Von Hippel-Lindau综合征致病基因的研究进展

Von Hippel-Lindau(VHL)综合征是一种较为罕见的常染色体显性遗传疾病,可引起包括中枢神经系统在内的多系统肿瘤。VHL基因是一种抑癌基因,VHL综合征由VHL基因突变引起,VHL基因通过促进缺氧诱导因子1α(HIF-1α)降解导致疾病发生,它通过编码VHL蛋白来调控其mRNA,在缺氧条件下,导致血管内皮生长因子过表达,影响肿瘤的生长浸润。随着基因检测技术日益成熟,VHL综合征的筛查与治疗逐渐出现了多种手段。因为VHL综合征具有遗传性,深入研究患者致病基因类型特点并结合临床表现,有助于深一步挖掘VHL综合征的发病机制,更好地完善基因靶向药物的研究,从而为患者及其家属提供更好的医疗指导。     

血管网织细胞瘤中VHL基因突变与异常甲基化检测

目的 :了解血管网织细胞瘤中VHL基因的突变与异常甲基化。方法 :采用PCR SSCP法检测血管网织细胞瘤中VHL基因的突变率及甲基化 ,敏感限制性内切酶消化法检测血管网织细胞瘤中VHL基因的异常甲基化率。结果 :34例血管网织细胞瘤标本中 ,VHL基因突变率为 6 4 7% ,VHL基因异常甲基化率为 2 3.5 % ,2例同时存在突变与异常甲基化。结论 :VHL基因突变及异常甲基化导致其失活是血管网织细胞瘤发生中的一个经常性事件。     

血管网织细胞瘤中VHL基因突变与异常甲基化检测

目的：了解血管网织细胞瘤中VHL基因的突变与异常甲基化。方法：采用PCR-SSCP法检测血管网织细胞瘤中VHL基因的突变率及甲基化,敏感限制性内切酶消化法检测血管网织细胞瘤中VHL基因的异常甲基化率。结果：34例血管网织细胞瘤标本中,VHL基因突变率为64.7%,VHL基因异常甲基化率为23.5%,2例同时存在突变与异常甲基化。结论：VHL基因突变及异常甲基化导致其失活是血管网织细胞瘤发生中的一个经常性事件。     

VHL病的治疗原则与筛查

一、VHL病各临床表现的治疗原则 以下介绍VHL病各临床表现的治疗原则. 中枢神经系统血管母细胞瘤 对于单发或位于脊髓的中枢神经系统血管母细胞瘤可手术切除.对于多发性中枢神经系统血管母细胞瘤,应根据影像学检查结果选择合适的治疗措施.若肿瘤直径＞2 cm者予以一次或分次手术切除;若肿瘤直径＜2cm应在手术后行γ刀冶疗以控制肿瘤进展.     

中枢神经系统血管母细胞瘤家系及基因学研究

目的探讨家族性中枢神经系统血管母细胞瘤(hemangioblastoma,HB)的临床特点及Von Hippel-Lin-dau(VHL)基因突变情况。方法对一个家族性中枢神经系统血管母细胞瘤所有成员进行临床资料收集及分析,绘制系谱图;并对家系成员进行VHL基因测序。结果该家系有5例患病,其中3例患者均行手术治疗,2例患者因该病死亡。VHL基因检测未发现VHL基因突变。结论早期发现及治疗能降低HB的危害,发现家族性HB应对家系成员进行普查,并行VHL基因检测,确诊为VHL病的患者需终生随访,以便及时处理复发或新发病灶。     

2个Von Hippel-Lindau病家系调查及基因突变检测

目的：探讨汉族人Von Hippel-Lindau（VHL）病临床特征及VHL基因变异情况。方法：调查2个VHL病家系临床资料,分别绘制树状图;抽取2个家族共30位成员外周血,提取基因组DNA,应用聚合酶链反应（PCR）扩增VHL基因片段并测序。将所得突变类型与人类基因突变数据库核对。结果：2个家系均以中枢神经系统血管网状细胞瘤为主要表现（13/15）,部分患者呈现多脏器损害。2个家系发病年龄16～47岁,外显率为30.6%（15/49）,男性发病较女性多见（13：2）,术后平均6.7年复发（2～17年）。家系1共29人,4位患者及3位家族成员VHL基因第716位核苷酸G突变为C,导致第168位编码氨基酸由丝氨酸变为苏氨酸;家系2共20人,1位患者及2位家族成员VHL基因第559位核苷酸C突变为G,导致第116位编码氨基酸由亮氨酸变为缬氨酸。结论：VHL病是一种常染色体显性遗传疾病,VHL基因检测在早期发现无症状患者和致病基因携带者及对该病家族成员进行筛查方面起着重要作用。     

