GENETIC DETERMINATES OF HUMAN COLON NEOPLASIA

Georgia Wiesner博士是凯斯西储大学（CWRU）遗传学系的一名初级教员，她是唯一有资格获得K23职业发展奖的人。她接受过医学遗传学和内科医学的双重培训，长期目标是开展以患者为导向的癌症易感性研究。Wiesner博士目前是她的导师Sanford Markowitz博士的一个研究项目的首席遗传学家，该项目旨在建立一个以结肠癌和结肠腺瘤性息肉患者为基础的家庭资源，以确定导致结肠肿瘤的新基因。与共同导师Robert Elston博士一起，Markowitz博士和他的团队将提供一个出色的研究和教育环境，这将使Wiesner博士能够朝着她在遗传学和分子生物学方面独立转化研究的目标前进。该提案的长期目标是确定美国人群中导致结肠癌或结肠腺瘤性息肉易感性的基因或基因。这将使用受影响的兄弟姐妹配对方法，对Wiesner博士目前在CWRU建立的一个独特的亲属队列进行研究。这些家庭至少有一对兄弟姐妹被诊断患有结肠癌和/或腺瘤性息肉。某些基因位点与结肠肿瘤的发展有关这一概念是癌变的核心概念，有令人信服的证据表明，很大一部分常见形式的结肠癌是由未知基因引起的，这些基因增加了个体一生中患结肠癌的风险。该提案的具体目标是：1。确定并收集300对患有结肠癌和/或腺瘤性息肉的兄弟姐妹的DNA。2. 确定并从连锁分析中排除与早期遗传性结肠癌相关的已知综合征的亲属。3. 为了检验受影响的兄弟姐妹群体中的肿瘤是否与在小鼠模型或有限人群中发现的结肠肿瘤易感性变异的任何候选基因位点APC、COX2、sPLA2和DNMT或NAT1/2有关联。利用一组350个多态标记对基因组进行完整扫描，以确定这些兄弟姐妹中与癌症或结肠息肉易感性相关的新基因。

Dr. Georgia Wiesner is a junior faculty member in the Department of Genetics at Case Western Reserve University (CWRU) who is uniquely qualified for a K23 career development award. She has dual training in Medical Genetics and Internal Medicine and has a long term goal of conducting patient-oriented research in cancer susceptibility. Dr. Wiesner is currently the principal Geneticist on a research project with her mentor, Dr. Sanford Markowitz, which is aimed at establishing a patient-based family resource of kindreds with colon cancer and colon adenomatous polyps in order to identify new genes that cause colon neoplasia. Along with Dr. Robert Elston, co-mentor, Dr. Markowitz and his group will provide an outstanding research and educational environment that will allow Dr. Wiesner to advance toward her goal of independent translational research in genetics and molecular biology. The long range objectives of this proposal are to identify the gene or genes in the American population that cause susceptibility for colon cancer or colon adenomatous polyps. This will be done using the affected sibling pair methodology on a unique cohort of kindreds that Dr. Wiesner is currently establishing at CWRU. These families have at least one pair of siblings who have both been diagnosed with colon cancer and/or adenomatous polyps. The notion that certain genetic loci are linked to the development of colon neoplasms is a central concept of carcinogenesis and there is compelling evidence that a significant fraction of common forms of colon cancer are caused by unknown genes that increase an individuals life-time risk for colon cancer development. The specific aims of the proposal are: 1. To ascertain and collect DNA from 300 sibling pairs who are both affected with colon cancer and/or adenomatous polyps. 2. To identify, and exclude from linkage analysis, kindreds with known syndromes that have been linked to early onset forms of inherited colon cancer. 3. To test whether neoplasia in the study analysis population of affected sibling pairs demonstrates linkage to any of the candidate gene loci APC, COX2, sPLA2, and DNMT, or NAT1/2 for which colon neoplasia susceptibility variants have been identified in murine models or in restricted human populations and 4. To employ a set of 350 polymorphic markers to conduct a complete scan of the genome to identify new genes that are associated with susceptibility for cancer or colon polyps in these sibships.