Clinical Studies of the Molecular Genetic Basis of Kidney Cancer

肾癌分子遗传学基础的临床研究

• 批准号: 8157588
• 负责人: William Marston Linehan
• 金额: $ 73.22万
• 依托单位: DIVISION OF BASIC 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/8157588
• 关键词: Clinical Research; Molecular Genetics; Renal carcinoma; base

Clinical Studies of the Molecular Genetic Basis of Kidney Cancer Kidney cancer affects 54,390 Americans each year and over 13,000 die of this disease in the U.S. annually. Our work has shown that kidney cancer is not a single disease; it is made up of a number of different types of cancer, each with a different histology, a different clinical course, responding differently to therapy and each caused by a different gene. Our approach has been to identify the genes that cause kidney cancer in order to provide the foundation targeted therapeutic approaches to this disease. In order to identify the genes that cause kidney cancer we have studied the inherited forms of cancer of the kidney. Kidney cancer occurs in both a hereditary and a sporadic (nonhereditary) form. There are a number of different types of inherited kidney cancer including: 1) von Hippel Lindau (VHL), the inherited form of clear cell renal carcinoma; 2) Hereditary Papillary Renal Carcinoma (HPRC), hereditary Type 1 kidney cancer, 3) Birt Hogg Dub (BHD), the inherited form of chromophobe renal carcinoma and 4) Hereditary Leiomyomatosis Renal Carcinoma (HLRCC), type 2 papillary renal carcinoma. In order to develop new methods for treatment of patients with sporadic as well as familial kidney cancer we established an NIH kidney cancer working group involving clinicians and investigators from 29 different laboratories and branch from 9 different NIH Institutes. von Hippel-Lindau: Clear Cell Kidney Cancer-The VHL Gene Individuals affected with von Hippel Lindau (VHL) are at risk for the development of bilateral, multifocal clear cell kidney cancer as well as tumors in the brain, spine, eyes, pancreas, adrenal gland and inner ear. By studying VHL families we were able to perform genetic linkage analysis to localize and subsequently identify the VHL gene on chromosome 3. We have identified the VHL gene mutation in the germline of 246/246 VHL kindreds and are currently studying genotype/phenotype relationships as well as evaluating novel minimally invasive forms of therapy for kidney and adrenal tumors in VHL. We have described the surgical management of VHL kidney cancers as well as VHL pheochromocytoma, pancreas tumors, ear tumors and brain and spine tumors. We currently have two clinical trials in progress targeting the VHL gene pathway in patients affected with VHL. Clear Cell Kidney Cancer: The VHL Gene We have shown that the VHL gene is also the gene for the common form of sporadic (non-hereditary) kidney cancer (clear cell renal carcinoma). In a series of studies we have identified mutation/methylation of the VHL gene in up to 92% of tumors from patients with sporadic (non-inherited) clear cell kidney cancer. Study of the VHL gene pathway has provided the foundation for the development of targeted therapeutics for patients with both clear cell kidney cancer as well as von Hippel-Lindau. We currently are conducting