Epigenomic Markers of HNSCC Survival Across Ethnic Groups

描述(申请人提供)：这是Rafael Guerrero-Preston博士提交的K01申请，以回应资助机会公告“NCI促进多样性的指导性研究科学家发展奖(K01)”-PAR-09-052。拉斐尔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部癌症研究部的讲师。Rafael的短期目标是研究非裔美国人和拉丁裔社区不成比例地负担的肿瘤中的全球、全基因组和特定于基因的表观基因组变化：肝细胞癌、宫颈癌和头颈癌。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，以改善头颈部癌症(HNSCC)的早期发现和临床治疗；并为减少口腔和口咽癌患者的生存差距做出贡献。拟议的K01项目涉及与国家癌症研究所的任务相关的两个目标：培训不同文化背景的癌症研究人员；以及消除癌症健康差异。30多年来，美国非裔美国人患者的总体HNSCC存活率一直比白人高出近20%，但这种差异的生物学基础尚不清楚。一个两阶段的表观基因组研究设计被提出，以检验表观遗传改变导致HNSCC存活率种族差异的假设，通过检查以下目的： 具体目标1：a)评估HNSCC患者(n=500)肿瘤-手术切缘中全球DNA甲基化在不同种族之间的差异；b)量化HNSCC患者肿瘤-手术切缘中NID2和HOXA9在不同种族之间的差异甲基化(n=500)；c)评估肿瘤-手术切缘中不同甲基化水平、TP53突变状态和临床结果之间的关系，包括跨种族组的局部复发和生存率。 具体目标2：a)评估HNSCC患者(n=300)和正常口腔黏膜对照(n=300)肿瘤组织中全球DNA甲基化在不同种族之间的差异；b)量化HNSCC患者(n=300)和正常口腔黏膜对照(n=300)肿瘤组织中NID2和HOXA9在不同种族之间的差异甲基化；c)评估组织中不同甲基化与临床结果，包括不同种族之间的局部复发和生存的关系。 K01项目的优势是多方面的：HNSCC基因组学两位世界领先者David Sidransky和Wayne Koch的指导；坚实的机构支持；使用约翰霍普金斯大学医学院的世界级研究设施；以及获得特征良好的样本库-ECOG E4393/RTOG 9614研究，这是一个大型多机构头颈癌手术切缘研究队列，具有丰富的结果数据；以及对约翰霍普金斯头颈部癌症孢子储存的样本进行的回顾性病例对照研究。 公共卫生相关性：30多年来，美国非裔美国人的头颈癌(HNSCC)患者的总体存活率一直比白人高出近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，以检验表观遗传改变导致HNSCC存活率种族差异的总体假设。

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.