VHL基因和HIF-1α在肾细胞癌中的研究进展

VHL基因是典型的抑癌基因,定位于常染色体3p25-26区域,其产物pVHL能与Elongin B-C、CUL2、Rbx1蛋白组成VHL-ElonginB/C-CUL2-Rbx1复合物,参与人体内多种蛋白的降解过程,同时和转录调控、细胞增殖、凋亡、肿瘤的侵袭和转移有关。多数肾透明细胞癌存在VHL基因的异常,主要包括VHL基因突变、甲基化和杂合性缺失。HIF-1是由α和β两个亚基组成的异源二聚体,其可通过调控红细胞和肿瘤血管生成、能量代谢、细胞周期以及细胞凋亡来促进肿瘤生长。VHL基因可通过抑制HIF1α的表达来抑制无氧代谢、血管生成、促红素生成及细胞侵袭等从而抑制肿瘤生长、侵袭及转移。同时在研究时发现VHL蛋白可以调控HIF-1αmRNA的表达,阐明其分子机制可为以VHL、HIF-1α为靶点的肾透明细胞癌的基因治疗提供进一步的理论依据。     

VHL相关型中枢神经系统血管母细胞瘤的研究进展

VHL相关型中枢神经系统血管母细胞瘤是起中枢神经系统高度血管化的良性肿瘤综合征,是一种常染色显性遗传病,具有中枢神经系统多发并常累及多个内脏器官的特点,常常因检查不全面、未常规随访等导致漏诊。这篇文章通过文献回顾对中枢神经系统血管母细胞瘤的流行病特点、发病机制、临床诊断、系统治疗予以总结分析,着重分析其发病机制、治疗进展。     

VHL病并发双侧肾癌1例报告及文献复习

VHL病是一种家族性常染色体显性遗传性肿瘤病,病变可累及多个器官、表现多样,包括中枢神经系统血管母细胞瘤、内脏肿瘤和内脏多发囊肿等。对本病的了解将有助于对本病的及时诊断,避免误诊和漏诊该病。本文将报道1例并发双侧肾癌的VHL患者并结合文献阐述VHL病的临床特点、诊断方法以及治疗。     

Von Hippel-Lindau综合征三例诊治分析

Von Hippel-Lindau(VHL)综合征是由VHL肿瘤抑制基因失活、突变引起的一种以家族性血管母细胞瘤为特征,涉及多个器官的常染色体显性遗传性肿瘤综合征,具有较高的外显率及多种表达方式,临床罕见。诊断需依赖影像学及眼底镜等多项检查,基因检测是其诊断的金标准。目前手术切除仍是本病的主要治疗方法,但难以根治,易复发。生物疗法有望成为未来VHL综合征新的有效治疗方法。     

Genetic study of a large Chinese kindred with von Hippel-Lindau disease

Background Von HippeI-Lindau (VHL) disease is a heraditary cancer syndrome caused by germline mutations of the VHL tumor on the suppressor gene. This study was to show the clinical characteristics of a large Chinese kindred with yon HippeI-Lindau disease and to evaluate the role of the genetic test of VHL disease in the diagnosis of VHL disease and clinical screening of members of the VHL disease family.Methods DNA extracted from peripheral blood was amplified by PCR to three exons of the VHL gene in 27 members of a large kindred with VHL disease. PCR products were directly sequenced. The involvements of multi-organs in the kindred with VHL disease were confirmed by history taking and radiography.Results Of 47 members in the four generations of the kindred, 18 members were diagnosed as having VHL desease. Clinical manifestations of 18 patients included: central nervous system (CNS)hemangioblastoma (5), renal cell carcinoma and CNS hemangioblastoma (3), renal cell carcinoma and retinal angioma (3), renal cell carcinoma and multiple pancreatic cysts (1), renal cell carcinoma and retinal angioma and multiple pancreatic cysts (2), renal cell carcinoma and CNS hemangioblastomas and multiple pancreatic cysts (1), and multiple pancreatic cysts and multiple renal cysts (1), multiple pancreatic cysts (2). The common lesions of the 18 patients were renal cell carcinoma (55.6%), CNS hemangioblastoma (50.0%), retinal angioma (27.8%), and multiple pancreatic cysts (38.9%). Among the 27 members who volunteered for genetic analysis, 15 members including 9 affected family patients and 2 asymptomatic patients and 4 carriers, who are still alive, presented a codon 78 from Asn to Ser change at nucleotide 446 (A→G) in exon 1. Four members were carriers with the same VHL gene mutation. Two asymptomatic patients were initially diagnosed by genetic testing and subsequently confirmed radiologically and surgically. Members without gene mutation had no clinical evidence of VHL disease.Conclusions The large Chinese kindred with VHL disease was classified as type I . The main characteristics in the kindred were higher incidence of renal cell carcinoma and lower incidence of retinal angioma. Genetic test plays an important role in early detecting asymptomatic patients and the carriers in clinical screening of members of the families with VHL disease. It is also important to prevent the transmission of VHL disease to their offsprings in the kindred.     

