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Moon SW, Lee JC, Lee JH, Kim TY, Park JH. Clinical and Prognostic Value of VHL in Korean Patients with Rectal Cancer. MEDICINA (KAUNAS, LITHUANIA) 2025; 61:306. [PMID: 40005423 PMCID: PMC11857133 DOI: 10.3390/medicina61020306] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/30/2024] [Revised: 01/28/2025] [Accepted: 02/02/2025] [Indexed: 02/27/2025]
Abstract
Background and Objectives: Von Hippel-Lindau (VHL) disease is caused by mutations in the VHL gene and can develop various cancers. Hypoxia-inducible factors 1 and 2 alphas, regulated by the VHL gene, can increase the levels of vascular endothelial growth factor, thereby activating cancer progression. Here, we demonstrated clinical and prognostic values of VHL expression in rectal cancer (RC). Materials and Methods: Von Hippel-Lindau mRNA expression was examined in 60 patients with RC. Furthermore, we evaluated survival to determine the prognostic significance of VHL mRNA expression levels in RC using the Cancer Genome Atlas (TCGA) data. Results: Lower VHL expression was correlated with the recurrence (p = 0.058) and lymphatic invasion (p = 0.078), although it was not statistically significant. In TCGA data, VHL expression level was correlated with the M stage (p = 0.044); however, it had a possible association with lymphatic invasion (p = 0.068) and N stage (p = 0.104). Survival analysis showed that lower VHL gene expression predicted poorer survival in both patients with RC and TCGA data. Conclusions: This study identified a significant correlation between VHL gene expression and RC for the first time using patient tissues and TCGA data, suggesting that the VHL gene expression level could be a potential biomarker or candidate for the treatment of RC. Further studies are required to identify the molecular pathogenesis and clinical characteristics of VHL disease in RC.
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Affiliation(s)
- Sang-Won Moon
- Medical Course, School of Medicine, Keimyung University, Daegu 42601, Republic of Korea; (S.-W.M.); (J.-C.L.)
| | - Jun-Chae Lee
- Medical Course, School of Medicine, Keimyung University, Daegu 42601, Republic of Korea; (S.-W.M.); (J.-C.L.)
| | - Jae-Ho Lee
- Department of Anatomy, School of Medicine & Institute for Medical Science, Keimyung University, Daegu 42601, Republic of Korea;
| | - Tae-Young Kim
- Department of Anatomy, School of Medicine & Institute for Medical Science, Keimyung University, Daegu 42601, Republic of Korea;
| | - Jong Ho Park
- Department of Anatomy, School of Medicine & Institute for Medical Science, Keimyung University, Daegu 42601, Republic of Korea;
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Graham DW, Thompson B, Mantry P. Unusual Presentation of Von Hippel-Lindau Syndrome With Gastric Variceal Bleeding. Cureus 2024; 16:e64685. [PMID: 39156424 PMCID: PMC11327004 DOI: 10.7759/cureus.64685] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/16/2024] [Indexed: 08/20/2024] Open
Abstract
Gastric varices are most commonly a complication of portal hypertension or splenic vein thrombosis (SVT). The presence of gastric varices due to portal hypertension is significantly less than the prevalence of esophageal varices. SVT is a known complication of pancreatitis due to inflammation or compression of the splenic vein coursing along the posterior surface of the pancreas. Occlusion of the splenic vein leads to left-sided portal hypertension. Left-sided portal hypertension results in the development of collateral vessels that bypass the splenic vein by connecting with the short gastric veins. The associated increased pressure within the gastric vessels results in gastric varices. Gastric varices due to SVT may occur in the absence of or be disproportionate to esophageal varices. We report an interesting case of gastrointestinal bleeding from gastric varices related to cirrhosis secondary to metabolic dysfunction-associated steatohepatitis and SVT secondary to chronic pancreatitis due to pancreatic neuroendocrine tumor (NET) in a patient diagnosed with von Hippel-Lindau (VHL) syndrome.
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Affiliation(s)
- David W Graham
- Internal Medicine, Methodist Dallas Medical Center, Dallas, USA
| | - Blake Thompson
- Gastroenterology, Methodist Dallas Medical Center, Dallas, USA
| | - Parvez Mantry
- Hepatology, Methodist Dallas Medical Center, Dallas, USA
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3
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Stampone E, Bencivenga D, Capellupo MC, Roberti D, Tartaglione I, Perrotta S, Della Ragione F, Borriello A. Genome editing and cancer therapy: handling the hypoxia-responsive pathway as a promising strategy. Cell Mol Life Sci 2023; 80:220. [PMID: 37477829 PMCID: PMC10361942 DOI: 10.1007/s00018-023-04852-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2023] [Revised: 06/14/2023] [Accepted: 06/29/2023] [Indexed: 07/22/2023]
Abstract
The precise characterization of oxygen-sensing pathways and the identification of pO2-regulated gene expression are both issues of critical importance. The O2-sensing system plays crucial roles in almost all the pivotal human processes, including the stem cell specification, the growth and development of tissues (such as embryogenesis), the modulation of intermediate metabolism (including the shift of the glucose metabolism from oxidative to anaerobic ATP production and vice versa), and the control of blood pressure. The solid cancer microenvironment is characterized by low oxygen levels and by the consequent activation of the hypoxia response that, in turn, allows a complex adaptive response characterized mainly by neoangiogenesis and metabolic reprogramming. Recently, incredible advances in molecular genetic methodologies allowed the genome editing with high efficiency and, above all, the precise identification of target cells/tissues. These new possibilities and the knowledge of the mechanisms of adaptation to hypoxia suggest the effective development of new therapeutic approaches based on the manipulation, targeting, and exploitation of the oxygen-sensor system molecular mechanisms.
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Affiliation(s)
- Emanuela Stampone
- Department of Precision Medicine, University of Campania "L. Vanvitelli", Via Luigi De Crecchio, 7, 80138, Naples, Italy
| | - Debora Bencivenga
- Department of Precision Medicine, University of Campania "L. Vanvitelli", Via Luigi De Crecchio, 7, 80138, Naples, Italy
| | - Maria Chiara Capellupo
- Department of Precision Medicine, University of Campania "L. Vanvitelli", Via Luigi De Crecchio, 7, 80138, Naples, Italy
| | - Domenico Roberti
- Department of the Woman, the Child and of the General and Specialty Surgery, University of Campania "L. Vanvitelli", Via Luigi De Crecchio, 2, 80138, Naples, Italy
| | - Immacolata Tartaglione
- Department of the Woman, the Child and of the General and Specialty Surgery, University of Campania "L. Vanvitelli", Via Luigi De Crecchio, 2, 80138, Naples, Italy
| | - Silverio Perrotta
- Department of the Woman, the Child and of the General and Specialty Surgery, University of Campania "L. Vanvitelli", Via Luigi De Crecchio, 2, 80138, Naples, Italy
| | - Fulvio Della Ragione
- Department of Precision Medicine, University of Campania "L. Vanvitelli", Via Luigi De Crecchio, 7, 80138, Naples, Italy.
| | - Adriana Borriello
- Department of Precision Medicine, University of Campania "L. Vanvitelli", Via Luigi De Crecchio, 7, 80138, Naples, Italy.
