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 肾癌以遗传性和散发性（非遗传性）两种形式发生。遗传性肾癌至少有三种已知类型：冯·希佩尔·林道 (VHL)、遗传性乳头状肾癌 (HPRC) 和遗传性肾癌 (HRC)。我们于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病例的原因。 Met 基因编码系统循环生长因子、肝细胞生长因子 (HGF) 的细胞表面受体。 HPRC 亲属中发现的种系突变位于 MET 基因的酪氨酸激酶结构域中，预计会激活该受体。这项工作首次鉴定了该基因的种系突变，并证实了其作为癌症基因的重要性。我们最近证明，遗传性乳头状肾癌中，7 三体性含有突变 MET 等位基因的非随机重复，并且是该基因中酪氨酸激酶突变的影响，与肾脏和其他肿瘤的发展相关。 Met 基因的种系突变与其他癌症（如结肠癌、黑色素瘤和胃癌）的出现之间的关联正在研究中。种系 Met 突变的鉴定使得对 HPRC 家族中的高危个体进行症状前基因检测成为可能，并为进一步研究了解 HPRC 的病理学以及设计针对所带来的特定缺陷的有效新疗法铺平了道路通过 Met 基因突变。 患有与冯·希佩尔·林道相关的遗传性肾癌的个体也容易在大脑、脊柱、眼睛、胰腺、肾上腺和内耳中罹患肿瘤。 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 科学家正在深入研究 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，研究表明 VHL 蛋白复合物与 CUL-2 蛋白结合，CUL-2 蛋白是来自最近鉴定的多基因 cullin 家族的蛋白。 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，这一发现为肾癌和冯·希佩尔·林道病新疗法的开发研究提供了新途径。我们最近证明了对 von Hippel Lindau 病肿瘤抑制基因中胚芽突变的检测得到了改进。我们现在可以检测近 100% 的家庭中的突变。我们还检测到一种与 VHL 基因完全删除相关的新表型。我们正在深入研究与不同类型种系突变患者的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巨大的机会。