中国家族遗传性肿瘤临床诊疗专家共识（2021年版）（6）—家族遗传性肾癌

<正>肾癌发病率居中国泌尿生殖系统肿瘤的第3位,仅次于膀胱癌和前列腺癌,占成人恶性肿瘤的2%～3%,发病率呈现逐年上升的趋势。2%～4%的肾癌患者由易感基因胚系突变导致,表现为发病年龄早、双侧、多灶性肾癌比例高、肾癌家族史阳性,被称为家族遗传性肾癌综合征。目前发现的家族遗传性肾癌综合征及相应的易感基因包括:VHL综合征(VHL基因)、结节性硬化综合征(TSC1/TSC2基因)、遗传性乳头状肾癌(MET基因)、遗传性平滑肌瘤和肾细胞癌综合征(FH基因)、     

乳头状肾细胞癌和肾透明细胞癌中HIF-1α、VEGF的表达及相关性

目的：研究缺氧诱导因子-1α（HIF—1α）、血管内皮生长因子（VEGF）在肾透明细胞癌（clear cell renal cell cancer，CC—RCC）和乳头状肾细胞癌（papillary renal cell cancer，PRCC）中的表达和相关性。方法：采用免疫组化法检测13例乳头状肾细胞癌、20例透明细胞癌及10例正常肾组织中HIF—1α，VEGF的表达，并比较它们之间的差异性及相关性。结果：HIF—1α在乳头状肾细胞癌、透明细胞癌及正常肾组织中阳性表达率分别为38．46％、85％、0，提示其表达在乳头状肾细胞癌组、透明细胞癌组与正常肾组织组之间差异有统计学意义（P〈0．05）。VEGF在乳头状肾细胞癌、透明细胞癌及正常肾组织中阳性表达率分别为76．92％、90％、10％，乳头状肾细胞癌组与透明细胞癌组之间无显著性差异，但两组与正常肾组织组之间差异有统计学意义（P〈0．05）。HIF—1α与VEGF的表达在乳头状肾细胞癌组中无相关性．在肾透明细胞癌组中呈正相关（r=0．79，P〈0．001）。结论：在乳头状肾细胞癌组中HIF—1α低表达，VEGF高表达，但HIF—1α与VEGF的表达无相关性，提示乳头状肾细胞癌的肿瘤血管生成与透明细胞癌有所不同。     

VHL综合征伴发双侧肾癌个案分析

Von Hippel-Lindau(VHL)综合征为临床十分罕见的家族性常染色体显性遗传性肿瘤综合征, 表现为多发、多器官的良、恶性肿瘤征候群, 包括中枢神经系统血管母细胞瘤、内脏肿瘤和囊肿等。发病率约1/3.6万, 平均发病年龄为26.3~30.9岁。预后不良, 平均生存年龄 < 49岁, 其主要死亡原因是中枢神经系统血管母细胞瘤破裂出血、肾细胞癌和嗜铬细胞引起的恶性高血压。现介绍1例经浙江湖州师范学院附属第一医院泌尿外科收治的中枢神经系统血管母细胞瘤伴发双侧肾癌, 附睾、肝、胰腺多发囊肿病例。该患者经左侧保留肾单位的肾癌切除术, 索尼替尼分子靶向治疗后效果较佳, 随访30个月, 生存良好。      

囊性肾透明细胞癌1例及文献复习

目的：探讨囊性肾透明细胞癌的临床病理特征、诊断及鉴别诊断。方法：对1例囊性肾透明细胞癌进行光镜观察,行组织化学及免疫组化染色,并复习文献。结果：肿瘤细胞主要由透明细胞组成。癌细胞免疫表型Ckpan、EMA、CEA呈阳性表达,CD68阴性。结论：囊性肾透明细胞癌是一种罕见的肾癌病理类型。其诊断依赖组织病理学和免疫组化标记。     

