还将探讨视网膜母细胞瘤（RBI）途径在肺癌中的作用。 RBI是第一个 肿瘤抑制基因要被发现，但其作为肿瘤抑制剂的效力仅保持部分 解释了。在令人兴奋的新实验中，我们发现了PRB的作用（RB1的蛋白质产物 基因）在细胞间相互作用的调节中。这是一个新颖的作用 细胞周期调节剂。发现PRB是钙粘蛋白的调节表达所必需的， 粘附结构的组件参与细胞粘附。钙粘蛋白的异常表达 由于PRB损失，导致细胞具有破坏的粘附连接和粘合特性受损的细胞。 比较RB+/+和RB - / - 细胞的表达微阵列表明PRB会影响宽的转录 细胞粘附相关基因的曲目，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，表达水平 这些PRB调节的细胞粘附基因的子集与肺的总生存率密切相关 腺癌（AC）。这表明异常细胞粘附相关的基因表达，可能是由于PRB引起的 灭活（指导或由于CDKN2A沉默的结果）可能与AC的分子病因有关。 该应用程序具有三个具体目标。第一个目的将重点用于创建分子数据库 使用肿瘤衍生的DNA对应于-100 PR NSCLC（非小细胞肺癌）患者。首先，我们 将确定NSCLC中通常突变基因中存在的突变（包括KFIAS，TP53， EFGR，RB1，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。第二个目标将利用 来自相同-100例基于微阵列的基因表达分析的肿瘤衍生的mRNA。我们将使用 聚类方法在突变模式（在AIM 1中观察到）与表达之间的相关性 profileis（在AIM 2中观察到）。我们假设CDKN2A/RB1途径的遗传改变可能是 发现与RB调节的CELI粘合基因的放松管制良好相关。最后，第三个目标将 专注于PRB如何影响细胞对细胞和分子水平的细胞粘附的基本生物学。 具体而言，该目标集中于PRB促进的分子机制的表征 细胞粘合剂的核位置。我们将在AIM 3中测试的假设是PRB会影响细胞 通过以某种方式在细胞膜上粘附和稳定粘附连接的粘附 这涉及小的Rho GTPase RAC 1。