Molecular Biology of Lung Cancer among Puerto Ricans

波多黎各人肺癌的分子生物学

• 批准号: 8464957
• 负责人: Doug Cress
• 金额: $ 11.12万
• 依托单位: H. LEE MOFFITT CANCER CTR & RES INST
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-24 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8464957
• 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 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.

导致个体癌症的突变差异可以极大地影响最好的 治疗选择”，而且越来越清楚的是，不同种族的人群在以下方面存在显著差异： 突变导致他们的肺癌。肺癌是波多黎各（PR）男性的主要癌症杀手 也是公关界女性的第二杀手尽管如此，关于分子机制知之甚少， 在公关中引发肺癌。例如，最近的研究表明，表皮生长因子 在拉丁美洲人群中，EGFF受体突变显著高于维族人和非洲人。 美国人^.该信息很重要，因为EGFR突变在临床中是可靶向的。本申请 建议建立一个肺癌分子数据库约100 PR肺癌患者。描述的工作 本文将具体阐述PR肺癌患者具有不同的肺转移模式的假设。 美国本土白色人群中最常见的基因突变。实验将 评估KRAS、TP 53、EGFR、BF 1AF、CDKN 1C和RBI的改变。如果这一假设得到证实， 显著影响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靶向治疗。也许最重要的是，这些努力将创造一个重大的 数据和组织库，将有利于未来的研究，对主要癌症杀手的公关男子。 该提案还将探索视网膜母细胞瘤（RBI）通路在肺癌中的作用。RBI是第一个 肿瘤抑制基因尚未被发现，但其作为肿瘤抑制基因的效力仅部分保留 解释道在令人兴奋的新实验中，我们发现了pRb（RB 1的蛋白质产物）的作用， 基因）在调节细胞与细胞的相互作用？这是一个新的作用，因为pRb主要被称为 细胞周期调节因子研究发现pRb是钙粘蛋白调节表达所需的，钙粘蛋白是 参与细胞粘附的粘附连接结构的组分。钙粘蛋白异常表达 由于pRb丢失导致细胞粘附连接破坏和粘附特性受损。 比较Rb+/+和Rb-/-细胞的表达微阵列显示，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。 对实验上可获得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中的总存活率强烈相关 腺癌（AC）。这表明异常的细胞粘附相关基因表达，可能是由于pRb CDKN 2A的失活（直接或作为CDKN 2A沉默的结果）可能与AC的分子病因学有关。 这项申请有三个具体目标。第一个目标是建立一个分子数据库 对应于约100个PR NSCLC（非小细胞肺癌）患者，使用肿瘤来源的DNA。一是 将鉴定NSCLC中常见突变基因中存在的突变（包括KF 1AS，TP 53， EFGR、RB 1、B-RAF和ALK融合体;此外，我们将通过以下方式监测RBI途径的放松管制： 测量CDKN 2A启动子甲基化和CDKN 2A基因重排。第二个目标是利用 来自相同~ 100名患者的肿瘤来源的mRNA用于基于微阵列的基因表达分析。我们将使用 聚类方法，以绘制突变模式（在目标1中观察到）与表达之间的相关性 profileis（在目标2中观察到）。我们推测，CDKN 2A/RB 1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密切相关。最后，第三个目标将 重点是pRb如何在细胞和分子水平上影响细胞与细胞粘附的基础生物学。 具体来说，这一目标是集中在表征的分子机制，pRb促进 细胞从其核位置粘附。我们将在目的3中检验的假设是pRb撞击细胞， 通过调节细胞膜上粘附连接的组装和稳定， 这涉及到小的Rho GTdom Rac 1。