Patterns of Somatic Gene Alterations in Oral Cancer

描述（由申请方提供）：我们提出了一项头颈部鳞状细胞癌（HNSCC）的仅病例研究，目的是确定视网膜母细胞瘤途径中致癌物诱导的基因体细胞失活模式。在美国，每年有超过42，000名男性和女性发生HNSCC，导致每年超过13，000人死亡。近年来，在HNSCC的分子病理学研究中发现了一些重要的关键基因，这些基因在HNSCC的发生中发生了改变。此外，随着这些基因被鉴定，病理学家开始了解它们与疾病的关系，基因组已被鉴定为多个组件的成员，细胞调节的关键途径。事实上，现在已知体细胞失活可以以多种方式发生;基因突变长期以来一直被认为是一种重要的改变类型，但纯合基因丢失和表观遗传沉默最近也被认为是HNSCC中体细胞基因改变的常见和重要机制。大多数分子病理学只认为基因失活的频率是重要的，而不是检查改变的类型和体细胞改变的确切性质的可能后果。我们已经开发了一个新的假设，根据我们的观察，一个强大的，显着的关联，吸烟与PRB途径中的p161 NK 4A基因的失活的精确性质。我们的致癌物作用机制的新工作模型预测了易感个体的特征。从本质上讲，我们假设纯合子缺失事件通常发生在易感个体中，因此定义易感个体。p161 NK 4A的表观遗传失活更常见于吸烟史相对较长的患者，这些患者对烟草致癌物的影响相对“抵抗”。我们建议确认，扩展和进一步发展这个模型的HNSCC的易感性使用的Pl的资源。已经资助的，独立的，病例系列，是从一个基于人群的病例对照研究，目前在其第四年的登记情况。

DESCRIPTION (provided by applicant): We propose a case-only study of Head and Neck Squamous Cell Cancer (HNSCC) with the goal of defining the carcinogen-induced patterns of somatic inactivation of genes in the Retinoblastoma pathway. HNSCC occurs in over 42,000 men and women annually in the United States, resulting in over 13,000 deaths per year. Recent developments in the molecular pathology of this disease have delineated the important critical genes that are altered in the genesis of HNSCC. Further, as these genes have been identified and pathologists have begun to understand their relationship with disease, groups of genes have become identified as members of multiple components, critical pathways in cellular regulation. Indeed, it is now known that somatic cell inactivation can occur in multiple ways; gene mutation has long been realized as a critical type of alteration, but homozygous gene loss and epigenetic silencing have also recently been recognized as common and important mechanisms of somatic gene alteration in HNSCC. Most molecular pathology has considered only frequency of gene inactivation as important, rather than examining the type of alteration and the possible consequences of the precise nature of somatic alteration. We have developed a novel hypothesis based upon our observation of a strong, significant association of smoking with the precise nature of inactivation of the p161NK4A gene in the PRB pathway. Our new working model for the mechanism of action of carcinogens predicts the characteristics of susceptible individuals. In essence, we hypothesize that homozygous deletion events commonly occur in, and therefore define, susceptible individuals. Epigenetic inactivation of p161NK4A is more often found in patients with relatively longer smoking histories and these patients then are relatively "resistant" to the effects of tobacco carcinogens. We propose to confirm, extend and further develop this model of HNSCC susceptibility using the resources of the Pl.'s already funded, independent, case series that is derived from a population-based case control study currently in its fourth year of enrolling cases.