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1.
Lehtonen HJ Kiuru M Ylisaukko-Oja SK Salovaara R Herva R Koivisto PA Vierimaa O Aittomäki K Pukkala E Launonen V Aaltonen LA 《Journal of medical genetics》2006,43(6):523-526
Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a tumour predisposition syndrome caused by heterozygous germline mutations in the fumarate hydratase (FH) gene. The condition is characterised by predisposition to benign leiomyomas of the skin and the uterus, renal cell carcinoma (RCC), and uterine leiomyosarcoma (ULMS). To comprehensively examine the cancer risk and tumour spectrum in Finnish FH mutation positive families, genealogical and cancer data were obtained from 868 individuals. The cohort analysis of the standardised incidence ratios (SIR) was analysed from 256 individuals. FH mutation status was analysed from all available individuals (n=98). To study tumour spectrum in FH mutation carriers, loss of the wild type allele was analysed from all available tumours (n=22). The SIR was 6.5 for RCC and 71 for ULMS. The overall cancer risk was statistically significantly increased in the age group of 15–29 years, consistent with features of cancer predisposition families in general. FH germline mutation was found in 55% of studied individuals. Most RCC and ULMS tumours displayed biallelic inactivation of FH, as did breast and bladder cancers. In addition, several benign tumours including atypical uterine leiomyomas, kidney cysts, and adrenal gland adenomas were observed. The present study confirms with calculated risk ratios the association of early onset RCC and ULMS with FH germline mutations in Finns. Some evidence for association of breast and bladder carcinoma with HLRCC was obtained. The data enlighten the organ specific malignant potential of HLRCC. 相似文献
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DL Smit AR Mensenkamp S Badeloe MH Breuning MEH Simon KY Van Spaendonck CM Aalfs JG Post S Shanley IPC Krapels LH Hoefsloot RJA Van Moorselaar TM Starink J‐P Bayley J Frank MAM Van Steensel FH Menko 《Clinical genetics》2011,79(1):49-59
Smit DL, Mensenkamp AR, Badeloe S, Breuning MH, Simon MEH, van Spaendonck KY, Aalfs CM, Post JG, Shanley S, Krapels IPC, Hoefsloot LH, van Moorselaar RJA, Starink TM, Bayley J‐P, Frank J, van Steensel MAM, Menko FH. Hereditary leiomyomatosis and renal cell cancer in families referred for fumarate hydratase germline mutation analysis. Heterozygous fumarate hydratase (FH) germline mutations cause hereditary leiomyomatosis and renal cell cancer (HLRCC), an autosomal dominant syndrome characterized by multiple cutaneous piloleiomyomas, uterine leiomyomas and papillary type 2 renal cancer. The main objective of our study was to evaluate clinical and genetic data from families suspected of HLRCC on a nationwide level. All families referred for FH mutation analysis in the Netherlands were assessed. We performed FH sequence analysis and multiplex ligation‐dependent probe amplification. Families with similar FH mutations were examined for haplotype sharing. In 14 out of 33 families, we identified 11 different pathogenic FH germline mutations, including 4 novel mutations and 1 whole‐gene deletion. Clinical data were available for 35 FH mutation carriers. Cutaneous leiomyomas were present in all FH mutation carriers older than 40 years of age. Eleven out of 21 female FH mutation carriers underwent surgical treatment for symptomatic uterine leiomyomas at an average of 35 years. Two FH mutation carriers had papillary type 2 renal cancer and Wilms' tumour, respectively. We evaluated the relevance of our findings for clinical practice and have proposed clinical diagnostic criteria, indications for FH mutation analysis and recommendations for management. 相似文献
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Nicolas Wyvekens Nadejda Valtcheva Axel Mischo Birgit Helmchen Thomas Hermanns Matthias Choschzick Andreas M. Htker Anita Rauch Beda Mühleisen Dilara Akhoundova Achim Weber Holger Moch Niels J. Rupp 《Genes, chromosomes & cancer》2020,59(11):611-619