家族性肾肿瘤

作者报告一母子皆患肾肿瘤的病例,母患肾细胞癌,子(4岁)患肾母细胞瘤。并讨论了以下几个问题:(1)肿瘤发生的因素:认为正常细胞的恶变,是遗传易感性和环境因素的联合作用。遗传因素最高的是视网膜母细胞瘤,其中40％的病例是常染色体显性遗传。属于原发遗传的泌尿生殖系肿瘤,常伴有生殖泌尿系畸形,提示畸形的发生和癌症的发生之间有联系。相同组织类型肿瘤的遗传型比散发型发病年龄早,常为两侧性和多灶性,且有较高的家族性发病率。(2)肾细胞癌的发病率世界各地不同,最高的是丹麦,每年7/10万人,炼焦炉工人和机械工作者发病尤高。(3)遗传型肾细胞癌有某些遗传机制。一种常染色体显性遗传的 Von Hippel-Lindau 综合征中,肾细胞癌的发生率为10％～25％,且常为双侧和多灶性。肾细胞癌单基因遗传比特异性肾细胞癌体质、3和8染色体间平衡易位多见。文献曾报告10例家族性肾细胞癌三代遗传患者,5例     

透明细胞性肾细胞癌在不同组织学分类中的比较研究

比较2004年WHO肾细胞癌组织学分类标准与1997年WHO及更早的分类标准的异同,总结常见的诊断差异及可能原因,纠正及更新对肾细胞癌的传统病理分类的观念。方法:收集天津医科大学肿瘤医院2004年2月至2008年2月间,根治性肾切除术后病理诊断为透明性肾细胞癌249例,按2004年WHO肾癌组织学分类标准重新分类,并收集相关临床资料进行分析。结果:原分类法的249例透明细胞癌,经重新分类后,发现透明细胞癌176例,乳头状肾细胞癌42例,嫌色细胞癌5例,多房性囊性肾细胞癌3例,混合型肾细胞癌23例（透明细胞癌+乳头状肾细胞癌21例,乳头状肾细胞癌+嫌色性肾细胞癌2例）。结论:部分乳头状肾细胞癌与嫌色肾细胞癌过去易被诊断为透明细胞癌,两者具有相似的胞浆特点,及对其组织学特点认识不清是其主要原因;中国人乳头状肾细胞癌的发病率与国外相近,且其亚型的分类及诊断有待进一步的研究。      

肾癌的CT表现及其病理新分型21例分析

[目的]提高基于新病理分型的肾细胞癌的CT诊断认识。[方法]回顾性分析经病理证实的21例肾细胞癌CT表现和病理结果。[结果]11例透明细胞癌,1例颗粒细胞癌,4例混合细胞癌,1例多房囊性肾细胞癌,1例乳头状癌,2例嫌色细胞癌,1例集合管癌。新分型中颗粒细胞癌和多房囊性肾细胞癌均归于透明细胞癌,此型血供丰富,增强扫描后强化明显,不复杂性囊变为其特征;而乳头状癌和嫌色细胞癌相对少血供,易于坏死囊性变,强化程度低于透明细胞癌;集合管癌较少见,CT表现缺乏特异性。[结论]各型肾细胞癌CT表现特异性不强,组织学类型确诊仍依靠病理。了解其CT表现与病理之间的关系有助于CT诊断与鉴别诊断。     

肾透明细胞癌中Ang-2的表达及与血管生成的关系

目的:探讨Ang-2及CD34在肾透明细胞癌中的表达及与肾透明细胞癌血管生成的关系.方法:应用免疫组化S-P法,分别检测80例肾透明细胞癌组织及10例癌旁肾组织中Ang-2及CD34的表达.结果:肾透明细胞癌组织中Ang-2阳性表达率为61.25%(49/80),明显高于癌旁肾组织.Ang-2的表达与肾透明细胞癌患者血尿、临床分期及淋巴结转移显著相关.结论:Ang-2可能在肾透明细胞癌血管生成中起重要作用,与肾透明细胞癌的分期、转移相关.     