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A Clinicopathologic and Molecular Analysis of Fumarate Hydratase-deficient Pheochromocytoma and Paraganglioma. Am J Surg Pathol 2023; 47:25-36. [PMID: 35993574 PMCID: PMC9760464 DOI: 10.1097/pas.0000000000001945] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Up to 40% of pheochromocytomas (PCCs) and paragangliomas (PGLs) are hereditary. Germline mutations/deletions in fumarate hydratase ( FH ) cause hereditary leiomyomatosis and renal cell carcinoma syndrome which manifests predominantly with FH-deficient uterine/cutaneous leiomyomas and renal cell carcinomas (RCCs)-tumors characterized by loss of immunohistochemical (IHC) expression of FH and/or positive staining for S-(2-succino)-cysteine. Occasional patients develop PCC/PGL. We investigated the incidence, morphologic, and clinical features of FH-deficient PCC/PGL. We identified 589 patients with PCC/PGLs that underwent IHC screening for FH and/or S-(2-succino)-cysteine. Eight (1.4%) PCC/PGLs were FH deficient (1.1% in an unselected population). The median age for FH-deficient cases was 55 (range: 30 to 77 y) with 50% arising in the adrenal. All 4 with biochemical data were noradrenergic. Two (25%) metastasized, 1 dying of disease after 174 months. Germline testing was performed on 7 patients, 6 of whom had FH missense mutations. None were known to have a significant family history before presentation or developed cutaneous leiomyomas, or FH-deficient RCC at extended follow-up. The patient wild-type for FH on germline testing was demonstrated to have somatic FH mutation and loss of heterozygosity corresponding to areas of subclonal FH deficiency in her tumor. One patient did not undergo germline testing, but FH mutation was demonstrated in his tumor. We conclude that FH-deficient PCC/PGL are underrecognized but can be identified by IHC. FH-deficient PCC/PGL are strongly associated with germline missense mutations but are infrequently associated with leiomyoma or RCC, suggesting there may be a genotype-phenotype correlation. FH-deficient PCC/PGL may have a higher metastatic risk.
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5
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Li Y, Xin X, Song W, Zhang X, Chen S, Wang Q, Li A, Li Y. VHL syndrome without clear family history: A rare case report and literature review of Chinese patients. Front Neurol 2022; 13:951054. [PMID: 36324386 PMCID: PMC9618664 DOI: 10.3389/fneur.2022.951054] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Accepted: 09/05/2022] [Indexed: 11/26/2022] Open
Abstract
Objective To analyze the clinical manifestations and imaging features of a hospitalized patient with intermittent headache who was finally diagnosed with von Hippel–Lindau (VHL) syndrome and to perform whole-exon gene detection to improve the understanding of the diagnosis and treatment strategies of the disease. Methods A case of suspected VHL syndrome in Shanxi Provincial People's Hospital was analyzed. Proband DNA was also extracted for whole exome sequencing and screened for causative mutation sites, which were validated by Sanger sequencing. The literature about VHL gene mutations in Chinese patients in the past 10 years were also reviewed. Results There is a heterozygous mutation site c.499C > G on the VHL gene on the short arm of chromosome 3 of the patient, which is a missense mutation. The mutation results in the substitution of arginine with glycine at amino acid 167 of the encoded protein, which may be primarily responsible for the disease in the patient with VHL syndrome. However, the mutation did not occur in other family members. Conclusion Early recognition and treatment of VHL syndrome can be available with genetic testing technology. Strengthening the understanding of this complex genetic disease and improving the diagnostic rate of VHL syndrome are helpful for the precise treatment of patients with this disease, which may help prolong the survival time of patients to a certain extent and improve their quality of life.
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Affiliation(s)
- Yaheng Li
- Department of Nephrology, Shanxi Provincial People's Hospital (Fifth Hospital) of Shanxi Medical University, Taiyuan, China
- Shanxi Provincial Key Laboratory of Kidney Disease, Taiyuan, China
| | - Xiaohong Xin
- Core Laboratory, Shanxi Provincial People's Hospital (Fifth Hospital) of Shanxi University, Taiyuan, China
- Academy of Microbial Ecology, Shanxi Medical University, Taiyuan, China
| | - Wenzhu Song
- School of Public Health, Shanxi Medical University, Taiyuan, China
| | - Xuan Zhang
- Department of Neurosurgery, Shanxi Provincial People's Hospital (Fifth Hospital) of Shanxi Medical University, Taiyuan, China
| | - Shengli Chen
- Department of Neurosurgery, Shanxi Provincial People's Hospital (Fifth Hospital) of Shanxi Medical University, Taiyuan, China
| | - Qian Wang
- Department of Nephrology, Shanxi Provincial People's Hospital (Fifth Hospital) of Shanxi Medical University, Taiyuan, China
- Shanxi Provincial Key Laboratory of Kidney Disease, Taiyuan, China
| | - Aizhong Li
- Department of Nephrology, Shanxi Provincial People's Hospital (Fifth Hospital) of Shanxi Medical University, Taiyuan, China
- Shanxi Provincial Key Laboratory of Kidney Disease, Taiyuan, China
| | - Yafeng Li
- Department of Nephrology, Shanxi Provincial People's Hospital (Fifth Hospital) of Shanxi Medical University, Taiyuan, China
- Shanxi Provincial Key Laboratory of Kidney Disease, Taiyuan, China
- Core Laboratory, Shanxi Provincial People's Hospital (Fifth Hospital) of Shanxi University, Taiyuan, China
- Academy of Microbial Ecology, Shanxi Medical University, Taiyuan, China
- *Correspondence: Yafeng Li
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Hudler P, Urbancic M. The Role of VHL in the Development of von Hippel-Lindau Disease and Erythrocytosis. Genes (Basel) 2022; 13:362. [PMID: 35205407 PMCID: PMC8871608 DOI: 10.3390/genes13020362] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2022] [Revised: 02/14/2022] [Accepted: 02/15/2022] [Indexed: 12/20/2022] Open
Abstract
Von Hippel-Lindau disease (VHL disease or VHL syndrome) is a familial multisystem neoplastic syndrome stemming from germline disease-associated variants of the VHL tumor suppressor gene on chromosome 3. VHL is involved, through the EPO-VHL-HIF signaling axis, in oxygen sensing and adaptive response to hypoxia, as well as in numerous HIF-independent pathways. The diverse roles of VHL confirm its implication in several crucial cellular processes. VHL variations have been associated with the development of VHL disease and erythrocytosis. The association between genotypes and phenotypes still remains ambiguous for the majority of mutations. It appears that there is a distinction between erythrocytosis-causing VHL variations and VHL variations causing VHL disease with tumor development. Understanding the pathogenic effects of VHL variants might better predict the prognosis and optimize management of the patient.
