Molecular Genetics of Kidney Cancer

肾癌有遗传性和散发性（非遗传性）两种形式。目前已知的遗传性肾癌至少有三种类型：von Hippel Lindau （VHL）、遗传性乳头状肾癌（HPRC）和遗传性肾癌（HRC）。我们在1994年报道了HPRC的最初描述，最近确定位于7号染色体上的Met原癌基因是HPRC基因。在HPRC家族的种系中发现了Met基因的缺陷，这些突变似乎是大多数遗传性乳头状肾癌的原因。Met基因编码一种系统循环生长因子——肝细胞生长因子（HGF）的细胞表面受体。在HPRC种类中发现的种系突变位于MET基因的酪氨酸激酶结构域，预计会激活该受体。这项工作首次发现了该基因的种系突变，并证实了其作为癌症基因的重要性。我们最近已经证明，遗传性乳头状肾癌中的7号三体包含突变MET等位基因的非随机重复，并且该基因中的酪氨酸激酶突变与肾脏和其他肿瘤的发展有关。Met基因的种系突变与其他癌症（如结肠癌、黑色素瘤和胃癌）之间的关系正在研究中。种系Met突变的发现使得对HPRC家族中高危个体进行症状前基因检测成为可能，并为进一步研究HPRC的病理，以及针对Met基因突变带来的特定缺陷设计有效的新疗法铺平了道路。患有与von Hippel Lindau相关的遗传性肾癌的个体也容易在大脑、脊柱、眼睛、胰腺、肾上腺和内耳发生肿瘤。VHL基因已被证明是与von Hippel Lindau相关的遗传性肾癌以及散发性（非遗传性）肾癌（透明细胞肾癌）的常见形式的基因。NCI的科学家们正在深入研究VHL基因的损伤（突变）如何导致VHL和散发性肾癌患者的表现。最近有研究表明，VHL蛋白复合物可与CUL-2蛋白结合，CUL-2蛋白是最近发现的多基因cullin家族的一种蛋白。VHL肿瘤抑制基因蛋白与CUL-2相关的发现表明VHL与细胞周期相互作用，这为了解该癌基因的作用提供了重要的见解。此外，这一发现为肾癌和von Hippel Lindau病的新疗法的开发提供了新的研究途径。我们最近证明了改进的检测在冯希佩尔林道病肿瘤抑制基因的生殖突变。我们现在可以在几乎100%的家庭中检测到突变。我们还发现了一种与VHL基因完全缺失相关的新表型。我们正在深入研究与不同类型种系突变患者肿瘤发展相关的体细胞事件（基因组，细胞遗传学）。检测VHL和Met基因的种系和体细胞突变的能力也为改进遗传性和散发性肾癌的诊断提供了大量机会。

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 hereditary 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 insights into the role of this cancer gene. In addition, this finding provides new avenues for studies in 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 tumor suppressor 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 the diagnosis of both hereditary as well as sporadic forms of kidney cancer.