Patterns of Somatic Gene Alterations in Oral Cancer

描述（由申请人提供）：在美国，今年将诊断出近40，000例头颈部鳞状细胞癌（HNSCC）的新病例，大约11，000例死亡将由这种疾病引起。饮酒和吸烟协同作用导致这种疾病，尽管暴露于人乳头状瘤病毒（HPV）现在也与HNSCC风险有关。除了与暴露和生活方式因素相关的风险外，HNSCC的易感性还与关键基因的多态性变异有关，这些基因对许多与致癌相关的细胞过程很重要。然而，总体而言，负责诱导引起HNSCC的细胞变化的机制仍然不完全清楚，需要新的方法来进一步推进我们的知识。在后基因组时代，表观遗传调控已成为控制基因表达的重要模式。DNA CpG岛甲基化是一种特异性的表观遗传标记，可以导致基因的失活，并具有可遗传性和稳定性。最近的研究表明，致癌暴露存在系统性差异，可诱导癌细胞发生不同类型的改变。目前的建议是基于一个新的范式，即暴露的变化与癌细胞表观基因组体细胞改变的可预测差异有关。我们相信，研究这种模式可能会产生人类癌症易感性的强大标志物。具体而言，我们假设有不同的HNSCC亚组，其特征在于可以广泛分组为显示遗传改变或表观遗传改变的主要表型。此外，我们的数据表明，环境，生活方式和病毒（HPV）因素显着驱动这些表型。我们将应用分子流行病学的方法来检验这一假设，利用现有的，以人群为基础的病例对照研究HNSCC的资源。该项目的目的是研究母研究中从志愿者中收集的所有癌症，并确定肿瘤亚组，其中（1）体细胞遗传缺失事件占主导地位或（2）体细胞DNA甲基化沉默（表观遗传事件）占主导地位。我们将研究关键DNA区域甲基化和缺失的差异如何与吸烟暴露、饮酒和饮食缺陷在驱动口腔癌发生中相关。我们将进一步使用途径方法来询问是否存在与这些体细胞事件相互作用的正常遗传多态性，使个体对任何特定类型的癌症相关体细胞变化易感。所有这些都将使用经过验证的高通量方法来完成。使用这种新的方法，这些数据将有助于确定与酒精，吸烟和饮食不足的致癌活动的易感性相关的致癌机制。公共卫生相关性：本研究课题“口腔癌的体细胞基因变异模式”将研究头颈癌的主要危险因素与导致这些肿瘤的主要基因失活模式之间的关系。我们相信，基因变化的潜在模式可以预测疾病的结果，并导致对这种癌症的新理解，提高我们预防和治疗这种疾病的能力。

DESCRIPTION (provided by applicant): In the United States this year, almost 40,000 new cases of head and neck squamous cell carcinoma (HNSCC) will be diagnosed, and approximately 11,000 deaths will result from this disease. Alcohol use and tobacco smoking act synergistically in causing this disease, although exposure to the human papilloma virus (HPV) is now also linked to HNSCC risk. In addition to risks related to exposures and lifestyle factors, susceptibility for HNSCC has been linked to polymorphic variation in key genes important to a number of cellular processes related to carcinogenesis. However, overall, the mechanism responsible for induction of the cellular changes that give rise to HNSCC remains incompletely understood and novel approaches are needed to further advance our knowledge. In the post-genomic era, epigenetic regulation has emerged as critical mode by which the expression of genes can be controlled. DNA CpG island methylation, a specific and well studied epigenetic mark, can lead to inactivation of a gene in a heritable and stable fashion. Recent work has suggested that there are systematic differences in the carcinogenic exposures that induce distinct classes of alterations in cancer cells. The current proposal is based upon a new paradigm stating that variation in exposure is associated with predictable differences in somatic alteration to the cancer cell epigenome. We believe that investigating this paradigm may yield powerful markers of susceptibility for human cancer. Specifically, we hypothesize that there are distinct subgroups of HNSCCs characterized by a predominant phenotype that can be broadly grouped as displaying genetic alterations or epigenetic alterations. Further, our data suggest that environmental, lifestyle and viral (HPV) factors significantly drive these phenotypes. We will apply molecular epidemiologic methods to examine this hypothesis, utilizing the resources of an existing, population-based case control study of HNSCC. The aims of this project are to study all of the cancers collected from volunteers in the parent study and to identify subgroups of tumors where (1) somatic genetic deletion events predominate or (2) somatic DNA methylation silencing (epigenetic events) predominates. We will examine how differences in methylation and deletion of critical DNA regions associate with smoking exposure, alcohol use and dietary deficiencies in driving oral carcinogenesis. We will further use a pathway approach to ask if there are normal genetic polymorphisms that interact with these somatic events, predisposing individuals to susceptibility to either particular type of cancer associated somatic change. All of this will be completed using validated, high- throughput methodologies. Using this novel approach, this data will aid in identifying the carcinogenic mechanisms associated with susceptibility to the carcinogenic activities of alcohol, smoking, and dietary deficiencies. PUBLIC HEALTH RELEVANCE: This project "Patterns of Somatic Gene Alterations in Oral Cancer" will investigate the relationship of the major risk factors for Head and Neck cancers with the pattern of inactivation of the major genes responsible for causing these tumors. We believe that the underlying patterns of gene changes may predict disease outcome and lead to new understanding of this cancer, enhancing our ability to both prevent and treat the disease.