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Affiliation(s)
- Petra Hudler
- Medical Centre for Molecular Biology, Institute of Biochemistry and Molecular Genetics, Faculty of Medicine, University of Ljubljana, Vrazov trg 2, 1000 Ljubljana, Slovenia;
| | - Mojca Urbancic
- Eye Hospital, University Medical Centre Ljubljana, Grabloviceva ulica 46, 1000 Ljubljana, Slovenia
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Watts D, Jaykar MT, Bechmann N, Wielockx B. Hypoxia signaling pathway: A central mediator in endocrine tumors. Front Endocrinol (Lausanne) 2022; 13:1103075. [PMID: 36699028 PMCID: PMC9868855 DOI: 10.3389/fendo.2022.1103075] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2022] [Accepted: 12/21/2022] [Indexed: 01/11/2023] Open
Abstract
Adequate oxygen levels are essential for the functioning and maintenance of biological processes in virtually every cell, albeit based on specific need. Thus, any change in oxygen pressure leads to modulated activation of the hypoxia pathway, which affects numerous physiological and pathological processes, including hematopoiesis, inflammation, and tumor development. The Hypoxia Inducible Factors (HIFs) are essential transcription factors and the driving force of the hypoxia pathway; whereas, their inhibitors, HIF prolyl hydroxylase domain (PHDs) proteins are the true oxygen sensors that critically regulate this response. Recently, we and others have described the central role of the PHD/HIF axis in various compartments of the adrenal gland and its potential influence in associated tumors, including pheochromocytomas and paragangliomas. Here, we provide an overview of the most recent findings on the hypoxia signaling pathway in vivo, including its role in the endocrine system, especially in adrenal tumors.
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8
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Pinti E, Nemeth K, Staub K, Lengyel A, Fekete G, Haltrich I. Diagnostic difficulties and possibilities of NF1-like syndromes in childhood. BMC Pediatr 2021; 21:331. [PMID: 34325699 PMCID: PMC8320045 DOI: 10.1186/s12887-021-02791-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2021] [Accepted: 06/30/2021] [Indexed: 12/28/2022] Open
Abstract
BACKGROUND Neurofibromatosis type 1 (NF1), which is caused by heterozygous inactivating pathogenic variants in the NF1, has poor phenotypic expressivity in the early years of life and there are numerous conditions, including many other tumor predisposition syndromes, that can mimic its appearance. These are collectively termed NF1-like syndromes and are also connected by their genetic background. Therefore, the NF1's clinical diagnostic efficiency in childhood could be difficult and commonly should be completed with genetic testing. METHODS To estimate the number of syndromes/conditions that could mimic NF1, we compiled them through an extensive search of the scientific literature. To test the utility of NF1's National Institutes of Health (NIH) clinical diagnostic criteria, which have been in use for a long time, we analyzed the data of a 40-member pediatric cohort with symptoms of the NF1-like syndromes' overlapping phenotype and performed NF1 genetic test, and established the average age when diagnostic suspicion arises. To facilitate timely identification, we compiled strongly suggestive phenotypic features and anamnestic data. RESULTS In our cohort the utility of NF1's clinical diagnostic criteria were very limited (sensitivity: 80%, specificity: 30%). Only 53% of children with clinically diagnosed NF1 had a detectable NF1 pathogenic variation, whereas 40% of patients without fulfilled clinical criteria tested positive. The average age at first genetic counseling was 9 years, and 40% of children were referred after at least one tumor had already been diagnosed. These results highlight the need to improve NF1-like syndromes' diagnostic efficiency in childhood. We collected the most extensive spectrum of NF1-like syndromes to help the physicians in differential diagnosis. We recommend the detailed, non-invasive clinical evaluation of patients before referring them to a clinical geneticist. CONCLUSIONS Early diagnosis of NF1-like syndromes can help to prevent severe complications by appropriate monitoring and management. We propose a potential screening, diagnostic and management strategy based on our findings and recent scientific knowledge.
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Affiliation(s)
- Eva Pinti
- II. Department of Pediatrics, Semmelweis University, Tuzolto utca 7-9, Budapest, 1094, Hungary.
| | - Krisztina Nemeth
- II. Department of Pediatrics, Semmelweis University, Tuzolto utca 7-9, Budapest, 1094, Hungary
| | - Krisztina Staub
- II. Department of Pediatrics, Semmelweis University, Tuzolto utca 7-9, Budapest, 1094, Hungary
| | - Anna Lengyel
- II. Department of Pediatrics, Semmelweis University, Tuzolto utca 7-9, Budapest, 1094, Hungary
| | - Gyorgy Fekete
- II. Department of Pediatrics, Semmelweis University, Tuzolto utca 7-9, Budapest, 1094, Hungary
| | - Iren Haltrich
- II. Department of Pediatrics, Semmelweis University, Tuzolto utca 7-9, Budapest, 1094, Hungary
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Wang L, Feng Y, Jiang LY. Anesthetic management of bilateral pheochromocytoma resection in Von Hippel-Lindau syndrome: A case report. World J Clin Cases 2021; 9:3711-3715. [PMID: 34046474 PMCID: PMC8130083 DOI: 10.12998/wjcc.v9.i15.3711] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2020] [Revised: 02/01/2021] [Accepted: 03/17/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Von Hippel-Lindau disease (also known as VHL syndrome), is an autosomal dominant inherited disease. We describe a sporadic case of VHL syndrome where bilateral pheochromocytomas were unexpectedly identified. The patient underwent selective laparoscopic resections of the pheochromocytomas, and the anesthetic management during surgery was complex and challenging.
CASE SUMMARY A 22-year-old man presented to our hospital to seek medical advice for infertility without any other complaints. The results of computed tomography and catecholamine levels in blood and urine demonstrated adrenal gland masses which were diagnosed as pheochromocytomas. Further examination confirmed that the patient also had VHL syndrome. After thorough preparation, the patient underwent selective laparoscopic resection of the pheochromocytomas and was discharged 10 d after surgery. We describe the process of perioperative anesthesia management in this patient undergoing pheochromocytoma resection.
CONCLUSION This case summaries specific clinical traits and considerations in perioperative anesthesia management for VHL syndrome patients undergoing bilateral pheochromocytoma resection.
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Affiliation(s)
- Lu Wang
- Department of Anesthesiology, Peking University People’s Hospital, Beijing 100044, China
| | - Yi Feng
- Department of Anesthesiology, Peking University People’s Hospital, Beijing 100044, China
| | - Lu-Yang Jiang
- Department of Anesthesiology, Peking University People’s Hospital, Beijing 100044, China
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Wang H, Hu B, Chen W, Ren J, Liu P, Shi H. Clinicopathological features of sclerosing angiomatoid nodular transformation of the spleen. Pathol Res Pract 2021; 224:153490. [PMID: 34098199 DOI: 10.1016/j.prp.2021.153490] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2020] [Revised: 05/15/2021] [Accepted: 05/20/2021] [Indexed: 10/21/2022]
Abstract
PURPOSE To explore the clinicopathological features of sclerosing angiomatoid nodular transformation (SANT) of the spleen. METHODS The clinicopathological data of 26 SANT patients were analyzed. RESULT There were 15 men and 11 women, aged 23-62 years (mean: 43.9 years; median: 43 years). Twenty patients were found during health check-ups. Magnetic resonance imaging had significantly higher specificity than other imaging modes in the diagnosis of SANT. Macroscopically, the lesions were gray-red and gray-white, along with well-demarcated nodules. Microscopy showed multiple angiomatoid nodules embedded in hyperplastic fibrous tissues and dense collagen fiber; the angiomatoid structures inside the nodules had varied morphology. Patchy and nodular fresh and old hemorrhages were observed in each lesion. Proliferative fibroblasts were seen in the stroma, along with infiltration of a few mixed inflammatory cells. Serum tumor markers were negative. Fourteen patients (53.8 %) had benign or malignant lesions in other parts of the body, including the liver, kidneys, and adrenal and pituitary glands which were similar to von Hippel-Lindau (VHL) syndrome. The reasons for occurrence of SANT may be as follows: hemangioma/lymphangioma or splenic congestion with extensive hemorrhage and secondary changes. CONCLUSIONS SANT is a rare benign vascular lesion with some clinical manifestations similar to VHL syndrome. Patients have good prognosis after tumor removal.