a clinical trial of an agent which targets the VHL pathway in patients with advanced clear cell kidney cancer. Hereditary Papillary Renal Cell Carcinoma: Type 1 Papillary Kidney Cancer-The MET Gene In 1994 we described a novel form of inherited kidney cancer, Hereditary Papillary Renal Carcinoma (HPRC) HPRC is an inherited cancer syndrome in which affected individuals are at risk for the formation of multifocal, bilateral type 1 papillary kidney cancer. In order to identify the gene for HPRC we studied families with this rare, inherited cancer syndrome to determine which individuals had the kidney cancers and which did not. Linkage analysis performed in the families to localized the gene to the long arm of chromosome 7. The proto-oncogene, MET, was subsequently identified as the HPRC gene. We have identified activating mutations in the tyrosine kinase domain of the MET gene in the germline of the HPRC families as well as in a subset of tumors from patients with sporadic, non-inherited type 1 papillary kidney cancer. These findings provided the foundation for the development of a targeted therapeutic approach to the treatment of patients affected with HPRC as well as for patients with sporadic, non-hereditary papillary kidney cancer. We are currently conducting a clinical trial with an agent which targets the MET gene pathway in patients with Hereditary Papillary Renal Carcinoma and sporadic papillary kidney cancer. Birt-Hogg-Dub: Chromophobe Kidney Cancer-The BHD gene We recently described another novel type of inherited kidney cancer associated with Birt Hogg Dub (BHD). Birt-Hogg-Dub patients are at risk for the development of bilateral, multifocal chromophobe and hybrid/oncocytic kidney cancer. By studying BHD families and we were able to localize and subsequently identify the BHD gene on chromosome 17. We have detected BHD gene mutations in over 95% of BHD families and are now able to 1) make the clinical diagnose of BHD with a blood test as well as determine which at-risk members of BHD families are affected with BHD. We have defined the kidney cancer phenotype of BHD and have described the surgical management of BHD-associated kidney cancer. Based on our preclinical studies we are planning a clinical trial targeting the BHD pathway in patients with BHD-associated kidney cancer. Hereditary Leiomyomatosis Renal Cell Carcinoma (HLRCC): Type 2 Papillary Kidney Cancer-The Fumarate Hydratase Gene We have described another inherited form of papillary kidney cancer which is now called Hereditary Leiomyomatosis Renal Cell Carcinoma (HLRCC). Affected individuals in HLRCC families are at risk for the development of a very aggressive form of type 2 papillary renal carcinoma. We have reported the identification of germline mutations of the fumarate hydratase gene (FH) in the germline of over 90% of North American HLRCC kindreds. We have described the HLRCC kidney cancer phenotype and the method of clinical management of HLRCC-associated kidney cancer. Based on our preclinical studies we are planning a clinical trial targeting the FH pathway in patients with HLRCC-associated kidney cancer. Kidney Cancer Genetic Testing The identification of germline VHL, c-Met, BHD and