Genetic Association Studies in African American Colorectal Cancer Patients

描述(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。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。这些差异还没有得到解释，在非裔美国人中，包括结直肠癌遗传易感性在内的生物风险因素也没有得到充分研究。我是一名胃肠病专家，致力于发展自己的事业，成为一名从事CRC遗传学研究的独立翻译内科医生兼科学家。我的长期职业目标要求我获得额外的培训：1)分子和统计遗传学；2)癌症生物学。这份申请书中描述的为期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，特别是在混合人群中，具有突出的地位。我很幸运在北卡罗来纳大学和伊利诺伊芝加哥大学有关键的合作者，我们总共有1000多名非洲裔美国人CRC患者的DNA和1000名非洲裔美国人对照对象的DNA可用于我提议的研究。医学教授兼人类遗传学主任南希·考克斯博士是我的导师，将提供统计遗传学方面的专业知识。内森·埃利斯博士，医学副教授，是一名共同导师，将提供CRC分子遗传学方面的专业知识。一个由混合人群遗传学专家里克·基特尔斯博士、国际公认的癌症遗传学领先者奥卢芬米拉约·奥洛帕德博士和胃肠病学领域成功的内科科学家尤金·张博士组成的跨学科咨询委员会将在这一发展阶段指导我并向我提供建议。这项研究提案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(SNPs)。含有这些SNP的区域可能含有功能变异。非洲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，我提出了三个具体目标：1)在非裔美国人病例和对照中验证候选的结直肠癌相关区域；2)通过使用下一代测序技术进行有针对性的重测序，在结直肠癌相关区域发现新的SNP；以及3)在候选的结直肠癌相关区域中确定假定的功能变异，这些变异可以在未来的功能研究中进一步评估。在我的职业发展阶段结束时，我将具备从事CRC遗传学进一步翻译研究的独特条件。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，特别是在像非裔美国人这样的高危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。这些差异的原因没有得到解释，遗传因素在这一高危人群中也没有得到广泛的研究。我们研究的目标是更好地了解增加结直肠癌风险的遗传因素，特别是在非裔美国人中。

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.