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Affiliation(s)
- Hongqun Wang
- Department of Pathology, the Third People's Hospital of Bengbu City, Bengbu City, Anhui Province, 233000, China; Department of Pathology, the First Medical Center of the Chinese People's Liberation Army (PLA) General Hospital, Beijing, 100083, China
| | - Bingrong Hu
- Department of Pathology, the First Medical Center of the Chinese People's Liberation Army (PLA) General Hospital, Beijing, 100083, China; Department of Pathology, Lu'an People's Hospital, Lu'an City, Anhui Province, 237000, China
| | - Wei Chen
- Department of Pathology, the First Medical Center of the Chinese People's Liberation Army (PLA) General Hospital, Beijing, 100083, China
| | - Jiaming Ren
- Department of Pathology, the First Medical Center of the Chinese People's Liberation Army (PLA) General Hospital, Beijing, 100083, China
| | - Peng Liu
- Department of Pathology, the First Medical Center of the Chinese People's Liberation Army (PLA) General Hospital, Beijing, 100083, China
| | - Huaiyin Shi
- Department of Pathology, the First Medical Center of the Chinese People's Liberation Army (PLA) General Hospital, Beijing, 100083, China.
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11
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Wang S, Lo Galbo MD, Blair C, Thyagarajan B, Anderson KE, Lazovich D, Prizment A. Diabetes and kidney cancer risk among post-menopausal women: The Iowa women's health study. Maturitas 2020; 143:190-196. [PMID: 33308628 DOI: 10.1016/j.maturitas.2020.07.010] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2019] [Revised: 06/22/2020] [Accepted: 07/28/2020] [Indexed: 01/13/2023]
Abstract
BACKGROUND Many studies have reported a positive association between diabetes and kidney cancer. However, it is unclear whether diabetes is a risk factor for kidney cancer independent of other risk factors, such as obesity and hypertension. We comprehensively examined the association of diabetes and its duration with incident kidney cancer in the prospective cohort Iowa Women's Health Study (1986-2011). METHODS Diabetes status was self-reported at baseline (1986) and on five follow-up questionnaires. Cox proportional hazards regression was used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for the associations of baseline and time-dependent diabetes with the risk of incident kidney cancer. RESULTS During the 25 years of follow-up, 245 cases of kidney cancer occurred among 36,975 post-menopausal women. In an age-adjusted model, there was a significant association between time-dependent diabetes and the risk of kidney cancer [HR (95% CI) = 1.76 (1.26, 1.45)]; the association was attenuated after multivariable adjustment for age, body mass index (BMI), waist-to-hip ratio (WHR), hypertension, physical activity, diuretic use, pack-years of smoking, alcohol intake, and total caloric intake [HR = 1.35 (0.94, 1.94)]. However, among non-obese women or women with a waist circumference less than 34.6 in., diabetes was significantly associated with kidney cancer risk: for time-dependent diabetes, HRs (95% CIs) were 1.82 (1.10, 3.00) among those with BMI < 30 kg/m2 and 2.18 (1.08, 4.38) among those with a waist circumference <34.6 in.. CONCLUSIONS Our results suggest that diabetes is associated with kidney cancer risk among non-obese post-menopausal women.
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Affiliation(s)
- Shuo Wang
- Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, United States
| | - Mark D Lo Galbo
- Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, United States; Children's Minnesota, Minneapolis, MN, United States
| | - Cindy Blair
- Department of Internal Medicine, University of New Mexico, United States; University of New Mexico Comprehensive Cancer Center, United States
| | - Bharat Thyagarajan
- Masonic Cancer Center, University of Minnesota, United States; Department of Laboratory Medicine and Pathology, Medical School, University of Minnesota, United States
| | - Kristin E Anderson
- Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, United States; Masonic Cancer Center, University of Minnesota, United States
| | - DeAnn Lazovich
- Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, United States; Masonic Cancer Center, University of Minnesota, United States
| | - Anna Prizment
- Masonic Cancer Center, University of Minnesota, United States; Division of Hematology, Oncology and Transplantation, Medical School, University of Minnesota, United States.
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12
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Lin G, Zhao Y, Zhang Z, Zhang H. Clinical diagnosis, treatment and screening of the VHL gene in three von Hippel-Lindau disease pedigrees. Exp Ther Med 2020; 20:1237-1244. [PMID: 32742360 PMCID: PMC7388314 DOI: 10.3892/etm.2020.8829] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2018] [Accepted: 08/23/2019] [Indexed: 12/22/2022] Open
Abstract
The present study aimed to investigate the clinical characteristics of von Hippel-Lindau (VHL) disease and the clinical significance of VHL gene detection. The clinical materials of patients with VHL disease were collected from 3 different families between May 1985 and October 2017. A systematic pedigree study and VHL gene detection at the germline level were performed together with a literature review. Of the 22 patients from 3 VHL pedigrees, 10 exhibited VHL gene mutations (3 genotypes) at the germline level. The genotypes of pedigree were VHL-p.R161Q (c.482G>A), VHL-p.N78S (c.233A>G), and VHL-p.R167Q (c.500G>A). During the follow-up period, the symptoms were stable in 10 patients, including 2 cases of central nervous system hemangioblastomas (CNS-HB), 3 cases of bilateral multiple renal cell carcinoma (RCC) and 5 cases of adrenal pheochromocytoma without local recurrence or distant metastasis. Patients with p.R161Q and p.N78S were not associated with CNS-HB, which was different from the clinical phenotype of previously reported families. RCC were Fuhrman II grade, which was consistent with the previous study. The results of the present study indicated that the standardization of early diagnosis and the improvement of long-term efficacy may be achieved by combining clinical screening and VHL gene detection.
