Epigenomic Markers of HNSCC Survival Across Ethnic Groups

项目摘要 这是拉斐尔·格雷罗·普雷斯顿博士提交的K 01申请，以响应资助机会 公告“NCI指导研究科学家发展奖，以促进多样性（K 01）”- PAR-09- 052.拉斐尔，出生和成长在波多黎各，目前被任命为教练在头部和颈部 约翰霍普金斯医学院耳鼻喉科癌症研究部。拉斐尔的 短期目标是检查肿瘤中的全局、全基因组和基因特异性表观基因组改变， 非洲裔美国人和拉丁裔社区的医疗负担：肝细胞癌、宫颈癌 和头颈部癌症。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志物， 改善头颈癌的早期发现和临床治疗，并促进 减少口腔癌和口咽癌的生存差异。建议的K 01项目解决两个问题 与国家癌症研究所的使命相关的目标：培养文化多样性的癌症研究人员; 消除癌症健康差距。研究中非洲裔美国人的HNSCC总生存率 30多年来，美国一直保持着比白人高出近20%的水平， 因为人们对这种差异知之甚少。两阶段表观基因组研究设计被提出来检验这一假设 表观遗传学改变有助于通过检查以下目标在HNSCC生存的种族差异： 具体目的1：a）评估肿瘤手术中不同种族群体的总体DNA甲基化差异 HNSCC患者的边缘对（n=500）; B）为了定量HNSCC患者中的NID 2和HOXA 9差异甲基化， HNSCC患者的肿瘤-手术切缘对中的种族群体（n=500）; c）评估 在肿瘤-手术切缘对中的差异甲基化、TP 53突变状态和临床结果之间， 包括局部复发和种族群体间的生存率。 具体目的2：a）评估来自不同种族的肿瘤组织中总体DNA甲基化的差异， HNSCC病例（n=300）和正常口腔粘膜对照（n=300）; B）定量NID 2和HOXA 9差异 来自HNSCC病例（n=300）和正常口腔粘膜对照的肿瘤组织中跨种族的甲基化 （n=300）; c）评估组织中差异甲基化与临床结果之间的关联， 包括局部复发和种族群体间的生存率。 这个K 01项目的优势是多方面的：由HNSCC基因组学的两位世界领导者指导，大卫 Sidransky和韦恩科赫;坚实的机构支持;使用约翰霍普金斯世界一流的研究设施 医学院;以及获得充分表征的样本库-ECOG E4393/RTOG 9614 一项大型多机构头颈癌肿瘤-手术切缘研究队列， 结果数据;以及一项回顾性病例对照研究，来自约翰霍普金斯医院院长和 颈部癌孢子

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