Establishing BRM Polymorphisms as Predictive Biomarkers for Lung Cancer Risk

描述（由申请人提供）：虽然毫无疑问吸烟是导致肺癌发生的直接因素，但并非每个吸烟者都会发生肺癌。事实上，只有10 - 15%的吸烟者会患上这种疾病，这表明其他因素使某些人更容易患上癌症。已知许多单核苷酸多态性与肺癌的发生相关，但负责这种关联的潜在基因并不总是清楚的。这些多态性中的任何一种本身的影响也不是非常显著的。事实上，到目前为止，还没有已知的基因与肺癌有令人信服的联系。我们的研究集中在SWI/SNF复合物上，该复合物控制和调节许多具有抗癌功能的蛋白质和信号通路的基因表达。我们已经发现，这种复合物的失活，特别是通过其关键的催化亚基，BRM的损失，促进癌症的发展。BRM表观遗传沉默发生在15 - 20%的大多数实体瘤中。有趣的是，这种基因在表观遗传学上是沉默的，但在细胞系或原发性肿瘤中从未发生突变。沉默的核心 BRM的两个多态性是在启动子区发现的。由于这些多态性似乎控制BRM的沉默，我们推测它们的存在与癌症次要相关。这项研究将使用三个独立的病例对照研究（每个约500名测试受试者），使用不同的地理群体直接测试这些多态性是否确实与肺癌相关。我们将对肺癌患者进行基因分型，并将这些结果与一组没有任何类型癌症病史的匹配受试者进行比较。将使用已建立的TaqMan测定法分析样本，以确定与肺癌相关的基因型和特定BRM多态性。这项研究将是一个重大的进步，不仅因为它可以确定与肺癌特异性相关的第一个基因之一， 还因为这个基因在表观遗传学上是沉默的，没有突变。因此，有可能重新激活BRM并消除这一风险因素。

DESCRIPTION (provided by applicant): While there is no doubt smoking is a direct causative factor underlying the development of lung cancer, not every smoker develops lung cancer. In fact, only 10-15% of smokers develop this disease, indicating that other factors make certain individuals more susceptible to cancer. A number of single nucleotide polymorphisms are known to correlate with the development of lung cancer, but the underlying genes responsible for this association are not always clear. Nor is the impact of any one of these polymorphisms by themselves known to be highly significant. Indeed, as of yet there are no known genes that have been convincingly associated with lung cancer. Our research has focused on the SWI/SNF complex, which controls and regulates gene expression for a number of proteins and signaling pathways that have anticancer functions. We have found that the inactivation of this complex-particularly via loss of its key catalytic subunit, BRM-promotes cancer development. BRM epigenetic silencing occurs in 15-20% of most solid tumors. Intriguingly, this gene is epigenetically silenced but never mutated in cell lines or primary tumors. Central to the silencing of BRM are two polymorphisms found in the promoter region. Because these polymorphisms appear to control the silencing of BRM, we surmise their presence is secondarily associated with cancer. This research will use three independent case-control studies (~500 test subjects each) using different geographic populations to directly test whether these polymorphisms are indeed associated with lung cancer. We will genotype lung cancer patients and compare these results with a matched set of subjects who do not have a history of any type of cancer. Samples will be analyzed using an established TaqMan assay to determine genotypes and the specific BRM polymorphisms associated with lung cancer. This research would be a major advance not only because it could identify one of the first genes specifically associated with lung cancer, but also because this gene is epigenetically silenced and not mutated. Thus, it may be possible to reactivate BRM and eliminate this risk factor.