The hereditary leiomyomatosis and renal cell carcinoma syndrome (HLRCC) is defined by germline mutations in the fumarate hydratase (FH) gene and associated with leiomyomas and aggressive renal cell carcinomas with FH deficiency. Here, we comprehensively characterize two new patients with HLRCC syndrome on a morphological, immunohistochemical and genetic level. The patients developed aggressive HLRCC syndrome‐associated RCCs, uterine leiomyomas and dermal leiomyomas. One HLRCC syndrome‐associated RCC exhibited an unusual morphology with accumulation of “colloid‐like” cytoplasmic inclusions, which might serve as a novel sentinel feature to trigger further testing. This case showed partially retained FH expression, initially hampering correct diagnosis. Comprehensive next‐generation sequencing analyses of HLRCC syndrome‐associated RCC and leiomyomas in our patients revealed divergent genetic changes in the FH gene in different tumors from the same patient. While all leiomyomas (uterine and cutaneous) showed a FH loss of heterozygosity (LOH) as a wildtype allele inactivating event, one HLRCC‐RCC showed a second, undescribed NM_000143.3; c.947C>T; p.Ala316Val FH mutation accompanying the preexisting splice site mutation c.378+2T>C. In the other HLRCC syndrome‐associated RCC, the FH mutation (NM_000143.3; c.462T>G; p.Asn154Lys with a somatic LOH) represents another variant of unknown significance that we link to HLRCC ‐ and thus classify as likely pathogenic. Due to the specific diagnosis of metastatic HLRCC syndrome‐associated RCC, both cases were treated in first line with bevacizumab/erlotinib and showed remarkable and long lasting responses. These findings allow new morphological and molecular insights into the biology of the HLRCC syndrome, corroborate the “second hit” hypothesis of tumor formation in HLRCC patients and may promote a distinct therapeutic approach. 相似文献
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Histopathological analysis of aggressive renal cell carcinoma harboring a unique germline mutation in fumarate hydratase 下载免费PDF全文
Kana Matsumoto Naoko Udaka Hisashi Hasumi Noboru Nakaigawa Yoji Nagashima Reiko Tanaka Ikuma Kato Masahiro Yao Mitsuko Furuya 《Pathology international》2018,68(8):473-478
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Bardella C El-Bahrawy M Frizzell N Adam J Ternette N Hatipoglu E Howarth K O'Flaherty L Roberts I Turner G Taylor J Giaslakiotis K Macaulay VM Harris AL Chandra A Lehtonen HJ Launonen V Aaltonen LA Pugh CW Mihai R Trudgian D Kessler B Baynes JW Ratcliffe PJ Tomlinson IP Pollard PJ 《The Journal of pathology》2011,225(1):4-11
Germline mutations in the FH gene encoding the Krebs cycle enzyme fumarate hydratase predispose to hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome. FH-deficient cells and tissues accumulate high levels of fumarate, which may act as an oncometabolite and contribute to tumourigenesis. A recently proposed role for fumarate in the covalent modification of cysteine residues to S-(2-succinyl) cysteine (2SC) (termed protein succination) prompted us to assess 2SC levels in our existing models of HLRCC. Herein, using a previously characterized antibody against 2SC, we show that genetic ablation of FH causes high levels of protein succination. We next hypothesized that immunohistochemistry for 2SC would serve as a metabolic biomarker for the in situ detection of FH-deficient tissues. Robust detection of 2SC was observed in Fh1 (murine FH)-deficient renal cysts and in a retrospective series of HLRCC tumours (n = 16) with established FH mutations. Importantly, 2SC was undetectable in normal tissues (n = 200) and tumour types not associated with HLRCC (n = 1342). In a prospective evaluation of cases referred for genetic testing for HLRCC, the presence of 2SC-modified proteins (2SCP) correctly predicted genetic alterations in FH in every case. In two series of unselected type II papillary renal cancer (PRCC), prospectively analysed by 2SCP staining followed by genetic analysis, the biomarker accurately identified previously unsuspected FH mutations (2/33 and 1/36). The investigation of whether metabolites in other tumour types produce protein modification signature(s) that can be assayed using similar strategies will be of interest in future studies of cancer. 相似文献
6.