多房性囊性肾细胞癌16例临床病理分析

目的：探讨多房性囊性肾透明细胞癌（muhilocular cystic renal cell carcinoma,MCRCC）的临床病理特征、组织发生、诊断与鉴别诊断、治疗及预后。方法：回顾性分析2006年1月-2011年3月间我院收治并诊断的16例囊性。肾透明细胞癌病例的临床病理特点,并结合相关文献进行复习。结果：男性14例,女性2例,发生于左右肾各8例。临床无明显症状,大部分为体检发现肾脏占位性病变而入院,部分有腰酸腰部胀痛表现。术后病理诊断为囊性肾细胞癌。结论：囊性肾透明细胞癌临床上单靠影像学不易被确诊,确诊需依赖术中快速冰冻病理、常规石蜡病理和免疫表型结果。需与透明细胞癌囊性变,单纯性肾囊肿,先天性多囊肾,多房囊肿性肾瘤,肾混合性上皮间质瘤相鉴别。     

多囊性肾细胞癌6例临床病理分析

[目的]探讨多囊性肾细胞癌的临床病理学特征及鉴别诊断。[方法]6例多囊性肾细胞癌标本行HE染色和免疫组化检测,观察肿瘤镜下形态。[结果]肿瘤由厚的假纤维包膜围绕,切面见大小不等的囊腔。镜下见肿瘤均由大小不等的囊腔构成,囊腔上皮为无明显异型的透明细胞,纤维性囊壁间隔内透明细胞呈巢状分布。癌细胞免疫表型:透明细胞CK-P、Vimentin阳性,CD68、Ki-67、PCNA阴性。[结论]多囊性肾细胞癌是一种低度恶性潜能肿瘤,具有独特的病理形态特征,预后良好。需与先天性多囊肾、肾细胞癌囊性变、囊性肾腺瘤等鉴别。     

Nuclear Pedigree Criteria for the Identification of Individuals Suspected to be at Risk of an Inherited Predisposition to Renal Cancer

Renal clear cell carcinomas represent about 3% of all visceral cancers and account for approximately 85% of renal cancers in adults. Environmental and genetic factors are involved in the development of renal cancer. Although to date there are 19 hereditary syndromes described in which renal cell cancer may occur, only four syndromes with an unequivocal genetic predisposition to renal cell carcinoma have been identified: VHL syndrome (mutations in the VHL gene), hereditary clear cell carcinoma (translocations t(3:8), t(2:3)), hereditary papillary carcinoma (mutations in the MET protooncogene) and tuberous sclerosis (mutations in the TSC1 and TSC2 genes). Little is known genetically about the other forms of familial renal cell cancer. Since there is a growing awareness about the necessity of early intervention, clinical criteria have been developed that aid in the identification of hereditary forms of renal cancer. The aim of the current study was to identify minimal inclusion criteria so that nuclear pedigree families can be ascertained for risk assessment and/or kidney tumour screening. The results reveal that inclusion features described herein, such as (a) renal clear cell cancer diagnosed before 55 years of age, and (b) renal clear cell cancer and gastric cancer or lung cancer among first degree relatives, are useful in identifying suspected hereditary clear cell renal cancer patients.     

