NOVEL FAMILIAL CLEAR CELL RENAL CARCINOMA LOCUS

在一级亲属中出现早发性、多灶性和双侧肾癌，使Fred Li及其同事发现，该家族中的透明细胞肾癌通过平衡的染色体易位分离，t(3；8)涉及3号染色体的短臂。我们使用易位的染色体断裂点，结合杂合性丢失研究，正向克隆FHIT基因，并表征其结构和在包括肾癌在内的多种癌症类型中的表达。位于FRA3B脆性区域的FHIT基因是烟草致癌物质的靶点，在支气管癌前病变的早期鳞状化生阶段，FHIT蛋白表达缺失。我们与什切钦医学院遗传学和病理学系成员的合作始于1990年之前，这对FHIT研究的发展非常重要，对我们计划的合作至关重要。Jacek Podolski和他在Szczecin的同事发现了第二个与RCC相关的家族性透明细胞染色体易位，并在他在PI的实验室担任Fogarty研究员期间完成了对相关染色体区域的初步定位克隆。在这项合作研究的扩展过程中，我们建议：分离和鉴定因易位断裂而改变的基因；确定组织特异性；确定全长基因(S)在正常细胞和易位携带者细胞中的表达和结构；确定基因结构和表达是否在散发性肾细胞癌和其他癌症中发生改变；在原核细胞(用于产生抗血清)和真核细胞中表达重组蛋白，以研究生物学效应；用免疫组织化学方法研究候选基因产物在肿瘤组织切片中的表达。长期目标是了解候选基因(S)在透明细胞肾癌的发生和发展中的作用，并确定其在诊断或预后中的作用。

Occurrence of early onset, multi-focal and bilateral kidney cancers in first degree relatives led Fred Li and colleagues to show that clear cell renal cancer in that family segregated with a balanced chromosome translocation, t(3;8) involving the short arm of chromosome 3. We used the chromosome breakpoints of the translocation, in conjunction with loss of heterozygosity studies, to positionally clone the FHIT gene and characterize its structure and expression in a large variety of cancer types, including RCC. The FHIT gene, at the FRA3B fragile region is a target of tobacco carcinogens and FHIT protein expression is lost at the early squamous metaplasia stage of bronchial pre-neoplasia. Our collaboration with members of the Genetics and Pathology Department of the Medical Academy at Szczecin, which began before 1990, was important in development of the FHIT study and is critical in our planned collaboration. Jacek Podolski and colleagues in Szczecin discovered a second familial clear cell RCC-associated chromosome translocation and has completed preliminary positional cloning of the involved chromosome regions during his Fogarty fellowship in the PI's laboratory. During the extension of this collaborative study we propose to: isolate and characterize the genes altered by the translocation breaks; determine tissue specific of expression and characterize the structure and expression of the full length gene(s) in normal cells and cells carrying the translocation; determine if the gene structure and expression is altered in sporadic RCCs and other cancers; express recombinant protein in pro-karyotic (for anti-serum production) and eukaryotic cells for study of biological effects; study expression of the candidate gene product in cancer tissue sections by immunohistochemistry. The long term goal is to understand the role of the candidate gene(s) in initiation and progression of clear cell renal carcinoma and determine diagnostic or prognostic usefulness.