INHERITED AND SOMATIC ALTERATIONS OF THE TGF-B LIGAND AND RECEPTOR COMPLEX IN C..

浸润性宫颈癌(ICC)是全球最常见的癌症死亡原因，虽然在大多数发达国家发病率有所下降，但在美国，这种疾病继续对某些人群造成不成比例的影响。特别是，阿巴拉契亚地区妇女的ICC发病率和死亡率是美国最高的。虽然已知许多危险因素影响ICC的发展，但对遗传和遗传易感因素的作用知之甚少。转化生长因子β是一种通用的关键调节因子，通过与细胞表面的受体复合体结合，调节包括细胞增殖在内的多种细胞功能。癌细胞通常通过体细胞失活信号通路的关键成分，包括配体和受体复合体来避免转化生长因子-β对细胞增殖的抑制影响。此外，配体和受体中的种系多态与癌症的发生和癌症易感性的增加有关。在这项建议中，我们假设阿巴拉契亚妇女比非阿巴拉契亚妇女ICC的发生率增加的部分原因是遗传和躯体改变了转化生长因子-β配体和受体复合体，这种改变可以在各种环境、行为和社会经济风险因素的作用下进一步增强。具体地说，我们将确定与健康的阿巴拉契亚女性相比，大量阿巴拉契亚ICC患者中关键的转化生长因子-B途径成分的遗传多态和躯体获得性变异的流行率。此外，我们将确定这些基因改变是否单独或与其他已知的环境因素(人乳头瘤病毒、爱泼斯坦-巴尔病毒)、行为(吸烟)和社会(压力、社会网络)风险因素一起导致阿巴拉契亚妇女对ICC的易感性增加。 发展。

Invasive cervical cancer (ICC) is the most common cause of cancer death worldwide, and while decreasing in prevalence in the majority of the developed world, this disease continues to disproportionately affect certain populations in the United States (US). In particular, the rate of ICC incidence and mortality in Appalachian women is the highest in the US. While many risk factors are known to influence ICC development, little is known about the role of hereditary and genetic susceptibility factors. The transforming growth factor beta (TGF-B) is a universal critical regulator of various cellular functions, including cell proliferation, via its binding with a receptors complex on the cell surface. Cancer cells frequently avoid the inhibitory influence of TGF-B on cell proliferation via somatic inactivation of key components of the signaling pathway, including the ligand and receptor complex. Additionally, germline polymorphisms in the ligand and receptors have been associated with cancer development and increased cancer susceptibility. In this proposal, we hypothesize that the increased incidence of ICC observed in Appalachian women over their non-Appalachian counterparts is due in part to inherited and somatic alteration of the TGF-B ligand and receptor complex that can be further potentiated in association with various environmental, behavioral, and socioeconomic risk factors. Specifically, we will determine prevalence of inherited polymorphic and somatically acquired variants of key TGF-B pathway components in a large cohort of Appalachian ICC patients compared to healthy Appalachian women. Furthermore, we will determine whether these genetic alterations contribute individually or in combination with other known environmental (Human Papillomavirus, Epstein-Barr Virus), behavioral (smoking), and social (stress, social networks) risk factors, to the increased susceptibility of Appalachian women to ICC development.