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Affiliation(s)
- Guobing Lin
- Department of Urology, The First People's Hospital of Wenling, Wenling, Zhejiang 317500, P.R. China
| | - Yihua Zhao
- Department of Urology, Yueqing People's Hospital, Yueqing, Zhejiang 325600, P.R. China
| | - Zhewei Zhang
- Department of Urology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, P.R. China
| | - Huijiang Zhang
- Department of Urology, Lishui City People's Hospital, Lishui, Zhejiang 323000 P.R. China
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13
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Karimi S, Arabi A, Shahraki T, Safi S. Von Hippel-Lindau Disease and the Eye. J Ophthalmic Vis Res 2020; 15:78-94. [PMID: 32095212 PMCID: PMC7001024 DOI: 10.18502/jovr.v15i1.5950] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2019] [Accepted: 08/22/2019] [Indexed: 11/29/2022] Open
Abstract
Retinal hemangioblastoma (also referred to as retinal capillary hemangioma) is a benign lesion originating from the endothelial and glial components of the neurosensory retina and optic nerve head. Historically known as a manifestation of the von Hippel-Lindau (VHL) disease, it can be seen as an isolated finding or in association with some rare ocular conditions. In addition to characteristic ophthalmoscopic features, results of numerous ancillary tests including angiography, ultrasound, optical coherence tomography, and genetic tests may support the diagnosis and differentiate it from similar conditions. Because of serious life-threatening complications of VHL disease, every ocular approach to retinal hemangioblastomas should be in relationship with additional multidisciplinary diagnostic and therapeutic efforts. In addition, any patient with actual or probable diagnosis of VHL disease should be screened for ocular involvement. Unfavorable visual loss can occur early, and ocular complications of VHL range from exudative retinopathy to tractional retinal detachment, neovascular glaucoma, and phthisis bulbi. Accordingly, various treatment methods have been tested with overall acceptable responses, including photocoagulation, cryotherapy, photodynamic therapy, plaque radiotherapy, vitrectomy, and more novel intravitreal injections of anti-vascular endothelial growth factors and propranolol.
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Affiliation(s)
- Saeed Karimi
- Ophthalmic Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.,Department of Ophthalmology, Torfeh Medical Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Amir Arabi
- Ophthalmic Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.,Department of Ophthalmology, Torfeh Medical Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Toktam Shahraki
- Ophthalmic Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.,Department of Ophthalmology, Torfeh Medical Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Sare Safi
- Ophthalmic Epidemiology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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14
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Wang J, Cao W, Wang Z, Zhu H. Novel gene mutation in von Hippel-Lindau disease - a report of two cases. BMC MEDICAL GENETICS 2019; 20:194. [PMID: 31823746 PMCID: PMC6902464 DOI: 10.1186/s12881-019-0930-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/26/2018] [Accepted: 11/28/2019] [Indexed: 01/01/2023]
Abstract
BACKGROUND Von Hippel-Lindau (VHL) syndrome is a familial autosomal dominant hereditary neoplastic disease caused by mutations in the VHL gene. Approximately 503 kinds of VHL gene mutations have been reported. Different types of mutations manifest various clinical phenotypes, from benign to malignant tumours or coexisting cysts. Thus, a gene mutation test is essential in the diagnosis of VHL syndrome. CASE PRESENTATION We reported two cases in which a novel mutation site in the c530-536delGACTGGA region in exon 3 of the VHL gene resulted in the development of VHL syndrome. According to the ACMG guidelines, this variation is pathogenic and consistent with autosomal dominant inheritance. This variation has not been reported anywhere in the databases or literature. CONCLUSION This report will add a new mutation site to VHL gene databases. The newly added gene mutation and its associated clinical phenotypes will help improve the accuracy of VHL diagnosis and benefit the community of VHL gene mutation carriers.
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Affiliation(s)
- Jitian Wang
- Department of Cancer Medicine, Gaomi People's Hospital, Shandong, 261500, Shandong Province, China.
| | - Wenjie Cao
- Department of Cancer Medicine, Gaomi People's Hospital, Shandong, 261500, Shandong Province, China.
| | - Zhaoxia Wang
- Department of Cancer Medicine, Gaomi People's Hospital, Shandong, 261500, Shandong Province, China
| | - Hong Zhu
- Department of Cancer Medicine, Gaomi People's Hospital, Shandong, 261500, Shandong Province, China
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15
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Abstract
Pheochromocytomas and extra-adrenal paragangliomas are rare neuroendocrine neoplasms with characteristic histologic and immunohistochemical features. These tumors can arise in several anatomic locations, necessitating that their diagnostic recognition extends beyond the realm of endocrine disorders. A practical and reproducible risk stratification system for these tumors is still in development. In this rapidly evolving era of molecular medicine, it is essential for pathologists to equip themselves with a framework for understanding the classification of paragangliomas and pheochromocytomas and be informed of how they might advise their colleagues with regard to prognostication and appropriate follow-up.
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Affiliation(s)
- Julie Guilmette
- Department of Pathology, Charles-Lemoyne Hospital, Sherbrooke University Affiliated Health Care Center, 3120 Boulevard Taschereau, Greenfield Park, Quebec J4V 2H1, Canada
| | - Peter M Sadow
- Department of Pathology, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Boston, MA 02114-2696, USA.
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16
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Hong B, Ma K, Zhou J, Zhang J, Wang J, Liu S, Zhang Z, Cai L, Zhang N, Gong K. Frequent Mutations of VHL Gene and the Clinical Phenotypes in the Largest Chinese Cohort With Von Hippel-Lindau Disease. Front Genet 2019; 10:867. [PMID: 31620170 PMCID: PMC6759728 DOI: 10.3389/fgene.2019.00867] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2018] [Accepted: 08/20/2019] [Indexed: 01/31/2023] Open
Abstract
Von Hippel–Lindau (VHL) disease is a rare autosomal-dominant inherited tumor syndrome. We aimed to analyze the correlations between frequent VHL mutations and phenotypes in Chinese VHL families. We screened 540 patients from 187 unrelated Chinese VHL families for 19 frequent VHL mutations. The penetrance and mean age at onset for VHL-associated susceptible organs were calculated and compared. The overall survival of VHL patients was described with Kaplan–Meier curves. Among the 19 frequent germline mutations, there were four hotspot mutation sites (194, 481, 499, and 500). Missense mutations were the most common types of mutations (70.0%) followed by nonsense mutations (20.0%) and splicing mutations (10.0%). Due to the diversity of these mutations, the penetrance for each organ and the age at onset are distinct. Even in cases of similar mutations, variance in the penetrance and age at onset was observed. The mean age at death for the patients in this cohort was 42.4 ± 13.5 years, and variability was observed in the Kaplan–Meier curves. We present a precise summary of the phenotypes for the frequent VHL mutations in the largest Chinese VHL cohort, which provides valuable strategies for genetic counseling and clinical surveillance of VHL individuals.