Novel mutations in FH and expansion of the spectrum of phenotypes expressed in families with hereditary leiomyomatosis and renal cell cancer 总被引:2,自引:1,他引:2
Wei MH Toure O Glenn GM Pithukpakorn M Neckers L Stolle C Choyke P Grubb R Middelton L Turner ML Walther MM Merino MJ Zbar B Linehan WM Toro JR 《Journal of medical genetics》2006,43(1):18-27
Background
Hereditary leiomyomatosis and renal cell cancer (HLRCC; OMIM 605839) is the predisposition to develop smooth muscle tumours of the skin and uterus and/or renal cancer and is associated with mutations in the fumarate hydratase gene (FH). Here we characterise the clinical and genetic features of 21 new families and present the first report of two African‐American families with HLRCC.Methods
Using direct sequencing analysis we identified FH germline mutations in 100% (21/21) of new families with HLRCC.Results
We identified 14 germline FH mutations (10 missense, one insertion, two nonsense, and one splice site) located along the entire length of the coding region. Nine of these were novel, with six missense (L89S, R117G, R190C, A342D, S376P, Q396P), one nonsense (S102X), one insertion (111insA), and one splice site (138+1G>C) mutation. Four unrelated families had the R58X mutation and five unrelated families the R190H mutation. Of families with HLRCC, 62% (13/21) had renal cancer and 76% (16/21) cutaneous leiomyomas. Of women FH mutation carriers from 16 families, 100% (22/22) had uterine fibroids. Our study shows that expression of cutaneous manifestations in HLRCC ranges from absent to mild to severe cutaneous leiomyomas. FH mutations were associated with a spectrum of renal tumours. No genotype‐phenotype correlations were identified.Conclusions
In combination with our previous report, we identify 31 different germline FH mutations in 56 families with HLRCC (20 missense, eight frameshifts, two nonsense, and one splice site). Our FH mutation detection rate is 93% (52/56) in families suspected of HLRCC. 相似文献7.
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Ronald L. Thibert Melanie B. Berkmen 《American journal of medical genetics. Part A》2020,182(3):504-507
Fumarate hydratase deficiency (FHD) is a rare metabolic disease caused by two defective copies of the FH gene, which encodes the Krebs cycle enzyme fumarase. FHD is associated with brain and developmental abnormalities, seizures, and high childhood mortality. We describe the symptoms and treatment of a patient with FHD. While infantile spasms are common in FHD, the patient presented with epileptic spasms later in childhood. Also unexpectedly, the patient responded excellently to lacosamide for her non‐convulsive status epilepticus and epileptic spasms after three first‐line medication trials failed. We biochemically analyzed the patient's two fumarase variants (E432Kfs*17 and D65G). While E432Kfs*17 was extremely enzymatically defective, D65G exhibited only a mild defect, possibly playing a role in the patient's longer survival. 相似文献
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Pithukpakorn M Wei MH Toure O Steinbach PJ Glenn GM Zbar B Linehan WM Toro JR 《Journal of medical genetics》2006,43(9):755-762
Background
Hereditary leiomyomatosis and renal cell cancer (HLRCC) is the autosomal dominant heritable syndrome with predisposition to development of renal cell carcinoma and smooth muscle tumours of the skin and uterus.Objective
To measure the fumarate hydratase (FH) enzyme activity in lymphoblastoid cell lines and fibroblast cell lines of individuals with HLRCC and other familial renal cancer syndromes.Methods
FH enzyme activity was determined in the whole cell, cytosolic, and mitochondrial fractions in 50 lymphoblastoid and 16 fibroblast cell lines including cell lines from individuals with HLRCC with 16 different mutations.Results
Lymphoblastoid cell lines (n = 20) and fibroblast cell lines (n = 11) from individuals with HLRCC had lower FH enzyme activity than cells from normal controls (p<0.05). The enzyme activity in lymphoblastoid cell lines from three individuals with mutations in R190 was not significantly different from individuals with other missense mutations. The cytosolic and mitochondrial FH activity of cell lines from individuals with HLRCC was reduced compared with those from control cell lines (p<0.05). There was no significant difference in enzyme activity between control cell lines (n = 4) and cell lines from affected individuals with other hereditary renal cancer syndromes (n = 22).Conclusions
FH enzyme activity testing provides a useful diagnostic method for confirmation of clinical diagnosis and screening of at‐risk family members. 相似文献10.