Familial non-VHL clear cell (conventional) renal cell carcinoma: clinical features, segregation analysis, and mutation analysis of FLCN

PURPOSE: Familial renal cell carcinoma (RCC) is genetically heterogeneous. The most common histopathologic subtype of sporadic and familial RCC is clear cell (cRCC) and von Hippel-Lindau (VHL) disease is the most common cause of inherited cRCC. Familial cRCC may also be associated with chromosome 3 translocations and has recently been described in patients with Birt-Hogg-Dube (BHD) syndrome, caused by germline FLCN mutation. Fewer than 20 kindreds with familial cRCC without VHL disease or a constitutional translocation have been described. The purpose of this investigation was to define the clinical and genetic features of familial non-VHL cRCC (FcRCC) and to evaluate whether unrecognized BHD syndrome might be present in patients with apparent nonsyndromic RCC susceptibility. EXPERIMENTAL DESIGN: We analyzed the clinical features of, and undertook segregation analysis in, 60 kindreds containing two or more cases of RCC (at least one confirmed case of cRCC) and no evidence of an RCC susceptibility syndrome. We also undertook FLCN analysis to evaluate whether unrecognized BHD syndrome might be present in 69 patients with apparent nonsyndromic RCC susceptibility. RESULTS: FcRCC was characterized by an earlier age at onset than sporadic cases and more frequent occurrence of bilateral or multicentric tumors. Segregation analysis showed autosomal dominant inheritance with sex- and age-dependent penetrance. A germline FLCN mutation was detected in 3 of 69 (4.3%) patients with apparent nonsyndromic RCC susceptibility. CONCLUSIONS: We describe the clinical and genetic features of the largest series of FcRCC and recommend these patients be offered FLCN analysis, in addition to constitutional cytogenetic and VHL analysis.     

Analysis of the TSC1 and TSC2 genes in sporadic renal cell carcinomas.

The genetic events involved in the aetiology of non-clear-cell renal cell carcinoma (RCC) and a proportion of clear cell RCC remain to be defined. Germline mutations of the TSC1 and TSC2 genes cause tuberous sclerosis (TSC), a multi-system hamartoma syndrome that is also associated with RCC. We assessed 17 sporadic clear cell RCCs with a previously identified VHL mutation, 15 clear-cell RCCs without an identified VHL mutation and 15 non-clear-cell RCCs for loss of heterozygosity (LOH) at chromosomes 9q34 and 16p13.3, the chromosomal locations of TSC1 and TSC2. LOH was detected in 4/9, 1/11 and 3/13 cases informative at both loci. SSCP analysis of the whole coding region of the retained allele did not reveal any cases with a detectable intragenic second somatic mutation. Furthermore, RT-PCR analysis of TSC1 and TSC2 on total RNA from 8 clear-cell RCC cell lines confirmed expression of both TSC genes. These data indicate that biallelic inactivation of TSC1 or TSC2 is not frequent in sporadic RCC and suggests that the molecular mechanisms of renal carcinogenesis in TSC are likely to be distinct.     

Genetic basis of cancer of the kidney

Kidney cancer is not a single disease. It is made up of a number of different types of cancer that occur in the kidney, each with a different histologic type, having a different clinical course, responding differently to therapy and caused by a different gene. The identification of families with a predisposition to the development of renal neoplasms, including von Hippel-Lindau (VHL), hereditary papillary renal carcinoma (HPRC), Birt-Hogg-Dubé (BHD), and hereditary leiomyomatosis and renal cell cancer (HLRCC), has made possible the identification of the different genes for these cancers. The genetic basis for each of these has been identified with current investigation focusing on the mechanisms of carcinogenesis. The elucidation of molecular pathogenesis in these familial forms of kidney cancer should provide the opportunity to determine successful approaches for novel therapeutic agents.     

