Genetic Association Studies in African American Colorectal Cancer Patients

描述（由申请人提供）：结直肠癌 (CRC) 是癌症发病和死亡的一个重要原因，每年影响近 150,000 名美国人。非裔美国人的结直肠癌发病率和死亡率是美国所有人口中最高的。这些差异尚未得到解释，并且对非裔美国人的生物学风险因素（包括对结直肠癌的遗传易感性）的研究还不够。我是一名胃肠病学家，希望成为结直肠癌遗传学领域的独立转化医师科学家。我的长期职业目标要求我获得以下方面的额外培训：1）分子和统计遗传学； 2）癌症生物学。本申请中描述的为期 5 年的职业发展计划将在芝加哥大学进行，该大学在人类和癌症遗传学领域尤其是混合人群中脱颖而出。我很幸运有北卡罗来纳大学和伊利诺伊大学芝加哥分校的重要合作者，我们共同获得了 1000 多名非裔美国 CRC 患者和 1000 名非裔美国对照受试者的 DNA，可用于我提出的研究。医学教授兼人类遗传学主任南希·考克斯博士是我的导师，他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。由混合人群遗传学专家 Rick Kittles 博士、国际公认的癌症遗传学领域领军人物 Olufunmilayo Olopade 博士和胃肠病学领域成功的医师科学家 Eugene Chang 博士组成的跨学科咨询委员会将在这一发展阶段为我提供指导和建议。该研究计划的主要目标是确定导致非裔美国人患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)。包含这些 SNP 的区域可能含有功能变异。非裔美国人是识别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相关区域的新型SNP； 3) 确定候选 CRC 相关区域中假定的功能变异，这些变异可以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，我将具备独特的能力来开展结直肠癌遗传学的进一步转化研究。我的长期研究目标是了解结直肠癌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结直肠癌筛查的风险分层，从而预防疾病，特别是在非裔美国人等高风险但研究不足的人群中。 公共卫生相关性：在所有美国人口中，非裔美国人的结直肠癌发病率和死亡率最高。这些差异的原因尚未得到解释，遗传因素也尚未在这一高危人群中得到广泛研究。我们研究的目的是更好地了解增加结直肠癌风险的遗传因素，尤其是非洲裔美国人。

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.