Liying Zhang Michael F. Walsh Sowmya Jairam Diana Mandelker Yi Zhong Yelena Kemel Ying‐Bei Chen David Musheyev Ahmet Zehir Gowtham Jayakumaran Edyta Brzostowski Ozge Birsoy Ciyu Yang Yirong Li Joshua Somar Deborah DeLair Nisha Pradhan Michael F. Berger Karen Cadoo Maria I. Carlo Mark E. Robson Zsofia K. Stadler Christine A. Iacobuzio‐Donahue Vijai Joseph Kenneth Offit 《Human mutation》2020,41(1):103-109
Fumarate hydratase (FH) mutations underpin the autosomal recessive syndrome. FH deficiency and the autosomal dominant syndrome hereditary leiomyomatosis and renal cell carcinoma (HLRCC). The FH c.1431_1433dupAAA (p.Lys477dup) genomic alteration has been conclusively shown to contribute to FH deficiency when occurring with another FH germline alteration. However, a sufficiently large dataset has been lacking to conclusively determine its clinical significance to cancer predisposition in the heterozygous state. We reviewed a series of 7,571 patients with cancer who received germline results through MSK‐IMPACT testing at the Memorial Sloan Kettering Cancer Center. The FH c.1431_1433dupAAA (p.Lys477dup) variant was detected in 24 individuals, none of whom was affected with renal cancer. Eleven of the 372 patients with renal cancer were identified to carried pathogenic FH variants associated with HLRCC. None of these 372 patients with renal cancer carried the FH c.1431_1433dupAAA variant. Our data indicate the FH c.1431_1433dupAAA is not associated with cancer including renal cell carcinoma. 相似文献
11.
Reassessing the clinical spectrum associated with hereditary leiomyomatosis and renal cell carcinoma syndrome in French FH mutation carriers 下载免费PDF全文
M. Muller G. Le Teuff C. Genestie S. Deveaux A. Slama N. Poulalhon B. Escudier L. Albiges N. Soufir M.‐F. Avril B. Gardie C. Saldana Y. Allory A.‐P. Gimenez‐Roqueplo B. Bressac‐de Paillerets P.R. Benusiglio 《Clinical genetics》2017,92(6):606-615
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A distinctive,low‐grade oncocytic fumarate hydratase‐deficient renal cell carcinoma,morphologically reminiscent of succinate dehydrogenase‐deficient renal cell carcinoma 下载免费PDF全文
Steven C Smith Deepika Sirohi Chisato Ohe Jonathan B McHugh Jason L Hornick Jigna Kalariya Sushil Karia Katie Snape Shirley V Hodgson Andi K Cani Daniel Hovelson Daniel J Luthringer Guido Martignoni Ying‐Bei Chen Scott A Tomlins Rohit Mehra Mahul B Amin 《Histopathology》2017,71(1):42-52
14.