Inactivation of BHD in sporadic renal tumors

Studies of families with Birt-Hogg-Dubé syndrome (BHD) have recently revealed protein-truncating mutations in the BHD gene, leading to tumorigenesis of the skin and of different cell types of kidney. To additionally evaluate the role of BHD in kidney tumorigenesis, we studied 39 sporadic renal tumors of different cell types: 7 renal oncocytomas, 9 chromophobe renal cell carcinomas (RCCs), 11 papillary RCCs, and 12 clear cell RCCs. We screened for BHD mutations and identified a novel somatic mutation in exon 13: c.1939_1966delinsT in a papillary RCC. We performed loss of heterozygosity (LOH) analysis on 28 matched normal/tumor sets, of which 10 of 28 (36%) demonstrated LOH: 2 of 6 (33%) chromophobe RCCs, 5 of 6 (83%) papillary RCCs, 3 of 12 (25%) clear cell RCCs, but 0 of 4 renal oncocytomas. BHD promoter methylation status was examined by a methylation-specific PCR assay of all of the tumors. Methylation was detected in 11 of 39 (28%) sporadic renal tumors: 2 of 7 (29%) renal oncocytomas, 1 of 9 (11%) chromophobe RCCs, 4 of 11 (36%) papillary RCCs, and 4 of 12 (33%) clear cell RCCs. Five tumors with methylation also exhibited LOH. Mutation and methylation were absent in 9 kidney cancer cell lines. Our results showed that somatic BHD mutations are rare in sporadic renal tumors. The alternatives, LOH and BHD promoter methylation, are the two possible inactivating mechanisms involved. In conclusion, unlike other hereditary kidney cancer-related genes (i.e., VHL and MET), which are cell type-specific, BHD is involved in the entire spectrum of histological types of renal tumors, suggesting its major role in kidney cancer tumorigenesis.     

Von Hippel-Lindau抑癌基因在散发性肾透明细胞癌中的突变及其意义

背景与目的：von Hippel-Lindau（VHL）基因是一种抑癌基因,其突变在肾透明细胞癌的发生发展中发挥重要的作用.本研究旨在了解VHL抑癌基因在中国人散发性.肾透明细胞癌中的突变特点,并探讨基因突变与肿瘤分期、病理分级等临床病理特征的关系.方法：应用聚合酶链反应（PCR）、双向测序方法检测72例散发性肾透明细胞癌患者肾癌组织及正常肾组织中VHL抑癌基因的突变情况.结果：72例肿瘤组织中检测出VHL抑癌基因突变25例,突变率为35%.其中移码突变13例,错义突变8例,无义突变3例,同义突变l例.第1外显子6例,第2外显子5例,第3外显子12例,内含子区2例.25例突变中,6例突变位于密码子157～166区域.VHL抑癌基因突变与肿瘤分期、分级等临床病理指标无关（P＞0.05）.结论：中国人散发性肾透明细胞癌中VHL抑癌基因突变率较低,突变主要位于第3外显子,该外显子区可能存在一个突变热点区域.VHL抑癌基因突变与肿瘤分期、分级等临床病理指标无关,是肾透明细胞癌发生发展的早期遗传事件.     

Mutations in BHD and TP53 genes, but not in HNF1beta gene, in a large series of sporadic chromophobe renal cell carcinoma

BHD, TP53, and HNF1beta on chromosome 17 were studied in 92 cases of renal cell carcinoma (46 chromophobe, 19 clear cell, 18 oncocytoma, and nine papillary). Six, thirteen, and zero cases had, respectively BHD, TP53, and HNF1beta mutations, (84% mutations involved chromophobe), suggesting a role for BHD and TP53 in chromophobe subtype.     

基于数据挖掘分析VHL，PBRM1，TTN，SETD2，BAP1在肾透明细胞癌中的表达及预后意义

目的:研究相关基因在肾透明细胞癌中的表达变化,评价相关基因与肾透明细胞癌的关系及其对预后的影响。方法:在TCGA（The Cancer Genome Atlas）数据库中配对肾透明细胞癌组织和正常肾细胞组织相关基因表达谱数据,通过数据挖掘技术挖掘相关基因（VHL,PBRM1,TTN,SETD2,BAP1）与肾透明细胞癌表达及预后的关系。结果:相对比正常肾透明细胞组织,VHL,PBRM1,SETD2,BAP1均呈低表达,TTN呈高表达,通过建立相关生存曲线,可知PBRM1低表达与TTN高表达能够减少肾透明细胞癌患者的生存时间,而VHL、SETD2、BAP1基因低表达与肾透明细胞癌患者的生存时间无统计学差异。结论:PBRM1的低表达与TTN高表达是影响肾透明细胞癌预后的不良因素,因此PRBM1、TTN基因的表达对判断肾透明细胞癌患者的生存预后具有参考价值。     

Hepatocyte growth factor-stimulated renal tubular mitogenesis: effects on expression of c-myc, c-fos, c-met, VEGF and the VHL tumour-suppressor and related genes.

