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: 10262205
• 负责人: William Marston Linehan
• 金额: $ 153.09万
• 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/10262205
• 关键词: Adrenal Gland Neoplasms; Adrenal Glands; Affect; American; Bilateral; Blood Tests; Brain; Brain Neoplasms; Chromosome 17; Chromosome 3; Chromosome 7; Chromosome Arm; Chromosome Mapping; Clear Cell; Clinical; Clinical Management; Clinical Research; Clinical Trials; Complex; Conventional (Clear Cell) Renal Cell Carcinoma; Cytogenetics; Defect; Detection; Development; Diagnosis; Disease; Ear Neoplasms; Event; Eye; Family; Family Study; Foundations; Fumarate Hydratase; Gene Mutation; Genes; Genetic; Genetic study; Genomics; Genotype; Germ-Line Mutation; Hereditary Leiomyomatosis and Renal Cell Cancer; Hereditary Papillary Renal Carcinoma; Histology; Hybrids; Iceland; Individual; Inherited; Institutes; Kidney; Kidney Neoplasms; Laboratories; Labyrinth; Leiomyomatosis; MET gene; Malignant Neoplasms; Methods; Methylation; Molecular Genetics; Mutation; New Agents; Oncogenes; Pancreas; Papillary; Pathology; Pathway interactions; Patients; Pattern; Phenotype; Pheochromocytoma; Proto-Oncogenes; Renal carcinoma; Reporting; Research Personnel; Risk; Running; Series; Somatic Mutation; Surgical Management; Syndrome; Tumor Suppressor Genes; Tyrosine Kinase Domain; United States National Institutes of Health; VHL gene; VHL mutation; Vertebral column; Von Hippel-Lindau Syndrome; Work; base; cancer type; clinical Diagnosis; design; genetic linkage analysis; genetic testing; improved; kindred; member; minimally invasive; new therapeutic target; novel; pancreatic neoplasm; preclinical study; targeted treatment; tumor; working group

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. 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. 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. 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. We also 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. In addition, 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. 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.

我们的工作表明，肾癌不是一种单一的疾病；它是一种疾病。它由多种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，并且每种癌症都由不同的基因引起。我们的方法是确定导致肾癌的基因，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。遗传性肾癌有多种不同类型，包括： 1) von Hippel Lindau (VHL)，透明细胞肾癌的遗传性形式； 2) 遗传性乳头状肾癌 (HPRC)，遗传性 1 型肾癌；3) Birt Hogg Dub (BHD)，遗传性嫌色肾癌；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，我们成立了 NIH 肾癌工作组，成员包括来自 29 个不同实验室和 9 个不同 NIH 研究所分支机构的临床医生和研究人员。患有 von Hippel Lindau (VHL) 的个体有患双侧多灶性透明细胞肾癌以及大脑、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，以定位并随后识别 3 号染色体上的 VHL 基因。我们已经在 246/246 个 VHL 亲属的种系中识别出 VHL 基因突变，目前正在研究基因型/表型关系，并评估 VHL 中肾脏和肾上腺肿瘤的新型微创疗法。我们描述了 VHL 肾癌以及 VHL 嗜铬细胞瘤、胰腺肿瘤、耳肿瘤以及脑和脊柱肿瘤的手术治疗。目前，我们正在进行两项针对 VHL 患者 VHL 基因通路的临床试验。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）常见形式的基因。在一系列研究中，我们在散发性（非遗传性）透明细胞肾癌患者的肿瘤中发现了高达 92% 的 VHL 基因突变/甲基化。 VHL 基因通路的研究为透明细胞肾癌和 von Hippel-Lindau 患者的靶向治疗的开发奠定了基础。我们目前正在对一种针对晚期透明细胞肾癌患者的 VHL 通路的药物进行临床试验。 1994 年，我们描述了一种新型遗传性肾癌，即遗传性乳头状肾癌 (HPRC)。 HPRC 是一种遗传性癌症综合征，受影响的个体有形成多灶性双侧 1 型乳头状肾癌的风险。为了识别 HPRC 基因，我们研究了患有这种罕见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。在该家族中进行连锁分析，将该基因定位于 7 号染色体的长臂。原癌基因 MET 随后被鉴定为 HPRC 基因。我们在 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子集中发现了 MET 基因酪氨酸激酶结构域的激活突变。这些发现为开发靶向治疗方法来治疗 HPRC 患者以及散发性非遗传性乳头状肾癌患者奠定了基础。我们目前正在针对遗传性乳头状肾癌和散发性乳头状肾癌患者进行一项针对 MET 基因通路的药物的临床试验。我们还描述了另一种与 Birt Hogg Dub (BHD) 相关的新型遗传性肾癌。 Birt-Hogg-Dub 患者有患双侧、多灶性嫌色细胞和混合/嗜酸细胞肾癌的风险。通过研究 BHD 家族，我们能够定位并随后识别 17 号染色体上的 BHD 基因。我们已在超过 95% 的 BHD 家族中检测到 BHD 基因突变，现在能够 1) 通过血液检测对 BHD 进行临床诊断，并确定 BHD 家族中哪些高危成员患有 BHD。我们定义了 BHD 肾癌表型，并描述了 BHD 相关肾癌的手术治疗。根据我们的临床前研究，我们正在计划针对 BHD 相关肾癌患者的 BHD 途径进行临床试验。此外，我们还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病肾细胞癌 (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。我们报道了超过 90% 的北美 HLRCC 种系中富马酸水合酶基因 (FH) 种系突变的鉴定。我们描述了 HLRCC 肾癌表型以及 HLRCC 相关肾癌的临床治疗方法。根据我们的临床前研究，我们正在计划针对 HLRCC 相关肾癌患者的 FH 通路进行临床试验。肾癌基因检测 种系 VHL、c-Met、BHD 和 FH 突变的鉴定使得对 VHL、HPRC、BHD 和 HLRCC 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这些疾病的病理学以及设计针对这些疾病基因突变带来的特定缺陷的有效新疗法铺平了道路。我们最近证明了对冯希佩尔林道病肿瘤抑制基因种系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的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，我们正在研究家族性肾癌（FRC）的遗传基础。 FRC 这个术语描述的是不属于先前描述的遗传性肾癌综合征的家族中的肾脏。冰岛的研究表明，近 60% 的肾癌可能是遗传性的。我们怀疑 FRC 存在复杂的遗传模式，我们目前正在评估 FRC 亲属，以便 1) 描述这种临床综合征，2) 确定其遗传基础。