石蜡包埋肾肿瘤标本VHL基因突变研究

目的：研究石蜡包埋肾肿瘤标本ＶＨＬ基因突变情况。方法：采用ＰＣＲ－ＳＳＣＰ银染法分析３８ 例肾透明细胞癌、１０ 例肾颗粒细胞癌、１０ 例肾盂移行细胞癌、１０ 例肾胚瘤ＶＨＬ基因突变情况。结果：９ 例肾透明细胞癌ＶＨＬ基因外显子２ 发生突变,突变率为２３％ ,其他３ 种肾肿瘤均未发现ＶＨＬ基因突变。结论：ＶＨＬ基因突变与肾透明细胞癌的发生关系密切,ＰＣＲ－ＳＳＣＰ方法检测ＶＨＬ基因突变可用于ＶＨＬ病及肾透明细胞癌的诊断     

von Hippel-Lindau syndrome: molecular diagnosis of two Lebanese families and analysis of the genotype-phenotype correlation

The von Hippel-Lindau syndrome (VHL) is a dominantly transmitted hereditary disorder associating multisystemic tumors affecting mainly the central nervous system, the kidneys, the pancreas, as well as pheochromocytomas. Mutations of the tumor suppressor gene VHL on chromosome 3 are responsible for the disease. This article reports for the first time the study of two Lebanese VHL affected families, presenting particularly hemangioblastomas of the central nervous system. Two different mutations of the VHL gene, S65W and F76S, respectively identified in the two families, confirmed the clinical diagnosis of the patients. Molecular diagnosis was then performed for at risk members of these families. This article reveals the importance of molecular diagnosis for suspected patients and of presymptomatic diagnosis for at risk members, especially that a close follow-up of carriers allows an early detection of tumors and prevents the metastasis stage, the most common cause of death of these patients.     

Screening for von Hippel-Lindau disease by DNA polymorphism analysis.

OBJECTIVE--Von Hippel-Lindau (VHL) disease is a rare, inherited multisystem neoplastic disorder. There is no biochemical test available to distinguish VHL disease gene carriers from their healthy siblings. We evaluated DNA polymorphism analysis as a method for identifying disease gene carriers. DESIGN--Prospective comparison of the results of DNA analysis with a comprehensive clinical screening examination. SETTING--The Clinical Center of the National Institutes of Health. PATIENTS--Blood was collected from 182 members of 16 families with VHL disease. Forty-eight asymptomatic individuals, at risk of developing this hereditary illness (with an affected parent or sibling), were examined for occult disease at the Clinical Center of the National Institutes of Health and tested by DNA polymorphism analysis. RESULTS--DNA polymorphism analysis predicted nine disease gene carriers and 33 individuals with the wild-type (normal) allele among the 48 individuals at risk of developing VHL disease; the test was not informative in six individuals. All nine individuals predicted to carry the VHL gene had evidence of occult disease on clinical examination. There was no clinical evidence of VHL disease in 32 of 33 individuals predicted to carry the wild-type allele. CONCLUSIONS--DNA polymorphism analysis can identify individuals likely to carry the VHL disease gene among asymptomatic members of disease families. This technique serves to focus attention on those individuals who require periodic medical examination and may help to alleviate the morbidity and mortality associated with this disease.     

