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

侵袭性宫颈癌（ICC）是世界范围内最常见的癌症死亡原因，虽然在大多数发达国家的患病率有所下降，但这种疾病继续不成比例地影响美国的某些人群。特别是，阿巴拉契亚妇女的ICC发病率和死亡率是美国最高的。虽然已知许多危险因素会影响ICC的发展，但对遗传和遗传易感性因素的作用知之甚少。转化生长因子（TGF-B）通过与细胞表面的受体复合物结合，是多种细胞功能（包括细胞增殖）的普遍关键调节剂。癌细胞经常通过信号通路关键组分（包括配体和受体复合物）的体细胞失活来避免TGF-B对细胞增殖的抑制作用。此外，配体和受体的种系多态性与癌症的发展和癌症易感性的增加有关。在这项建议中，我们假设，在阿巴拉契亚女性中观察到的ICC发生率高于非阿巴拉契亚女性，部分原因是由于TGF-B配体和受体复合物的遗传和体细胞改变，这种改变可能与各种环境、行为和社会经济风险因素进一步增强。具体来说，我们将确定与健康的阿巴拉契亚女性相比，阿巴拉契亚ICC患者的一大队列中遗传多态性和体细胞获得性关键TGF-B通路组分变异的患病率。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（人类乳头瘤病毒，爱普斯坦-巴尔病毒），行为（吸烟）和社会（压力，社会网络）风险因素共同导致阿巴拉契亚妇女对ICC的易感性增加

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.