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，以便开发针对这种疾病的分子疗法，我们研究了肾癌的遗传形式。肾癌有遗传性和散发性两种形式。存在五种类型的遗传性肾癌：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），嫌色肾癌的遗传形式;和4）遗传性平滑肌瘤病肾癌（HLRCC），2型乳头状肾癌;和5）家族性肾癌（FRC）。患有与von Hippel Lindau相关的遗传性肾癌的个体倾向于在大脑，脊柱，眼睛，胰腺，肾上腺和内耳中发展肿瘤。通过研究VHL家族，我们能够进行遗传连锁分析，定位和随后确定的VHL基因3号染色体上。我们已经在292/292 VHL激酶的种系中鉴定了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微创治疗形式。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。我们在1994年描述了HPRC，发现位于7号染色体上的c-Met原癌基因是HPRC基因。在HPRC家族的生殖系中发现了Met基因的缺陷，这些突变似乎是大多数遗传性1型乳头状肾癌病例的原因。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。这些患者有发生嫌色细胞肾细胞癌的风险。我们研究了BHD激酶，并能够定位，然后确定17号染色体上的BHD基因。我们描述了51/61例BHD激酶的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）。这些个体有发展为非常侵袭性的2型乳头状肾癌的风险。我们最近报道了在北美HLRCC激酶的种系中鉴定富马酸水合酶基因（FH）的种系突变，并描述了FH基因的改变如何影响HLRCC相关肾肿瘤中HIF 1和HIF 2的水平。生殖系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所带来的特定缺陷的有效新疗法铺平了道路。我们最近已经证明了在冯希佩尔-林道病肿瘤抑制基因的种系突变检测的改进。我们现在可以在几乎100%的家庭中检测到突变。我们还发现了一个新的表型与VHL基因的完全缺失。我们正在深入研究与不同类型生殖系突变患者肿瘤发生相关的体细胞事件（基因组学、细胞遗传学）。检测VHL、Met、BHD和FH基因的生殖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机会。最后，我们正在研究家族性肾癌（FRC）的遗传基础。FRC是一个术语，描述了在不属于先前描述的遗传性肾癌综合征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.