MOLECULAR GENETICS OF KIDNEY CANCER

《肾癌肾脏的分子遗传学》 癌症既有遗传性的，也有散发性的(非遗传性) 形式。至少有三种已知的遗传性肾脏 癌症：von Hippel Lindau(VHL)，遗传性乳头状肾 癌(HPRC)和遗传性肾癌(HRC)。我们 在1994年报告了HPRC的初步描述，最近 确定了位于染色体上的Met原癌基因 7，是HPRC基因。甲硫氨酸基因缺陷已在 HPRC家族的种系和这些突变似乎 占遗传性乳头状肾癌病例的大部分。 Met基因编码一种细胞表面受体，可用于系统性 循环生长因子、肝细胞生长因子(HGF)。这个 在HPRC家系中发现的胚系突变位于 MET基因的酪氨酸激酶结构域，并预测 激活这个感受器。这项工作是第一次鉴定出生殖系 该基因的突变，并证实了其作为癌症基因的重要性。 我们最近证明了7号三体是一种 突变型MET等位基因在遗传中的非随机重复 肾乳头状癌和酪氨酸激酶的作用 该基因突变与肾脏发育相关 和其他肿瘤。人类生殖系突变之间的关联 MET基因与结肠癌等其他癌症的发生 癌症、黑色素瘤和胃癌正在调查中。这个 鉴定种系蛋氨酸突变成为可能 HPRC高危人群症状前基因检测 并为进一步的研究铺平了道路 HPRC的病理和有效的新疗法的设计 针对基因突变带来的特定缺陷 《米特·吉恩》 “遗传性肾癌患者” 与冯·希佩尔·林道有关的人也容易患上 脑、脊柱、眼、胰腺、肾上腺及内脏肿瘤 耳朵。VHL基因已被证明是导致 遗传性肾癌与冯·希佩尔相关 林道以及散发性(非遗传性)的常见形式 肾癌(透明细胞肾癌)。NCI的科学家们 深入研究VHL基因的损伤(突变)是如何导致 对VHL和散发性肾癌患者的临床表现进行分析。 最近的研究表明，vhl蛋白复合体可以与 Cul-2蛋白，这是最近发现的多基因蛋白 卡林一家。VHL肿瘤抑制基因的发现 与CuL-2相关的蛋白质提示VHL与 细胞周期，这提供了重要的视野中的作用 这种癌症基因。此外，这一发现提供了新的途径 两种肾癌新疗法的研究进展 以及冯·希佩尔·林道病。我们最近做了 证明改进了von中Germine突变的检测 Hippel-Lindau病Tuor抑制基因。我们现在可以检测到 几乎100%的家庭都有突变。此外，我们还检测到 一种与VHL完全缺失相关的新表型 吉恩。我们正在深入研究躯体事件(基因组， 细胞遗传学)与患者肿瘤的发生有关 不同类型的生殖系突变。能够检测到 VHL和Met基因的种系和体细胞突变 还为改进诊断提供了实质性的机会 遗传性肾癌和散发性肾癌都是如此。

"Molecular Genetics of Kidney Cancer Kidney cancer occurs in both a hereditary and a sporadic (nonhereditary) form. There are at least three known types of hereditary kidney cancer: von Hippel Lindau (VHL), Hereditary Papillary Renal Carcinoma (HPRC) and Hereditary Renal Carcinoma (HRC). We reported the initial description of HPRC in 1994 and have recently determined that the Met proto-oncogene, located on chromosome 7, is the HPRC gene. Defects in the Met gene have been found in the germline of HPRC families and these mutations appear to account for most of the cases of inherited papillary renal carcinoma. The Met gene codes for a cell surface receptor for a systemically circulating growth factor, hepatocyte growth factor (HGF). The germline mutations identified in the HPRC kindreds are located in the tyrosine kinase domain of the MET gene and are predicted to activate this receptor. This work is the first to identify a germline mutation of this gene and confirms its importance as a cancer gene. We have recently demonstrated trisomy 7 to be harboring non-random duplication of the mutant MET allele in hereditaary papillary renal carcinomas and are effect of tyrosine kinase mutations in the gene in association with development of kidney and other tumors. Associations between germline mutation of the Met gene and the appearance of other cancers, such as colon cancer, melanoma and stomach cancer are under investigation. The identification of germline Met mutations makes possible pre-symptomatic genetic testing for at-risk individuals in HPRC families and paves the way for additional studies to learn the pathology of HPRC and for the design of effective new therapies targeted to the specific defects brought about by mutation of the Met gene." "Individuals with the inherited form of kidney cancer associated with von Hippel Lindau are also predisposed to develop tumors in the brain, spine, eyes, pancreas, adrenal gland and inner ear. The VHL gene has been shown to be the gene for the hereditary form of renal carcinoma associated with von Hippel Lindau as well as the common form of sporadic (non-hereditary) kidney cancer (clear cell renal carcinoma). NCI scientists are studying intensively how damage (mutation) to the VHL gene leads to the manifestations in VHL and sporadic renal carcinoma patients. Recently, it is has been shown that the VHL protein complex binds to the CUL-2 protein, a protein from a recently identified multigene cullin family. The finding that the VHL tumor suppressor gene protein associates with CUL-2 suggests interaction of VHL with the cell cycle, which provides significant in sights into the role of this cancer gene. In addition, this finding provides new avenues for studies of the development of new therapies for both kidney cancer as well as von Hippel Lindau disease. We have recently demonstrated improved detection of germine mutations in the von Hippel-Lindau disease tuor suppresor gene. We can now detect mutations in nearly 100% of families. we have additionally detected a new phenotype associated with complete deletion of the VHL gene. We are intensively studying the somatic events (genomic, cytogenetic) associated with the development of tumors in patients with different types of germline mutations. The ability to detect germline as well as somatic mutations of the VHL and the Met gene also provides substantial opportunity for improvements in diagnosis of both hereditary as well as sporadic forms of kidney cancer."