BRM promoter polymorphism, a marker for cancer risks

BRM启动子多态性，癌症风险的标志

• 批准号: 7532235
• 负责人: DAVID N REISMAN
• 金额: $ 7.73万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-15 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7532235
• 关键词: Accounting; Affect; Animal Model; BRCA1 gene; Binding Sites; Biological Response Modifiers; Breast; Cancer cell line; Carcinogens; Cell Cycle Regulation; Cell Line; Cells; Cessation of life; Chemoprevention; Chromatin Remodeling Factor; Clinical; Colon; Complex; DNA; Development; Differentiation and Growth; Disease Progression; Epigenetic Process; Event; Gene Expression; Gene Silencing; Genes; Genetic Polymorphism; Genus Cola; Goals; Growth; Histone Deacetylase; Histone Deacetylase Inhibitor; Human; In Vitro; Incidence; Investigation; Link; Logistic Regressions; Loss of Heterozygosity; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of prostate; Microsatellite Repeats; Modeling; Molecular; Mus; Mutation; Numbers; Pathway interactions; Patients; Play; Polynucleotides; Primary Neoplasm; Promoter Regions; Proteins; Recruitment Activity; Research; Risk; Risk Factors; Role; Screening for cancer; Screening procedure; Signal Transduction Pathway; Site; Solid Neoplasm; Staging; TP53 gene; Testing; Tumorigenicity; base; brahma; cancer cell; cancer risk; genetic risk factor; in vivo; inhibitor/antagonist; laser capture microdissection; promoter; therapeutic target; transcription factor; tumor; tumor progression; tumorigenesis

DESCRIPTION (provided by applicant): Identifying genetic alterations underlying cancer risk is essential for cancer screening and chemoprevention strategies that can successfully reduce the growing incidence of cancer deaths. This is particularly true with lung cancer, which causes more cancer deaths than breast, colon and prostate cancer combined, and accounts for more than 162,000 deaths annually. To this end, we have found that the loss of the BRM gene may be an important factor underlying cancer risk. BRM is an essential subunit of the chromatin remodeling complex SWI/SNF, which is involved in cell development, differentiation, and growth control. This complex is required by a variety of transcription factors and key cellular proteins. The loss of BRM by abrogation of the SWI/SNF complex will disrupt the function of a number of important antitumorigenic proteins, such as Rb, p53 and BRCA1. In mice, loss of BRM yields cells that display abnormalities in cell cycle control in vitro, while in vivo, loss of BRM significantly potentiates carcinogen-induced tumorigenicity. In humans, we have found that BRM is silenced not only in cancer cell lines but also in a variety of solid tumor types. Moreover, in cells lacking BRM expression, we have found that the BRM gene is epigenetically silenced and can be restored using small molecular inhibitors known to inhibit histone deacetylase proteins. Given that BRM loss can antagonize antitumorigenic pathways and potentiate tumor development in animal models, the loss of BRM expression is likely involved cancer development. Significantly, we found in cancer cell lines that the loss of BRM expression specifically correlates with the presence of two polymorphic 6-7bp insertions within the BRM promoter. These polymorphic sites are highly similar to binding sites of the transcription factor MEF2; thus, the presence of these BRM-promoter polymorphic sites might not only correlate with the loss of BRM but also play a direct role in turning off the BRM gene during cancer development. As the homozygous presence of these polymorphic sites correlates with BRM silencing, we hypothesize that these polymorphic sites increase the risk of BRM silencing and as a consequence may be important markers for predicting cancer risk. The goal of this application is to validate our initial findings by determining in primary lung cancers whether the presence of these polymorphic sites indeed correlates with loss of BRM expression and whether this loss also involves loss of heterozygosity. . In addition, to further test this hypothesis, the goal of this study to determine if these polymorphic sites are associated with increase cancer risk. The establishment of such markers is needed to combat cancer but especially important in lung cancer, as no genetic risk factors have been identified for lung cancer and there is no effective screening test to detect it in its early stages.

描述（由申请人提供）： 识别潜在癌症风险的遗传改变对于癌症筛查和化学预防策略至关重要，这些策略可以成功降低癌症死亡率的增长。肺癌尤其如此，肺癌导致的癌症死亡人数超过乳腺癌、结肠癌和前列腺癌的总和，每年死亡人数超过16.2万人。为此，我们发现BRM基因的丢失可能是癌症风险的一个重要因素。BRM是染色质重塑复合物SWI/SNF的重要亚基，其参与细胞发育、分化和生长控制。该复合物是多种转录因子和关键细胞蛋白质所必需的。通过消除SWI/SNF复合物而导致的BRM的丧失将破坏许多重要的抗肿瘤发生蛋白如Rb、p53和BRCA 1的功能。在小鼠中，BRM的损失产生在体外细胞周期控制中显示异常的细胞，而在体内，BRM的损失显著增强致癌物诱导的致瘤性。在人类中，我们发现BRM不仅在癌细胞系中沉默，而且在各种实体瘤类型中也沉默。此外，在缺乏BRM表达的细胞中，我们发现BRM基因在表观遗传学上是沉默的，并且可以使用已知抑制组蛋白脱乙酰酶蛋白的小分子抑制剂来恢复。鉴于BRM缺失可以拮抗抗肿瘤发生途径并增强动物模型中的肿瘤发展，BRM表达的缺失可能涉及癌症发展。值得注意的是，我们在癌细胞系中发现，BRM表达的丧失与BRM启动子内两个多态性6- 7 bp插入的存在特别相关。这些多态性位点与转录因子MEF 2的结合位点高度相似;因此，这些BRM启动子多态性位点的存在可能不仅与BRM的丢失相关，而且在癌症发展期间关闭BRM基因中发挥直接作用。由于这些多态性位点的纯合存在与BRM沉默相关，我们假设这些多态性位点增加了BRM沉默的风险，因此可能是预测癌症风险的重要标志物。本申请的目的是通过确定原发性肺癌中这些多态性位点的存在是否确实与BRM表达的丢失相关以及这种丢失是否也涉及杂合性丢失来验证我们的初步发现。.此外，为了进一步验证这一假设，本研究的目的是确定这些多态性位点是否与癌症风险增加相关。建立这样的标记物是对抗癌症所必需的，但在肺癌中尤其重要，因为没有发现肺癌的遗传风险因素，也没有有效的筛查测试来在早期阶段检测它。