NOVEL FAMILIAL CLEAR CELL RENAL CARCINOMA LOCUS

一级亲属中早发性、多灶性和双侧肾癌的发生使Fred Li及其同事发现该家族中的透明细胞肾癌与涉及3号染色体短臂的平衡染色体易位t（3;8）分离。我们使用易位的染色体断裂点，结合杂合性丢失研究，定位克隆FHIT基因，并表征其在多种癌症类型（包括RCC）中的结构和表达。FRA 3B脆性区的FHIT基因是烟草致癌物的靶点，在支气管癌前病变的早期鳞状化生阶段FHIT蛋白表达丧失。我们与斯切钦医学院遗传学和病理学系成员的合作始于1990年之前，在FHIT研究的发展中非常重要，对我们计划的合作至关重要。斯切钦的Jacek Podolski和同事发现了第二个家族性透明细胞RCC相关染色体易位，并在PI实验室的Fogarty研究期间完成了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：分离和表征易位断裂改变的基因;确定组织特异性表达并表征正常细胞和携带易位的细胞中全长基因的结构和表达;确定散发性RCC和其他癌症中基因结构和表达是否改变;在原核细胞中表达重组蛋白（用于抗血清生产）和真核细胞中表达重组蛋白以研究生物学效应;通过免疫组织化学研究候选基因产物在癌组织切片中的表达。长期目标是了解候选基因在肾透明细胞癌的发生和发展中的作用，并确定诊断或预后的有用性。

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.