Reducing racial disparities in lung cancer outcomes by decoding neighborhood contextual environment (RECODE)

摘要 本申请旨在研究肺癌种族不平等的一种新的社会表观遗传机制： 通过解码社区背景环境减少肺癌结局的种族差异 （记录）。我们将研究暴露于暴力，炎症反应， 吸烟和蛋白质精氨酸甲基转移酶（PRMT6）的表观遗传变化增加了 患上肺癌我们的初步研究表明，吸烟诱导表达增加， PRMT6在肺上皮中的表达。我们还发现，PRMT6的过度表达触发了自发性肺 小鼠的肿瘤有趣的是，我们发现，与白色人相比，黑人男性的PRMT6表达上调 癌症基因组图谱（TCGA）因此，我们认为，PRMT6的过度表达增加， 可能解释了黑人男性肺癌发病率高于白色男性的原因。而 吸烟是导致肺癌的关键因素，吸烟的频率和数量不是 黑人必然更高，这表明其他因素是造成肺部疾病种族差异的原因。 癌黑人社区不成比例的社会压力可能是导致肺部感染率较高的原因。 黑人的癌症特别是，生活在过度邻里暴力中的个人， 慢性压力，这可能会加剧肺癌的表观遗传变化。我们假设暴露于 邻里暴力是一种社会压力，它增加了生物物理炎症反应， 吸烟，PRMT6过表达和肺癌之间的路径。 为了检验所提出的肺癌差异的社会表观遗传机制，首先，我们将测试 吸烟和暴露于邻里暴力的独立影响，以及两种风险的相互作用， 使用来自黑人和白色肺癌病例的回顾性组织样品的PRMT 6表达（目的2）。 其次，我们将测试暴露于暴力对炎症反应（头发皮质醇）和肺的影响。 通过对高风险黑人男性进行前瞻性调查和数据收集来进行癌症筛查的结果 (Aim 3）。最后，我们将建立一个多层次的，特定背景的肺癌风险概况（目标1），考虑到 不仅要考虑个人行为风险（吸烟），还要考虑邻里压力（接触暴力）， 生理炎症反应（皮质醇增加）和分子变化（PRMT6过表达）。 为了建立这样的风险特征，我们利用复合人群数据方法来建立准确的 人口普查区域内的所有个人，具有社会人口统计学、行为和邻里风险特征。 RECODE的优势在于其创新方法，揭示了肺癌的社会表观遗传机制 差距RECODE有可能改变对肺癌多层次风险的理解， 国家肺癌筛查指南，以反映少数民族社区的社会状况。

ABSTRACT This application proposes to examine a novel social epigenetic mechanism for racial inequality in lung cancer: Reducing racial disparities in lung cancer outcomes by decoding neighborhood contextual environment (RECODE). We will examine the relationships between exposure to violence, inflammatory responses, smoking and epigenetic changes in protein arginine methyl transferases (PRMT6) that increase the risk of developing lung cancer. Our preliminary studies demonstrated that smoking induces increased expression of PRMT6 in the lung epithelium. We also showed that overexpression of PRMT6 triggers spontaneous lung tumors in mice. Interestingly, we found that PRMT6 is upregulated among black men compared with white men in The Cancer Genome Atlas (TCGA). Thus we argue that the increased overexpression of PRMT6 among black men may explain a higher rate of lung cancer among black men compared with white men. While smoking is a key contributing factor for lung cancer, the frequency and amount of cigarette smoking are not necessarily higher for blacks, which suggests that other factors are responsible for racial disparity in lung cancer. Disproportionate social stress in black communities may be responsible for a higher rate of lung cancer among blacks. In particular, individuals living in excessive neighborhood violence are exposed to chronic stress, which may intensify the epigenetic changes for lung cancer. We hypothesize that exposure to neighborhood violence is social stress that increases biophysical inflammatory responses, which exacerbate the path between smoking, PRMT6 overexpression, and lung cancer. To examine the proposed social epigenetic mechanism of lung cancer disparity, first, we will test the independent effect of smoking and exposure to neighborhood violence, and the interaction of the two risks on PRMT6 expression using retrospective tissue samples from black and white lung cancer cases (Aim 2). Second, we will test the effect of exposure to violence on an inflammatory response (hair cortisol) and lung cancer screening outcomes by conducting a prospective survey and data collection with high-risk black men (Aim 3). Finally, we will build a multilevel, context-specific lung cancer risk profiles (Aim 1) that take into account not only individual behavioral risk (smoking), but neighborhood stress (exposure to violence), physiological inflammatory responses (increased cortisol), and molecular changes (PRMT6 overexpression). To develop such risk profiles, we utilize a composite population data approach to establish accurate counts of all individuals within census tracts with sociodemographic, behavioral, and neighborhood risk profiles. The strength of RECODE is its innovative approach to unveil a social epigenetic mechanism of lung cancer disparity. RECODE has the potential to transform understanding multilevel risks of lung cancer and improve the national lung cancer screening guidelines to reflect the social conditions of racial minority communities.