Patterns of Somatic Gene Alterations in Oral Cancer

描述(申请人提供)：我们提出了一项仅针对头颈部鳞状细胞癌(HNSCC)的病例研究，目的是确定致癌物诱导的视网膜母细胞瘤途径中躯体基因失活的模式。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。该疾病分子病理学的最新进展描述了在HNSCC发生过程中发生改变的重要关键基因。此外，随着这些基因被识别出来，病理学家开始了解它们与疾病的关系，一组基因已被确定为多个组成部分的成员，这是细胞调控的关键途径。事实上，现在已经知道体细胞失活可以通过多种方式发生；基因突变长期以来被认为是一种关键的改变类型，但纯合子基因丢失和表观遗传沉默也被认为是HNSCC中体细胞基因改变的常见和重要机制。大多数分子病理学认为只有基因失活的频率是重要的，而不是检查改变的类型和躯体改变的确切性质可能产生的后果。我们基于对吸烟与p161NK4A基因在pRB途径中失活的确切性质的强烈而显著的关联的观察，提出了一个新的假说。我们关于致癌物作用机制的新工作模型预测了易感人群的特征。本质上，我们假设纯合子缺失事件通常发生在易感个体中，因此定义了易感个体。在吸烟史相对较长的患者中，p161NK4A的表观遗传失活更常见，因此这些患者对烟草致癌物的影响具有相对的“抵抗力”。我们建议利用P1的资源来确认、推广和进一步发展这一HNSCC易感性模型。S已经资助了一项独立的病例系列，该系列病例来自一项基于人群的病例对照研究，目前已进入登记病例的第四年。

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.