Epigenomic Markers of HNSCC Survival Across Ethnic Groups

描述（由申请人提供）：这是拉斐尔·格雷罗·普雷斯顿博士提交的K 01申请，以回应资助机会公告“NCI指导研究科学家发展奖，以促进多样性（K 01）”- PAR-09-052。Rafael在波多黎各出生和长大，目前被任命为约翰霍普金斯医学院耳鼻喉科头颈癌研究部的讲师。Rafael的短期目标是研究全球范围内的，全基因组和基因特异性的肿瘤表观基因组改变，这些肿瘤给非洲裔美国人和拉丁裔社区带来了沉重的负担：肝细胞癌，宫颈癌和头颈癌。Guerrero-Preston博士的长期目标是：开发表观基因组生物标志物，以改善头颈癌（HNSCC）的早期检测和临床管理;并有助于减少口腔癌和口咽癌的生存差异。拟议的K 01项目解决了与国家癌症研究所使命相关的两个目标：培养文化多样性的癌症研究人员;消除癌症健康差距。在美国，非洲裔美国人患者的总体HNSCC生存率在30多年来一直比白人高出近20%，但这种差异的生物学基础尚不清楚。提出了一个两阶段表观基因组研究设计，通过检查以下目标来检验表观遗传改变导致HNSCC生存期种族差异的假设： 具体目标1：B）量化HNSCC患者（n= 500）的肿瘤-手术切缘对中跨种族的NID 2和HOXA 9差异甲基化; c）评估肿瘤-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的关联，包括局部复发和种族群体间的生存率。 具体目标二：B）量化来自HNSCC病例（n=300）和正常口腔粘膜对照（n=300）的肿瘤组织中跨种族的NID 2和HOXA 9差异甲基化; 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。 该K 01项目的优势是多方面的：由HNSCC基因组学领域的两位世界领导者大卫Sidransky和韦恩科赫指导;坚实的机构支持;使用约翰霍普金斯医学院的世界级研究设施;以及获得充分表征的样本库-ECOG E4393/RTOG 9614研究，一项大型多机构头颈癌肿瘤手术切缘研究队列，具有丰富的结果数据;以及一项来自约翰霍普金斯头颈部癌症研究中心储存的样本的回顾性病例对照研究 公共卫生相关性：在美国，非裔美国人的头颈癌（HNSCC）总体生存率比白人高出近20%，但这种差异的生物学基础尚不清楚。我们提出了一个新的两阶段表观基因组研究设计，以测试的总体假设，即表观遗传学改变有助于种族差异HNSCC生存。

DESCRIPTION (provided by applicant): 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 PUBLIC HEALTH RELEVANCE: The overall Head and Neck Cancer (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. We propose a novel two-stage epigenomic study design to test the overall hypothesis that epigenetic alterations contribute to ethnic disparities in HNSCC survival.