IDENTIFICATION OF A 12P PROSTATE TUMOR SUPPRESSOR GENE

描述(申请人描述)：本申请的两个目标 是为了支持我作为一名内科科学家的培训，并确定新的 肿瘤抑制基因(S)在前列腺癌中的作用 这一奖项将促进我向独立调查员的过渡 在博士的指导下提供详细的分子实验室培训 保罗·古德费罗，癌症遗传学研究项目主任 医学院。古德费罗博士非常适合做我的导师，因为 他对子宫内膜肿瘤发生的遗传决定因素的研究 与本申请中提出的研究非常相似；因此，所有 本申请中描述的技术已在他的实验室中使用。 重要的是，他之前曾成功指导过几位医生 科学家。分子生物学的教学计划将补充 古德费罗博士的实验室癌症遗传学提供的智力环境 研究计划和泌尿科。 我最近报告在以下位置发现了1-2Mb纯合缺失(HZD) 1转移性前列腺癌组织中p12-13的表达。频频丢失 同一区域的杂合性缺失(LOH)常见于肿瘤。这个 LOH的最小公共区域包围了HZD的位置并变窄 一致的缺失区约为600kb。频率和频率 这些缺失(LOH和HZD)的区域特异性指向前列腺 肿瘤抑制基因在这个位置。实验的理论基础和方法 拟克隆的12pl2-13前列腺癌抑制基因如下： (I)定义12pl2-13处的最小候选区域。一个重叠的HZD在 第二个前列腺癌样本将缩小感兴趣的区域。这就做 使用计算和实验室筛选技术确定候选人 这一区域的基因，然后确定候选人是否在一组 前列腺癌。(Ii)调查使基因失活的候选基因 事件。如果这些基因参与了前列腺癌的发生，失活 基因事件将出现在剩余的前列腺癌样本中。 癌症样本将被询问突变和启动子甲基化。 (三)肿瘤抑制功能演示。如果失去功能， 12p12-13基因有助于肿瘤的形成，重新引入野生- T y p e，但不能将突变的c DNA导入前列腺细胞系会抑制 肿瘤发生学。 发现一种新的肿瘤抑制因子将为 更好的前列腺癌治疗和/或更准确的预后信息 新诊断出患有这种疾病的男性。

DESCRIPTION (Applicant's Description): The two objectives of this application are to support my training as a physician scientist and to identify novel tumor suppressor gene(s) with functional significance in prostate carcinoma. This award will facilitate my transition to independent investigator by providing detailed molecular laboratory training under the mentorship of Dr. Paul Goodfellow, the Director of the Cancer Genetics Research Program at the School of Medicine. Dr. Goodfellow is ideally suited to be my mentor because his research into the genetic determinants of endometrial tumorigenesis closely parallels the research proposed in this application; therefore, all techniques described in this application have been used in his laboratory. Importantly, he has previously successfully mentored several physician scientists. A didactic program in molecular biology will complement the intellectual environment provided by Dr. Goodfellow's lab, the Cancer Genetics Research Program, and the Division of Urology. I have recently reported the discovery of a 1-2Mb homozygous deletion (HZD) at 1 2 p12-13 in metastatic prostate cancer specimens. Frequent loss of heterozygosity (LOH) of the same region is frequently seen in tumors. The smallest common region of LOH encompasses the location of the HZD and narrows the consensus deletion region to approximately 600kb. The frequency and regional specificity of these deletions (LOH and HZD) point to a prostate cancer suppressor gene at this site. The experimental rationale and methods proposed to clone this 12pl2-13 prostate tumor suppressor gene are as follows: (I) Define the minimal candidate region at 12pl2-13. An overlapping HZD in a second prostate cancer specimen would narrow the region of interest. I will use computational and laboratory screening techniques to identify candidate genes in this region and then determine if candidates are HZD in a panel of prostatic tumors. (II) Investigate candidate genes inactivating genetic events. If these genes contribute to prostate tumorigenesis, inactivating genetic events will be present in the remaining prostate carcinoma specimens. Cancer specimens will be interrogated for mutations and promotor methylation. (III) Functional demonstration of tumor suppression. If loss of function of the 12p12-13 gene contributes to tumor formation, reintroduction of the wild- t y p e , but not mutant cDNA into prostate cell lines will suppress tumorigenesis. The identification of a novel tumor suppressor would provide a target for better prostate cancer therapy and/or more accurate prognostic information for men newly diagnosed with the disease.