Molecular Genetics of Kidney Cancer

肾癌的分子遗传学基础为了确定导致肾癌的基因，为了开发治疗这种疾病的分子疗法，我们研究了肾癌的遗传形式。肾癌既有遗传性的，也有散发的(非遗传性的)。遗传性肾癌有五种类型：1)遗传性透明细胞肾癌(VHL)；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)遗传性平滑肌瘤病肾癌(HLRCC)，2型乳头状肾癌；5)家族性肾癌(FRC)。与冯·希佩尔·林道相关的遗传性肾癌患者容易患上大脑、脊柱、眼睛、胰腺、肾上腺和内耳的肿瘤。通过对VHL家系的研究，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292/292个VHL家系的胚系中发现了VHL基因突变，目前正在研究VHL的基因型/表型关系以及评估VHL肾脏和肾上腺肿瘤的微创治疗方式。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。我们在1994年描述了HPRC，发现7号染色体上的c-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，这些突变似乎是遗传性1型乳头状肾癌的主要原因。我们最近描述了另一种与Birt Hogg Dub综合征相关的新型遗传性肾癌。这些患者有患嫌色肾细胞癌的风险。我们对BHD家系进行了研究，并定位并鉴定了17号染色体上的BHD基因。我们描述了51/61个BHD家系的BHD突变。我们最近研究了另一种遗传性肾癌，称为遗传性平滑肌瘤病肾细胞癌(HLRCC)。这些人有患侵袭性2型乳头状肾癌的风险。我们最近在北美HLRCC家系中鉴定了富马酸水合酶基因(FH)的胚系突变，并描述了FH基因突变对HLRCC相关肾肿瘤中HIF1和HIF2水平的影响。胚系VHL、c-Met、BHD和FH突变的鉴定使对VHL、HPRC、BHD和HLRCC家族中的高危个体进行症状前基因测试成为可能，并为进一步研究这些疾病的病理机制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。我们最近证明改进了对von Hippel Lindau病肿瘤抑制基因胚系突变的检测。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、Met、BHD和FH基因的胚系和体细胞突变的能力可能为改善遗传性和散发性肾癌的诊断提供实质性的机会。最后，我们正在研究家族性肾癌(FRC)的遗传学基础。FRC是一个术语，描述的是在先前描述的遗传性肾癌综合征之外的家族中运行的肾脏。

Molecular Genetics Basis of Kidney Cancer In order to identify the genes that cause kidney cancer in order to develop molecular therapeutics for this disease, 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 five types of inherited kidney cancer: 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), an inherited form of chromophobe renal carcinoma and 4) Hereditary Leiomyomatosis Renal Carcinoma (HLRCC), type 2 papillary renal carcinoma; and 5) Familial Renal Carcinoma (FRC). Individuals with the inherited form of kidney cancer associated with von Hippel Lindau are predisposed to develop 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 292/292 VHL kindreds and are currently studying genotype/phenotype relationships as well as evaluating minimally invasive forms of therapy for kidney and adrenal tumors in VHL. 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). We described HPRC in 1994, found that the c-Met proto-oncogene, 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 type 1 papillary renal carcinoma. We recently described another new type of inherited kidney cancer associated with Birt Hogg Dub Syndrome. These patients are at risk for the development of chromophobe renal cell carcinoma. We studied BHD kindreds and were able to localize and then identify the BHD gene on chromosome 17. We have described BHD mutations in 51/61 BHD kindreds. We have recently studied another inherited form of kidney cancer called Hereditary Leiomyomatosis Renal Cell Carcinoma (HLRCC). These individuals are at risk for the development of a very aggressive form of type 2 papillary renal carcinoma. We have recently reported the identification of germline mutations of the fumarate hydratase gene (FH) in the germline of North American HLRCC kindreds and described how altration of the FH gene affects HIF1 and HIF2 levels in the HLRCC-associated kidney tumors. 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.