Molecular Genetics of Kidney Cancer

肾癌的分子遗传学

• 批准号: 6558354
• 负责人: William Marston Linehan
• 金额: --
• 依托单位: DIVISION OF CLINICAL SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6558354
• 关键词: Von Hippel Lindau syndrome; autosomal dominant trait; cancer risk; carcinoma; cell cycle proteins; family genetics; gene expression; gene mutation; genetic disorder; genetic mapping; growth factor receptors; hepatocyte growth factor; human genetic material tag; human subject; kidney neoplasms; molecular genetics; neoplasm /cancer diagnosis; neoplasm /cancer genetics; neoplastic process; oncogenes; patient oriented research; protooncogene; renal cell carcinoma; transcription factor; tumor suppressor genes

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.

肾癌的分子遗传学肾癌既有遗传性的，也有散发的(非遗传性的)。遗传性肾癌至少有三种已知类型：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的初步描述，最近确定位于7号染色体上的Met原癌基因就是HPRC基因。在HPRC家族的胚系中发现了Met基因的缺陷，这些突变似乎解释了大多数遗传性乳头状肾癌的病例。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家族中发现的胚系突变位于MET基因的酪氨酸激酶区域，并被预测激活该受体。这项工作首次鉴定了该基因的种系突变，并确认了其作为癌症基因的重要性。我们最近证实，在遗传性乳头状肾癌中，7号三体含有突变的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生有关。Met基因的胚系突变与其他癌症的出现之间的关系正在调查中，如结肠癌、黑色素瘤和胃癌。胚系Met突变的鉴定使HPRC家族中高危个体的症状前基因测试成为可能，并为进一步研究HPRC的病理机制以及针对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。与冯·希佩尔·林道相关的遗传性肾癌患者也容易患上大脑、脊柱、眼睛、胰腺、肾上腺和内耳的肿瘤。VHL基因已被证明是与von Hippel Lindau相关的遗传性肾癌以及常见的散发性(非遗传性)肾癌(透明细胞肾癌)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症状。最近，研究表明VHL蛋白复合体与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抑癌基因蛋白与CuL-2相关的发现提示了VHL与细胞周期的相互作用，这为了解该癌症基因的作用提供了重要的见解。此外，这一发现为研究肾癌和von Hippel Lindau病的新疗法提供了新的途径。我们最近证明改进了对von Hippel Lindau病肿瘤抑制基因Germine突变的检测。我们现在可以在几乎100%的家庭中检测到突变。我们还检测到一种与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生殖系突变患者的肿瘤发展相关的躯体事件(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善遗传性和散发性肾癌的诊断提供了实质性的机会。