Xiaolei Zhao Zhenhua Zhao Wenchao Xu Junqing Hou Xinyi Du 《International journal of clinical and experimental pathology》2015,8(1):758-764
Introduction: Clear cell renal cell carcinoma (ccRCC) is the most common type of cancer in the adult kidney, and the prognosis of metastatic ccRCC remains poor with high mortality. Recent study indicated that microRNAs (miRNAs) played critical roles in tumor progression. The aim of this study was to investigate the expression, biological role and clinical significance of miR-497 in ccRCC. Methods: Quantitative real-time PCR (qRT-PCR) was performed to detect the expression of miR-497 in renal cancer cell lines and ccRCC tissues. The association between miR-497 expression and overall survival was estimated by the Kaplan-Meier method. Gain of function assays were performed in the 786-O renal cancer cell line. Results: Expression of the miR-497 was significantly decreased in renal cancer cell lines and ccRCC tissues when compared with normal human proximal tubule epithelial cells and adjacent non-tumor tissues. Decreased miR-497 expression was significantly associated with tumor stage, histological grade and lymph node metastases. Significantly shorter overall survival was observed in patients with lower expression of the miR-497. Overexpression of miR-497 significantly inhibited renal cancer cell proliferation, migration and invasion. Conclusions: Our results demonstrated that miR-497 was decreased in ccRCC tissues and may provide a potential prognostic biomarker and a potential target for therapeutic intervention. 相似文献
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Automated immunofluorescence analysis defines microvessel area as a prognostic parameter in clear cell renal cell cancer 总被引:2,自引:0,他引:2
Mertz KD Demichelis F Kim R Schraml P Storz M Diener PA Moch H Rubin MA 《Human pathology》2007,38(10):1454-1462
Microvessel density (MVD) has been reported to have prognostic relevance for clear cell renal cell carcinoma (ccRCC). However, this finding is controversial because of the difficulty of MVD evaluation in this complex vascularized tumor type. The present study evaluates the use of an automated quantitative analysis (AQUA) system for objective and reproducible determination of tumor vascularization in clear cell renal cell carcinoma (ccRCC). The AQUA system was applied to tissue microarrays with 284 primary ccRCC tumors. To determine angiogenesis in ccRCC, we created an epithelial/stromal mask consisting of CD10, epithelial membrane antigen, and vimentin to distinguish epithelial tumor cells from CD34-positive endothelial cells. Using immunofluorescence and computer-aided quantification of CD34 expression, we measured the relative microvessel area (MVA) and compared the MVA to the manually counted MVD. The MVA determined by AQUA in a test set with 209 ccRCCs ranged from 0% to 30.3% (mean +/- SD, 10.1% +/- 6.3%). The manually determined MVD ranged from 6 to 987 vessels/mm(2) (416.8 +/- 252.8 vessels/mm(2)). MVA and MVD were significantly correlated (P < .001). A larger MVA was associated with histologic grade (P < .001), tumor stage (P =.008), presence of metastasis (P = .005), presence of sarcomatoid areas (P < .001), and tumor-specific survival (P < .001). Using MVA as defined in the test set, all associations with clinical and pathologic parameters were confirmed in a second independent validation set. MVA determination by AQUA is an objective and reliable method to quantify tumor vascularization in ccRCC. A large MVA correlates with a high MVD and is associated with better patient prognosis. 相似文献
19.
Naoto Kuroda Chisato Ohe Fumi Kawakami Shuji Mikami Mitsuko Furuya Keiko Matsuura Masatsugu Moriyama Yoji Nagashima Ming Zhou Fredrik Petersson José I López Ondrej Hes Michal Michal Mahul B Amin 《International journal of clinical and experimental pathology》2014,7(11):7312-7318
The disease concept of clear cell (tubulo) papillary renal cell carcinoma (CCP-RCC) as a distinct subtype of renal cell carcinoma has been recently established. First described in the setting of end stage renal disease, this tumor type is more frequently recognized and encountered in a sporadic setting. In this article, we provide an overview of the recent understanding of this tumor. Macroscopically, tumors are well circumscribed with well-developed tumor capsule. Histologically, the tumor cells are cuboidal to low columnar cell with clear cytoplasm and papillary and tubulo-papillary configuration. Immunohistochemically, tumor cells generally show diffuse expression for cytokeratin 7, CA9 (cup-shaped pattern), HIF-1, GLUT-1 and high molecular weight cytokeratin, but negative for AMACR, RCC Ma and TFE3. CD10 is negative or focally positive in most tumors. Genetically, this tumor has no characteristics of clear cell RCC or papillary RCC. Prognostically, patients with CCP-RCC behave in an indolent fashion in all previously reported cases. In conclusion, although this tumor has been integrated into recent International Society of Urologic Pathology Classification of renal neoplasia, both aspects of disease concept and clinical behavior are yet to be fully elucidated. Further publications of large cohorts of patients will truly help understand the biologic potential and the molecular underpinnings of this tumor type. 相似文献