RESTRICTION FRAGMENT LENGTH POLYMORPHISMS IN NORMAL AND NEOPLASTIC TISSUES

这项研究项目的主要目标是识别和表征 参与人类肾癌发病机制的基因。我们的专业 今年取得的成绩是： 1.我们证明了MET原癌基因的突变是 对最近发现的一种遗传性肾癌负有责任， 遗传性乳头状肾癌。与我们之前的 Von Hippel-Lindau病基因突变的研究 原癌基因都是错义的，都位于催化 蛋白质的结构域。检测到MET原癌基因的突变 在6/7个HPRC家族中，以及在散发性乳头状肾中 癌症。 2.我们证明了MET的突变产生了- 功能。HPRC和HPRC患者MET基因突变的检测 散发性肿瘤使NIH3T3细胞发生恶性转化。 MET蛋白的结构性磷酸化在 将突变的MET基因导入小鼠细胞。 3.MET中检测到的部分突变位于残基中 与其他受体酪氨酸激酶的突变同源，RET和 基特。这些结果表明，我们已经确定了 几种受体酪氨酸激酶共有的催化结构域 突变的形式会产生疾病。 4.我们发现了另一种不同的遗传性肾脏疾病 肿瘤。到目前为止，我们已经确定了5个具有多成员的家庭 患有肾嗜酸细胞瘤。受影响的人有多个， 双侧肾嗜酸细胞瘤。

The major goal of this research project is to identify and characterize genes involved in the pathogenesis of human kidney cancer. Our major accomplishments this year are: 1. We demonstrated that mutations in the MET proto- oncogene are responsible for a recently recognized inherited form of kidney cancer, hereditary papillary renal carcinoma (HPCR). In contrast to our previous studies with the von Hippel-Lindau disease gene, mutations in the MET proto-oncogene were all missense, and were located in the catalytic domain of the protein. Mutations in the MET proto-oncogene were detected in 6/7 HPRC families, and in a subset of sporadic papillary renal carcinomas. 2. We demonstrated that the mutations in MET produced a gain-of- function. The mutations in MET detected in patients with HPRC and sporadic tumors produced malignant transformation of NIH 3T3 cells. Constitutive phosphorylation of the MET protein was demonstrated in mouse cells transfected with mutant MET genes. 3. Some of the mutations detected in MET were located in residues homologous to those mutated in other receptor tyrosine kinases, RET and KIT. These results suggest that we have identified residues of the catalytic domain common to several receptor tyrosine kinases that in mutant form produce disease. 4. We have identified another distinct inherited form of renal neoplasia. So far, we have identified 5 families with multiple members affected with renal oncocytoma. Affected individuals have multiple, bilateral renal oncocytomas.