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Affiliation(s)
- Baoan Hong
- Department of Urology, Peking University First Hospital, Beijing, China.,Hereditary Kidney Cancer Research Center, Peking University First Hospital, Beijing, China.,Institute of Urology, Peking University, Beijing, China.,National Urological Cancer Center, Beijing, China.,Department of Urology, Beijing Cancer Hospital, Beijing, China.,Beijing Institute for Cancer Research, Beijing, China
| | - Kaifang Ma
- Department of Urology, Peking University First Hospital, Beijing, China.,Hereditary Kidney Cancer Research Center, Peking University First Hospital, Beijing, China.,Institute of Urology, Peking University, Beijing, China.,National Urological Cancer Center, Beijing, China
| | - Jingcheng Zhou
- Department of Urology, Peking University First Hospital, Beijing, China.,Hereditary Kidney Cancer Research Center, Peking University First Hospital, Beijing, China.,Institute of Urology, Peking University, Beijing, China.,National Urological Cancer Center, Beijing, China
| | - Jiufeng Zhang
- Department of Urology, Peking University First Hospital, Beijing, China.,Hereditary Kidney Cancer Research Center, Peking University First Hospital, Beijing, China.,Institute of Urology, Peking University, Beijing, China.,National Urological Cancer Center, Beijing, China
| | - Jiangyi Wang
- Department of Urology, Peking University First Hospital, Beijing, China.,Hereditary Kidney Cancer Research Center, Peking University First Hospital, Beijing, China.,Institute of Urology, Peking University, Beijing, China.,National Urological Cancer Center, Beijing, China
| | - Shengjie Liu
- Department of Urology, Peking University First Hospital, Beijing, China.,Hereditary Kidney Cancer Research Center, Peking University First Hospital, Beijing, China.,Institute of Urology, Peking University, Beijing, China.,National Urological Cancer Center, Beijing, China
| | - Zhongyuan Zhang
- Department of Urology, Peking University First Hospital, Beijing, China.,Hereditary Kidney Cancer Research Center, Peking University First Hospital, Beijing, China.,Institute of Urology, Peking University, Beijing, China.,National Urological Cancer Center, Beijing, China
| | - Lin Cai
- Department of Urology, Peking University First Hospital, Beijing, China.,Hereditary Kidney Cancer Research Center, Peking University First Hospital, Beijing, China.,Institute of Urology, Peking University, Beijing, China.,National Urological Cancer Center, Beijing, China
| | - Ning Zhang
- Department of Urology, Beijing Cancer Hospital, Beijing, China.,Beijing Institute for Cancer Research, Beijing, China
| | - Kan Gong
- Department of Urology, Peking University First Hospital, Beijing, China.,Hereditary Kidney Cancer Research Center, Peking University First Hospital, Beijing, China.,Institute of Urology, Peking University, Beijing, China.,National Urological Cancer Center, Beijing, China
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17
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Signorelli F, Piscopo G, Giraud S, Guerriero S, Laborante A, Latronico ME, Chimenti G, Maduri R, Chirchiglia D, Lavano A, Guyotat J, Alessio G, Gesualdo L. Von Hippel-Lindau disease: when neurosurgery meets nephrology, ophthalmology and genetics. J Neurosurg Sci 2019; 63:548-565. [DOI: 10.23736/s0390-5616.17.04153-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
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18
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Girardet L, Augière C, Asselin MP, Belleannée C. Primary cilia: biosensors of the male reproductive tract. Andrology 2019; 7:588-602. [PMID: 31131532 DOI: 10.1111/andr.12650] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2018] [Revised: 04/16/2019] [Accepted: 04/17/2019] [Indexed: 12/21/2022]
Abstract
BACKGROUND The primary cilium is a microtubule-based organelle that extends transiently from the apical cell surface to act as a sensory antenna. Initially viewed as a cellular appendage of obscure significance, the primary cilium is now acknowledged as a key coordinator of signaling pathways during development and in tissue homeostasis. OBJECTIVES The aim of this review was to present the structure and function of this overlooked organelle,with an emphasis on its epididymal context and contribution to male infertility issues. MATERIALS AND METHODS A systematic review has been performed in order to include main references relevant to the aforementioned topic. RESULTS Increasing evidence demonstrates that primary cilia dysfunctions are associated with impaired male reproductive system development and male infertility issues. DISCUSSION While a large amount of data exists regarding the role of primary cilia in most organs and tissues, few studies investigated the contribution of these organelles to male reproductive tract development and homeostasis. CONCLUSION Functional studies of primary cilia constitute an emergent and exciting new area in reproductive biology research.
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Affiliation(s)
- Laura Girardet
- Department of Obstetrics, Gynecology and Reproduction, Université Laval, CHU de Québec Research Center (CHUL), Quebec City, QC, Canada
| | - Céline Augière
- Department of Obstetrics, Gynecology and Reproduction, Université Laval, CHU de Québec Research Center (CHUL), Quebec City, QC, Canada
| | - Marie-Pier Asselin
- Department of Obstetrics, Gynecology and Reproduction, Université Laval, CHU de Québec Research Center (CHUL), Quebec City, QC, Canada
| | - Clémence Belleannée
- Department of Obstetrics, Gynecology and Reproduction, Université Laval, CHU de Québec Research Center (CHUL), Quebec City, QC, Canada
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19
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Peng S, Shepard MJ, Wang J, Li T, Ning X, Cai L, Zhuang Z, Gong K. Genotype-phenotype correlations in Chinese von Hippel-Lindau disease patients. Oncotarget 2018; 8:38456-38465. [PMID: 28388566 PMCID: PMC5503545 DOI: 10.18632/oncotarget.16594] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2017] [Accepted: 03/17/2017] [Indexed: 01/27/2023] Open
Abstract
von Hippel–Lindau (VHL) disease is caused by mutations in the VHL gene and demonstrates marked phenotypic variability. Genotype-phenotype correlations in Chinese VHL patients have been unclear. To establish genotype-phenotype correlations in Chinese VHL patients, we collected VHL mutations and phenotypes of 291 patients with VHL disease from 115 unrelated families. Genotype-phenotype correlations at mutation type level, mutation region level, and mutation codon level were analyzed by Kaplan-Meier curves and Cox regression models. We found missense mutations conferred an increased risk of pheochromocytoma developments, but a decreased risk of central nervous system hemangioblastomas (CHBs) and pancreatic lesions. Patients with VHL deletions were more prone to developing retinal angiomas. Renal cell carcinomas were more frequent in nonsense, frameshift or splice-site mutations. Mutations in Exon 2 conferred a higher risk and earlier diagnostic age of CHBs than mutations in other exons (HR = 1.684, 95% CI 1.082–2.620, p = 0.021; 27.0 ± 9.7 years versus 32.8 ± 11.7 years, p = 0.024), while patients with mutations in Exon 3 were more prone to developing pheochromocytomas (HR = 2.760, 95% CI 1.419–5.370, p = 0.003). Mutations at codon 80 or codon167 conferred significantly higher risks of pheochromocytomas than other mutations (HR = 4.678, 95% CI 1.392–15.724, p = 0.013; HR = 4.683, 95% CI 2.515–8.719, p < 0.001 respectively). In conclusion, VHL mutation types, mutation regions and mutation codons can act as phenotypic predictors of VHL disease. Mutation regions and mutation codons may aid in directed surveillance and monitoring of VHL patients.