结合临床特征探讨腹部超声在诊断Von-Hippel-Lindau综合征中的作用

目的 分析Von-Hippel-Lindau(VHL)综合征的临床特征,探讨腹部超声在诊断VHL综合征中的作用。方法 回顾性分析1994年1月至2017年12月在北京协和医院收治的35例VHL综合征患者的临床资料,包括首诊年龄、症状、体征、受累脏器、手术次数、检查方法等,分析腹部超声对诊断VHL综合征的作用。 结果 35例患者中,嗜铬细胞瘤(14例)及神经系统血管母细胞瘤(13例)为常见的首发肿瘤,神经系统血管母细胞瘤(21例)、嗜铬细胞瘤(19例)、肾癌(17例)及胰腺占位(15例)为常见的肿瘤。主要手术原因为神经系统血管母细胞瘤(22例次)、嗜铬细胞瘤(23例次)及肾癌(13例次)。33例患者腹部脏器受累,20例(60.6%)首次被腹部超声发现,其中6例为健康体检时发现。行肾上腺超声33次,27次诊断准确。行胰腺超声16次,13次诊断准确。行肾脏超声19次,8次诊断准确。结论 当超声发现肾脏、肾上腺、胰腺等部位的多发肿瘤时,超声医师要仔细询问家族史和神经系统疾病史,考虑VHL综合征的可能性。当临床提示存在VHL综合征时,超声能够发现及诊断腹部肿瘤,同时可以用于长期随访观察肿瘤的变化。超声是VHL综合征腹部疾病筛查和随诊的重要手段。     

Von Hippel-Lindau综合征4例影像学表现和遗传史回顾及文献复习

目的总结Von Hippel-Lindau(VHL)综合征的影像学表现和诊断方法。方法回顾分析4例vHL综合征患者的影像学、家族遗传史和其他临床资料,结合复习相关文献,探讨该少见遗传病的诊断方法。结果本组4例患者,男1例,女3例,年龄28⁴1岁,中位年龄34.3岁,影像学均表现为胰腺多发囊实性占位和双肾多发囊实性肿物。既往都有脑内肿瘤手术史和家族多人发病的遗传史,符合Maher等提出的该综合征诊断标准。结论 VHL基因不同突变类型导致不同表现型,临床表现形式复杂多样,认识VHL综合征的影像特征,结合临床病史可以明显提高其诊断水平。     

散发性肾透明细胞癌VHL基因突变的研究

目的 了解散发性肾透明细胞癌组织中VHL（Von Hippel-landau）基因突变率及其临床意义。材料与方法 提取28例1998年4月-2000年1月间手术并获得病理诊断的散发性肾透明细胞癌及远离肿瘤的正常肾组织基因组DNA，采用单链构象多态性（SSCP）分析明确是否存在VHL基因有突变，分析VHL基因突变与肿瘤体积、分期、分级以及患者生存率等的关系。结果 远离肿瘤的正常肾组织中未检测到VHL基因的突变，10例（35．7％）癌组织标本中存在VHL基因的突变。VHL基因的突变率在T1a与T1b～T3间存在显著差异（P=0．035），肿瘤最大径4cm及以下者VHL基因突变率显著高于4cm以上者（P=0．011）。伴随VHL基因突变的患者5年生存率为100％，不伴随VHL基因突变者5年生存率为83％。结论 散发性肾透明细胞癌肿瘤组织中存在VHL基因突变，VHL基因突变较多发生于肿瘤的早期，VHL基因突变可能是肾透明细胞癌的有利预后因素。     

非遗传性肾透明细胞癌中VHL抑癌基因的突变及其意义

目的:探讨国人非遗传性肾透明细胞癌中VHL抑癌基因的突变及其意义.分析希佩尔林道(von HippelLindau,VHL)抑癌基因突变与肾癌分期分级的关系.方法:采用聚合酶链反应(PCR)、变性高效液相色谱(DHPLC)以及DHPLC阳性者进行直接测序的方法,分析了57例非遗传性肾透明细胞癌中VHL抑癌基因突变的情况.结果:发现30例VHL基因突变,突变率为53%.这些突变主要发生在第1,2,3号外显子的后1/3区,其中13例缺失,2例插入,15例误义突变.结论:国人非遗传性肾透明细胞癌中存在VHL基因的突变,且与患者年龄,肿瘤分期、分级无相关性.