Genetic Association Studies in African American Colorectal Cancer Patients

描述（由申请人提供）：结直肠癌（CRC）是癌症发病率和死亡率的重要原因，每年影响近15万美国人。非裔美国人的CRC发病率和死亡率在所有美国人中最高。这些差异尚未得到解释，包括遗传易感性在内的生物学风险因素在非裔美国人中也未得到充分研究。我是一名胃肠病学家，希望在CRC遗传学领域成为一名独立的转化医师兼科学家。我的长期职业目标要求我在以下方面获得额外的培训：1)分子和统计遗传学；2)癌症生物学。本申请中描述的5年职业发展计划将在芝加哥大学进行，芝加哥大学在人类和癌症遗传学领域，特别是在混合人群中脱颖而出。我很幸运在北卡罗来纳大学和伊利诺伊大学芝加哥分校有重要的合作者，我们一起有来自1000多名非裔美国CRC患者和1000名非裔美国对照受试者的DNA，可以用于我的研究。南希·考克斯博士，医学教授和人类遗传学主任，是我的导师，将提供统计遗传学方面的专业知识。医学副教授Nathan Ellis博士是联合导师，将提供CRC分子遗传学方面的专业知识。一个由混杂人群遗传学专家Rick Kittles博士、国际公认的癌症遗传学领袖Olufunmilayo Olopade博士和成功的胃肠病学医师兼科学家Eugene Chang博士组成的跨学科咨询委员会将在这一发展期间为我提供指导和建议。本研究计划的广泛目标是确定导致非裔美国人发生结直肠癌风险的遗传易感性因素。我将研究在欧洲人群中使用全基因组关联研究发现的单核苷酸多态性（snp）。含有这些SNP的区域可能存在功能变异。非裔美国人是鉴定功能变异的理想人群，因为他们的基因组表现出较少的连锁不平衡。为此，我提出了三个具体目标：1)在非裔美国人病例和对照中验证候选crc相关区域；2)利用新一代测序技术进行靶向重测序，发现crc相关区域的新snp；3)确定候选crc相关区域的推测功能变异，以便在未来的功能研究中进一步评估。在我的职业发展期结束时，我将有独特的条件进行进一步的CRC遗传学转化研究。我的长期研究目标是了解CRC发病机制中的遗传易感性，并研究如何利用遗传易感性因素对个体进行CRC筛查的风险分层，从而预防疾病，特别是在非洲裔美国人等高风险但研究不足的人群中。

DESCRIPTION (provided by applicant): Colorectal cancer (CRC) is a significant cause of cancer morbidity and mortality affecting almost 150,000 Americans yearly. African Americans have the highest CRC incidence and mortality of all US populations. These disparities have not been explained, and biological risk factors including genetic susceptibility to CRC are understudied in African Americans. I am a gastroenterologist who seeks to develop a career as an independent translational physician-scientist in CRC genetics. My long-term career goals require me to obtain additional training in: 1) molecular and statistical genetics; and 2) cancer biology. The 5-year career development program described in this application will take place at the University of Chicago which distinguishes itself in the field of human and cancer genetics especially in admixed populations. I am fortunate to have key collaborators at the University of North Carolina and the University of Illinois Chicago, and together we have DNA from over 1000 African American CRC patients and 1000 African American control subjects available for my proposed study. Dr. Nancy Cox, Professor of Medicine and Chief of Human Genetics, is my mentor and will provide expertise in statistical genetics. Dr. Nathan Ellis, Associate Professor of Medicine, is a co-mentor and will provide expertise in CRC molecular genetics. An inter-disciplinary Advisory Committee comprised of Dr. Rick Kittles, an expert in genetics of admixed populations, Dr. Olufunmilayo Olopade, an internationally recognized leader in cancer genetics, and Dr. Eugene Chang, a successful physician-scientist in gastroenterology, will guide and advise me during this development period. The broad objectives of this research proposal are the identification of genetic susceptibility factors that contribute to risk of CRC development in African Americans. I will study single nucleotide polymorphisms (SNPs) discovered using genome-wide association studies in European populations. Regions containing these SNP are likely to harbor functional variants. African Americans are an ideal population in whom to identify functional variants because their genomes exhibit less linkage disequilibrium. To this end, I propose three specific aims: 1) Validate candidate CRC-associated regions in African American cases and controls; 2) Discover novel SNPs in CRC-associated regions by targeted resequencing using next-generation sequencing technologies; and 3) Identify putative functional variants in candidate CRC-associated regions that can be further evaluated in future functional studies. By the end of my career development period, I will be uniquely equipped to undertake further translational research in CRC genetics. My long-term research goals are to understand genetic susceptibility in CRC pathogenesis and to study how genetic susceptibility factors can be used to risk stratify individuals for CRC screening and thereby prevent disease especially in high risk but understudied populations like African Americans. PUBLIC HEALTH RELEVANCE: Of all US populations, African Americans have the highest incidence and mortality of colorectal cancer. Reasons for these differences are not explained, and hereditary factors have not been extensively studied in this high risk population. The goal of our study is to better understand hereditary factors that increase risk of colorectal cancer especially in African-Americans.