FH mutations makes possible pre-symptomatic genetic testing for at-risk individuals in VHL, HPRC, BHD and HLRCC families and paves the way for additional studies to understand the pathology of these diseases, and for the design of effective new therapies targeted to the specific defects brought about by mutation of the these disease genes. We have recently demonstrated improved detection of germline 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, Met, BHD and FH gene may provide substantial opportunity for improvements in the diagnosis of both hereditary as well as sporadic forms of kidney cancer. Familial Renal Carcinoma (FRC) Finally, we are studying the genetic basis of Familial Renal Carcinoma (FRC). FRC is a term that describes the kidney that runs in families that are not part of previously described hereditary kidney cancer syndromes. Studies in Iceland have suggested that nearly 60% of kidney cancer may be genetic. We suspect that there is a complex genetic pattern to FRC and we are currently evaluating FRC kindreds in order to 1) describe this clinical syndrome and 2) to identify its genetic basis.

肾癌的分子遗传学基础的临床研究肾癌每年影响54,390名美国人，在美国每年有超过13,000人死于这种疾病。我们的研究表明，肾癌不是一种单一的疾病；它由许多不同类型的癌症组成，每种癌症都有不同的组织学，不同的临床过程，对治疗的反应不同，每种癌症都是由不同的基因引起的。我们的方法是识别导致肾癌的基因，以便为这种疾病的靶向治疗方法提供基础。为了确定导致肾癌的基因，我们研究了肾癌的遗传形式。肾癌有遗传性和散发性（非遗传性）两种形式。有许多不同类型的遗传性肾癌，包括：1)von Hippel - Lindau (VHL)，透明细胞肾癌的遗传形式；2)遗传性乳头状肾癌（HPRC），遗传性1型肾癌，3)Birt Hogg Dub (BHD)，遗传性憎色性肾癌，4)遗传性平滑肌瘤性肾癌（HLRCC）， 2型乳头状肾癌。为了开发治疗散发性和家族性肾癌患者的新方法，我们建立了一个NIH肾癌工作组，包括来自29个不同实验室和9个不同NIH研究所分支的临床医生和研究人员。患有von Hippel-Lindau （VHL）的个体有发展为双侧、多灶透明细胞肾癌以及脑、脊柱、眼睛、胰腺、肾上腺和内耳肿瘤的风险。通过研究VHL家族，我们能够进行遗传连锁分析来定位并随后确定3号染色体上的VHL基因。我们已经在246/246种VHL种系中发现了VHL基因突变，目前正在研究基因型/表型关系，并评估VHL肾脏和肾上腺肿瘤的新型微创治疗方法。我们描述了VHL肾癌以及VHL嗜铬细胞瘤、胰腺肿瘤、耳部肿瘤、脑和脊柱肿瘤的手术治疗。我们目前正在进行两项针对VHL基因通路的VHL患者的临床试验。透明细胞肾癌：VHL基因我们已经证明，VHL基因也是散发性（非遗传性）肾癌（透明细胞肾癌）的常见形式的基因。在一系列研究中，我们已经在高达92%的散发性（非遗传性）透明细胞肾癌患者的肿瘤中发现了VHL基因的突变/甲基化。VHL基因通路的研究为开发针对透明细胞肾癌和von Hippel-Lindau患者的靶向治疗提供了基础。我们目前正在进行一项针对晚期透明细胞肾癌患者VHL通路的药物的临床试验。1994年，我们描述了一种新的遗传性肾癌，遗传性乳头状肾癌（HPRC） HPRC是一种遗传性癌症综合征，患者有形成多灶性双侧1型乳头状肾癌的风险。为了确定HPRC的基因，我们研究了患有这种罕见的遗传性癌症综合征的家庭，以确定哪些人患有肾癌，哪些人没有。通过连锁分析，将该基因定位在7号染色体长臂上。原癌基因MET随后被鉴定为HPRC基因。我们已经在HPRC家族的种系以及散发性非遗传性1型乳头状肾癌患者的肿瘤亚群中发现了MET基因酪氨酸激酶结构域的激活突变。这些发现为HPRC患者以及散发性、非遗传性乳头状肾癌患者的靶向治疗方法的开发提供了基础。我们目前正在进行一项针对遗传性乳头状肾癌和散发性乳头状肾癌患者MET基因通路的药物的临床试验。我们最近描述了另一种与Birt Hogg Dub （BHD）相关的新型遗传性肾癌。Birt-Hogg-Dub患者有发展为双侧、多灶性嫌色和混合型/嗜瘤性肾癌的风险。通过研究BHD家族，我们能够定位并随后识别出BHD基因在17号染色体上。我们已经在超过95%的BHD家族中检测到BHD基因突变，现在能够1)通过血液测试对BHD进行临床诊断，并确定哪些BHD家族中有风险的成员患有BHD。我们已经定义了BHD的肾癌表型，并描述了BHD相关肾癌的手术治疗。基于我们的临床前研究，我们正在计划一项针对BHD相关肾癌患者的BHD途径的临床试验。遗传性平滑肌瘤性肾细胞癌（HLRCC）： 2型乳头状肾癌-富马酸水合酶基因我们描述了另一种遗传性乳头状肾癌，现在称为遗传性平滑肌瘤性肾细胞癌（HLRCC）。HLRCC家族中受影响的个体有发展为极具侵袭性的2型乳头状肾癌的风险。我们已经报道了在北美90%以上的HLRCC种系中发现富马酸水合酶基因（FH）的种系突变。我们描述了HLRCC肾癌的表型和临床管理方法的HLRCC相关肾癌。基于我们的临床前研究，我们正在计划一项针对hhcc相关肾癌患者FH通路的临床试验。肾癌基因检测生殖系VHL、c-Met、BHD和FH突变的发现使得对VHL、HPRC、BHD和HLRCC家族的高危个体进行症状前基因检测成为可能，为进一步研究了解这些疾病的病理，以及针对这些疾病基因突变带来的特定缺陷设计有效的新疗法铺平了道路。我们最近证明了改进的检测种系突变在冯希佩尔林道病肿瘤抑制基因。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、Met、BHD和FH基因的种系和体细胞突变的能力可能为改进遗传性和散发性肾癌的诊断提供大量机会。最后，我们研究家族性肾癌（FRC）的遗传基础。FRC是一个描述肾脏的术语，在以前描述的遗传性肾癌综合征中没有家族遗传。冰岛的研究表明，近60%的肾癌可能是遗传的。我们怀疑FRC有一个复杂的遗传模式，我们目前正在评估FRC种类，以便1)描述这种临床综合征，2)确定其遗传基础。