BRM promoter polymorphism, a marker for cancer risks

描述(由申请人提供)： 确定癌症风险背后的基因改变对于癌症筛查和化学预防战略至关重要，这些战略可以成功地减少癌症死亡人数的增加。肺癌尤其如此，它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基因的缺失可能是导致癌症风险的一个重要因素。BRM是染色质重塑复合体SWI/SNF的一个重要亚基，参与细胞的发育、分化和生长控制。该复合体是多种转录因子和关键细胞蛋白所必需的。由于SWI/SNF复合体的去除而导致BRM的丢失，将破坏一些重要的抗肿瘤蛋白的功能，如Rb、P53和BRCA1。在小鼠中，BRM的缺失在体外产生了细胞周期控制异常的细胞，而在体内，BRM的缺失显著增强了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，而且在各种实体肿瘤类型中也是沉默的。此外，在缺乏BRM表达的细胞中，我们发现BRM基因在表观遗传上是沉默的，可以使用已知的抑制组蛋白脱乙酰酶蛋白的小分子抑制剂来恢复。鉴于在动物模型中BRM的缺失可以拮抗抗肿瘤的发生途径并促进肿瘤的发展，BRM表达的缺失可能与肿瘤的发生有关。值得注意的是，我们发现在癌细胞系中，BRM表达的丧失与BRM启动子中存在两个多态的6-7BP插入特别相关。这些多态位点与转录因子MEF2的结合位点高度相似；因此，这些BRM启动子的多态位点的存在可能不仅与BRM的缺失有关，而且在癌症发生过程中直接关闭BRM基因。由于这些多态位点的纯合存在与BRM沉默相关，我们假设这些多态位点增加了BRM沉默的风险，因此可能是预测癌症风险的重要标志。这项应用的目的是通过确定在原发性肺癌中这些多态位点的存在是否确实与BRM表达的缺失相关，以及这种缺失是否也涉及杂合性缺失，来验证我们的初步发现。。此外，为了进一步验证这一假说，这项研究的目标是确定这些多态位点是否与癌症风险的增加有关。建立这样的标记对于抗击癌症是必要的，但对肺癌尤其重要，因为还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肺癌的早期阶段进行检测。

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.