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Affiliation(s)
- Shuanghe Peng
- Department of Urology, Peking University First Hospital, Beijing, P.R China.,Institute of Urology, Peking University, Beijing, P.R China.,National Urological Cancer Center, Beijing, P.R China
| | - Matthew J Shepard
- Department of Neurological Surgery, University of Virginia, Charlottesville, Virginia, USA.,Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA
| | - Jiangyi Wang
- Department of Urology, Peking University First Hospital, Beijing, P.R China.,Institute of Urology, Peking University, Beijing, P.R China.,National Urological Cancer Center, Beijing, P.R China
| | - Teng Li
- Department of Urology, Peking University First Hospital, Beijing, P.R China.,Institute of Urology, Peking University, Beijing, P.R China.,National Urological Cancer Center, Beijing, P.R China
| | - Xianghui Ning
- Department of Urology, Peking University First Hospital, Beijing, P.R China.,Institute of Urology, Peking University, Beijing, P.R China.,National Urological Cancer Center, Beijing, P.R China
| | - Lin Cai
- Department of Urology, Peking University First Hospital, Beijing, P.R China.,Institute of Urology, Peking University, Beijing, P.R China.,National Urological Cancer Center, Beijing, P.R China
| | - Zhengping Zhuang
- Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA
| | - Kan Gong
- Department of Urology, Peking University First Hospital, Beijing, P.R China.,Institute of Urology, Peking University, Beijing, P.R China.,National Urological Cancer Center, Beijing, P.R China
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20
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Liu SJ, Wang JY, Peng SH, Li T, Ning XH, Hong BA, Liu JY, Wu PJ, Zhou BW, Zhou JC, Qi NN, Peng X, Zhang JF, Ma KF, Cai L, Gong K. Genotype and phenotype correlation in von Hippel-Lindau disease based on alteration of the HIF-α binding site in VHL protein. Genet Med 2018; 20:1266-1273. [PMID: 29595810 DOI: 10.1038/gim.2017.261] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2017] [Accepted: 12/14/2017] [Indexed: 11/09/2022] Open
Abstract
PURPOSE Von Hippel-Lindau (VHL) disease is a rare hereditary cancer syndrome that reduces life expectancy. We aimed to construct a more valuable genotype-phenotype correlation based on alterations in VHL protein (pVHL). METHODS VHL patients (n = 339) were recruited and grouped based on mutation types: HIF-α binding site missense (HM) mutations, non-HIF-α binding site missense (nHM) mutations, and truncating (TR) mutations. Age-related risks of VHL-associated tumors and patient survival were compared. RESULTS Missense mutations conferred an increased risk of pheochromocytoma (HR = 1.854, p = 0.047) compared with truncating mutations. The risk of pheochromocytoma was lower in the HM group than in the nHM group (HR = 0.298, p = 0.003) but was similar between HM and TR groups (HR = 0.901, p = 0.810). Patients in the nHM group had a higher risk of pheochromocytoma (HR = 3.447, p < 0.001) and lower risks of central nervous system hemangioblastoma (CHB) (HR = 0.700, p = 0.045), renal cell carcinoma (HR = 0.610, p = 0.024), and pancreatic tumor (HR = 0.382, p < 0.001) than those in the combined HM and TR (HMTR) group. Moreover, nHM mutations were independently associated with better overall survival (HR = 0.345, p = 0.005) and CHB-specific survival (HR = 0.129, p = 0.005) than HMTR mutations. CONCLUSION The modified genotype-phenotype correlation links VHL gene mutation, substrate binding site, and phenotypic diversity (penetrance and survival), and provides more accurate information for genetic counseling and pathogenesis studies.
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Affiliation(s)
- Sheng-Jie Liu
- Department of Urology, Peking University First Hospital, Beijing, P.R. China.,Institute of Urology, Peking University, Beijing, P.R. China.,National Urological Cancer Center, Beijing, P.R. China
| | - Jiang-Yi Wang
- Department of Urology, Peking University First Hospital, Beijing, P.R. China.,Institute of Urology, Peking University, Beijing, P.R. China.,National Urological Cancer Center, Beijing, P.R. China
| | - Shuang-He Peng
- Department of Urology, Peking University First Hospital, Beijing, P.R. China.,Institute of Urology, Peking University, Beijing, P.R. China.,National Urological Cancer Center, Beijing, P.R. China
| | - Teng Li
- Department of Urology, Peking University First Hospital, Beijing, P.R. China.,Institute of Urology, Peking University, Beijing, P.R. China.,National Urological Cancer Center, Beijing, P.R. China
| | - Xiang-Hui Ning
- Department of Urology, Peking University First Hospital, Beijing, P.R. China.,Institute of Urology, Peking University, Beijing, P.R. China.,National Urological Cancer Center, Beijing, P.R. China
| | - Bao-An Hong
- Department of Urology, Peking University First Hospital, Beijing, P.R. China.,Institute of Urology, Peking University, Beijing, P.R. China.,National Urological Cancer Center, Beijing, P.R. China
| | - Jia-Yuan Liu
- Department of Urology, Peking University First Hospital, Beijing, P.R. China.,Institute of Urology, Peking University, Beijing, P.R. China.,National Urological Cancer Center, Beijing, P.R. China
| | - Peng-Jie Wu
- Department of Urology, Beijing Hospital, Beijing, P.R. China
| | - Bo-Wen Zhou
- Department of Urology, Peking University First Hospital, Beijing, P.R. China.,Institute of Urology, Peking University, Beijing, P.R. China.,National Urological Cancer Center, Beijing, P.R. China
| | - Jing-Cheng Zhou
- Department of Urology, Peking University First Hospital, Beijing, P.R. China.,Institute of Urology, Peking University, Beijing, P.R. China.,National Urological Cancer Center, Beijing, P.R. China
| | - Nie-Nie Qi
- Department of Urology, Peking University First Hospital, Beijing, P.R. China.,Institute of Urology, Peking University, Beijing, P.R. China.,National Urological Cancer Center, Beijing, P.R. China
| | - Xiang Peng
- Department of Urology, Peking University First Hospital, Beijing, P.R. China.,Institute of Urology, Peking University, Beijing, P.R. China.,National Urological Cancer Center, Beijing, P.R. China
| | - Jiu-Feng Zhang
- Department of Urology, Peking University First Hospital, Beijing, P.R. China.,Institute of Urology, Peking University, Beijing, P.R. China.,National Urological Cancer Center, Beijing, P.R. China
| | - Kai-Fang Ma
- Department of Urology, Peking University First Hospital, Beijing, P.R. China.,Institute of Urology, Peking University, Beijing, P.R. China.,National Urological Cancer Center, Beijing, P.R. China
| | - Lin Cai
- Department of Urology, Peking University First Hospital, Beijing, P.R. China. .,Institute of Urology, Peking University, Beijing, P.R. China. .,National Urological Cancer Center, Beijing, P.R. China.
| | - Kan Gong
- Department of Urology, Peking University First Hospital, Beijing, P.R. China. .,Institute of Urology, Peking University, Beijing, P.R. China. .,National Urological Cancer Center, Beijing, P.R. China.
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21
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EZH2 promotes metabolic reprogramming in glioblastomas through epigenetic repression of EAF2-HIF1α signaling. Oncotarget 2018; 7:45134-45143. [PMID: 27259264 PMCID: PMC5216711 DOI: 10.18632/oncotarget.9761] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2015] [Accepted: 05/13/2016] [Indexed: 12/12/2022] Open
Abstract
Cancer cells prefer glycolysis for energy metabolism, even when there is sufficient oxygen to make it unnecessary. This is called the Warburg effect, and it promotes tumorigenesis and malignant progression. In this study, we demonstrated that EZH2, a multifaceted oncogenic protein involved in tumor proliferation, invasion and metastasis, promotes glioblastoma tumorigenesis and malignant progression through activation of the Warburg effect. We observed that HIF1α is a target of EZH2 whose activation is necessary for EZH2-mediated metabolic adaption, and that HIF1α is activated upon EZH2 overexpression. EZH2 suppressed expression of EAF2, which in turn upregulated HIF1α levels. We conclude from these results that EZH2 promotes tumorigenesis and malignant progression in part by activating glycolysis through an EAF2-HIF1α signaling axis.