Hepatocyte growth factor (HGF/SF) is a potent renal proximal tubular cell (PTEC) mitogen involved in renal development. HGF/SF is the functional ligand for the c-met proto-oncogene, and germline c-met mutations are associated with familial papillary renal cell carcinoma. Somatic von Hippel-Lindau disease tumour-suppressor gene (VHL) mutations are frequently detected in sporadic clear cell renal cell carcinomas (RCC), and germline VHL mutations are the commonest cause of familial clear cell RCC. pVHL binds to the positive regulatory components of the trimeric elongin (SIII) complex (elongins B and C) and has been observed to deregulate expression of the vascular endothelial growth factor (VEGF) gene. HGF/SF has similarly been reported to up-regulate expression of the VEGF gene in non-renal experimental systems. To investigate the mechanism of HGF/SF action in PTECs and, specifically, to examine potential interactions between the HGF/c-met and the VHL-mediated pathways for renal tubular growth control, we have isolated untransformed PTECs from normal kidneys, developed conditions for their culture in vitro and used these cells to investigate changes in mRNA levels of the VHL, elongin A, B and C, VEGF, c-myc, c-fos and c-met genes after HGF/SF exposure. Significant elevations in the mRNA levels of VEGF, c-myc, c-fos, c-met and elongins A, B and C, but not VHL, were detected after HGF/SF stimulation of human PTECs (P < 0.02), with a consistent order of peak levels observed over successive replicates (c-fos at 1 h, VEGF at 2-4 h, c-myc, at 4 h, followed by c-met and all three elongin subunits at 8 h). This study highlights the spectrum of changes in gene expression observed in PTECs after HGF/SF stimulation and has identified possible candidate mediators of the HGF/SF-induced mitogenic response. Our evidence would suggest that the changes in PTEC VEGF expression induced by HGF/SF are mediated by a VHL-independent pathway.     

Targeting the loss of the von Hippel-Lindau tumor suppressor gene in renal cell carcinoma cells

Late-stage clear cell renal carcinoma poses a formidable clinical challenge due to the high mortality rate associated with this disease. Molecular and genetic studies have identified functional loss of the von Hippel-Lindau (VHL) gene as a frequent and crucial event in the development of the malignant phenotype of clear cell renal carcinomas. Loss of VHL function thus represents a pathognomonic molecular defect for therapeutic exploitation. The objective of this study was to evaluate the possibility of targeting VHL loss through pharmacologic means. Chromomycin A3 (ChA3) was identified through in silico analysis of existing publicly available drug profiles from the National Cancer Institute as an agent that seemed to selectively target VHL-deficient clear cell renal carcinoma cells. Genotype-selective toxicity was first determined through short-term viability assays and then confirmed with clonogenic studies. Coculture of fluorescently labeled VHL-deficient and VHL-positive cells showed discriminate killing of the VHL-deficient cells with ChA3. Mechanistically, overexpression of hypoxia-inducible factor (HIF)-2alpha in VHL-positive clear cell renal carcinoma cells phenocopied loss of VHL with respect to ChA3 toxicity, establishing ChA3 as a HIF-dependent cytotoxin. This study shows the feasibility of selectively targeting the loss of the VHL tumor suppressor gene in clear cell renal carcinoma for potential clinical benefit and may have greater ramifications in the development of new targeted therapies for the treatment of cancer and other genetic diseases.