Epigenomic Markers of HNSCC Survival Across Ethnic Groups

项目摘要 这是Rafael Guerrero-Preston博士为回应资助机会而提交的K01申请 宣布“NCI促进多样性导师研究科学家发展奖(K01)”-PAR-09- 052.拉斐尔在波多黎各土生土长，目前被任命为头颈教练 约翰霍普金斯大学医学院耳鼻喉科癌症研究部。拉斐尔的 短期目标是检查全球的、全基因组的和特定于基因的肿瘤表观基因组改变 非裔美国人和拉丁裔社区不成比例的负担：肝细胞癌、宫颈癌 以及头颈部癌症。格雷罗-普雷斯顿博士的长期目标是：开发表观基因组生物标记物 改善头颈部癌(HNSCC)的早期发现和临床管理； 口腔和口咽癌患者生存差距的缩小。拟议的K01项目涉及两个 与国家癌症研究所使命相关的目标：培养具有文化多样性的癌症研究人员；以及 以消除癌症健康差距。美国非裔美国人患者的总体HNSCC存活率 30多年来，美国一直保持着比白人高出近20%的水平，但生物基础 因为人们对这种差异知之甚少。提出了一个两阶段表观基因组学研究设计来检验这一假说。 表观遗传改变通过检查以下目标导致HNSCC存活率的种族差异： 具体目标1：a)评估不同种族在肿瘤外科中全球DNA甲基化的差异 HNSCC患者的边缘对(n=500)；b)量化NID2和HOXA9的差异甲基化 HNSCC患者肿瘤-手术切缘配对中的种族(n=500)；c)评估相关性 在肿瘤-手术切缘对中不同的甲基化、TP53突变状态和临床结果之间， 包括局部复发和跨种族群体的生存。 具体目标2：a)评估不同种族肿瘤组织中全球DNA甲基化的差异 HNSCC患者(n=300)和正常口腔黏膜对照组(n=300)：b)NID2和HOXA9的差异 HNSCC患者(n=300)和正常口腔黏膜组织中不同种族的甲基化 (n=300)；c)评估组织中不同甲基化与临床结果之间的关系， 包括局部复发和跨种族群体的生存。 这个K01项目的优势是多方面的：HNSCC基因组学领域的两位世界领先者David Sidransky和Wayne Koch；坚实的机构支持；使用约翰霍普金斯大学的世界级研究设施 医学院；以及获取具有良好特征的样本库--ECOG E4393/RTOG 9614 研究，大型多机构头颈部肿瘤-手术切缘研究队列与丰富 结果数据；以及一项来自约翰·霍普金斯大学校长储存的样本的回溯性病例对照研究 子宫颈癌孢子

Project Summary This is a K01 application submitted by Dr. Rafael Guerrero-Preston in response to the funding opportunity announcement "NCI Mentored Research Scientist Development Award to Promote Diversity (K01)" - PAR-09- 052. Rafael, born and raised in Puerto Rico, is currently appointed as an Instructor at the Head and Neck Cancer Research Division of the Department of Otolaryngology at Johns Hopkins School of Medicine. Rafael's short term goals are to examine global, genome-wide and gene-specific epigenomic alterations in tumors that disproportionally burden African American and Latino communities: hepatocellular carcinoma, cervical cancer and head and neck cancers. Dr Guerrero-Preston's long-term goals are: to develop epigenomic biomarkers to improve Head and Neck Cancer (HNSCC) early detection and clinical management; and to contribute to the reduction of survival disparities in oral and oropharyngeal cancer. The proposed K01 project addresses two objectives relevant to the National Cancer Institute mission: to train culturally diverse cancer researchers; and to eliminate cancer health disparities. The overall HNSCC survival rates for African American patients in the United States has remained close to 20% higher than Whites for more than 30 years, but the biological basis for this disparity is poorly understood. A two-stage epigenomic study design is proposed to test the hypothesis that epigenetic alterations contribute to ethnic disparities in HNSCC survival by examining the following aims: Specific Aim 1: a) To assess differences of global DNA methylation across ethnic groups in tumor-surgical margins pairs of HNSCC patients (n=500); b) To quantify NID2 and HOXA9 differential methylation across ethnic groups in tumor-surgical margins pairs of HNSCC patients (n=500); c) To evaluate the association between differential methylation in tumor-surgical margin pairs, TP53 mutation status, and clinical outcome, including local recurrence and survival across ethnic groups. Specific Aim 2: a) To assess differences of global DNA methylation across ethnic groups in tumor tissue from HNSCC cases (n=300) and normal oral mucosa controls (n=300); b) To quantify NID2 and HOXA9 differential methylation across ethnic groups in tumor tissue from HNSCC cases (n=300) and normal oral mucosa controls (n=300); c) To evaluate the association between differential methylation in tissue and clinical outcome, including local recurrence and survival across ethnic groups. This K01 project strengths are multiple: mentorship by two world leaders in HNSCC genomics, David Sidransky and Wayne Koch; solid institutional support; use of world class research facilities in Johns Hopkins School of Medicine; and access to well characterized sample repositories - the ECOG E4393/RTOG 9614 study, a large multi-institutional head and neck cancer tumor-surgical margin study cohort with abundant outcome data; and a retrospective case-control study from samples stored by the Johns Hopkins Head and Neck Cancer SPORE