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22
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Genotype phenotype correlation in Asian Indian von Hippel–Lindau (VHL) syndrome patients with pheochromocytoma/paraganglioma. Fam Cancer 2017; 17:441-449. [DOI: 10.1007/s10689-017-0058-y] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
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23
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Abstract
Post-translational modification (PTM) of proteins by ubiquitination is an essential cellular regulatory process. Such regulation drives the cell cycle and cell division, signalling and secretory pathways, DNA replication and repair processes and protein quality control and degradation pathways. A huge range of ubiquitin signals can be generated depending on the specificity and catalytic activity of the enzymes required for attachment of ubiquitin to a given target. As a consequence of its importance to eukaryotic life, dysfunction in the ubiquitin system leads to many disease states, including cancers and neurodegeneration. This review takes a retrospective look at our progress in understanding the molecular mechanisms that govern the specificity of ubiquitin conjugation.
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24
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Mathó C, Sansó G, Diez B, Barontini M, Pennisi PA. VHL Germline Mutations in Argentinian Patients with Clinical Diagnoses or Single Typical Manifestations of Type 1 von Hippel-Lindau Disease. Genet Test Mol Biomarkers 2016; 20:771-776. [PMID: 27617348 DOI: 10.1089/gtmb.2016.0204] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
AIMS von Hippel-Lindau (VHL) disease is caused by mutations in the VHL tumor suppressor gene. As tumors that develop in the context of VHL also occur in a sporadic context, the frequency of this syndrome may be underestimated. Our aim was to identify VHL gene mutations in Argentinian patients who fulfilled the clinical criteria for type 1 VHL disease and in patients with VHL-associated manifestations that did not meet these criteria. METHODS We performed a retrospective cohort study, including patients who met current diagnostic criteria for type 1 VHL (Group 1, n = 19) and patients with VHL-associated manifestations that did not meet these criteria (Group 2, n = 21). Genomic DNA was extracted from peripheral blood leukocytes. Mutation analysis involved DNA sequencing, while large deletions were determined by universal primer quantitative fluorescent multiplex polymerase chain reaction (UPQFM-PCR) and multiplex ligation-dependent probe amplification (MLPA) analysis. RESULTS VHL mutations were detected in 16/19 (84.2%) patients in Group 1 and included: gross deletions (4/16); nonsense mutations (6/16); frameshift mutations (4/16); missense mutations (1/16); and splicing mutations (1/16). Three of these mutations were novel. No alterations were found in 3 of 19 VHL patients. In Group 2, one nonsense VHL mutation was detected in a young patient with a solitary central nervous system hemangioblastoma without familial history. A study of 30 first-degree relatives revealed four carriers with VHL mutations. CONCLUSIONS We found three novel mutations in the VHL gene in our population. Our results emphasize the importance of a complete genetic study of VHL to confirm type 1 VHL disease, not only in patients with clinical diagnostic criteria but also in those presenting a single typical manifestation.
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Affiliation(s)
- Cecilia Mathó
- 1 Centro de Investigaciones Endocrinológicas "Dr. César Bergadá" (CEDIE) CONICET-FEI-División de Endocrinología, Hospital de Niños Ricardo Gutiérrez , CABA, Argentina
| | - Gabriela Sansó
- 1 Centro de Investigaciones Endocrinológicas "Dr. César Bergadá" (CEDIE) CONICET-FEI-División de Endocrinología, Hospital de Niños Ricardo Gutiérrez , CABA, Argentina
| | - Blanca Diez
- 2 Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia , CABA, Argentina
| | - Marta Barontini
- 1 Centro de Investigaciones Endocrinológicas "Dr. César Bergadá" (CEDIE) CONICET-FEI-División de Endocrinología, Hospital de Niños Ricardo Gutiérrez , CABA, Argentina
| | - Patricia A Pennisi
- 1 Centro de Investigaciones Endocrinológicas "Dr. César Bergadá" (CEDIE) CONICET-FEI-División de Endocrinología, Hospital de Niños Ricardo Gutiérrez , CABA, Argentina
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25
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Kakkar A, Sharma MC, Yadav R, Panwar R, Mathur SR, Iyer VK, Sahni P. Pancreatic mixed serous neuroendocrine neoplasm with clear cells leading to diagnosis of von Hippel Lindau disease. Pathol Res Pract 2016; 212:747-50. [PMID: 27161305 DOI: 10.1016/j.prp.2016.04.008] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2016] [Revised: 04/22/2016] [Accepted: 04/26/2016] [Indexed: 02/08/2023]
Abstract
Mixed serous neuroendocrine neoplasms are extremely rare tumors that are usually seen in female patients and are often associated with von Hippel Lindau (VHL) disease. We describe the case of a 38-year-old male who presented with complaints of anorexia, weight loss, and abdominal pain. CT abdomen showed a mass in the head of the pancreas, multiple small nodules in the body of pancreas, and bilateral adrenal masses. Fine needle aspiration cytology (FNAC) from the mass showed features of a neuroendocrine tumor, with many of the cells demonstrating abundant clear cytoplasm. Histopathological examination of the pancreaticoduodenectomy specimen showed a mixed serous neuroendocrine neoplasm with two components viz. serous cystadenoma and neuroendocrine tumor (NET) World Health Organization (WHO) grade 2. In addition, he was diagnosed to have bilateral pheochromocytomas and a paraganglioma. The synchronicity of these tumors suggested the possibility of VHL disease. Thus, identification of a NET with clear cells or of a mixed serous neuroendocrine neoplasm should raise suspicion of VHL disease. In a mixed tumor, FNAC may identify only one of the two components. Thorough processing of all pancreatic serous tumors for pathological examination is recommended, as NET may occur as a small nodule within the serous cystadenoma.
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Affiliation(s)
- Aanchal Kakkar
- Department of Pathology, All India Institute of Medical Sciences, New Delhi 110029, India
| | - Mehar C Sharma
- Department of Pathology, All India Institute of Medical Sciences, New Delhi 110029, India.
| | - Rajni Yadav
- Department of Pathology, All India Institute of Medical Sciences, New Delhi 110029, India
| | - Rajesh Panwar
- Department of Gastrointestinal Surgery, All India Institute of Medical Sciences, New Delhi 110029, India
| | - Sandeep R Mathur
- Department of Pathology, All India Institute of Medical Sciences, New Delhi 110029, India
| | - Venkateswaran K Iyer
- Department of Pathology, All India Institute of Medical Sciences, New Delhi 110029, India
| | - Peush Sahni
- Department of Gastrointestinal Surgery, All India Institute of Medical Sciences, New Delhi 110029, India
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Abstract
Carcinoid tumours arise in cells of the diffuse neuroendocrine system and can develop in a number of anatomical sites including the lungs and the gastrointestinal tract. There has been a move away from the use of the term carcinoid tumour to the more appropriate use of neuroendocrine tumour (NET) to highlight the potential for invasion and metastasis associated with some NETs. Although most cases are sporadic, 15-20% of cases are related to a hereditary syndrome, the most common of these being multiple endocrine neoplasia 1 (MEN1). Other hereditary syndromes include the following: von Hippel-Lindau (VHL), neurofibromatosis 1 and tuberous sclerosis complex (TSC), which are all associated with a germline mutation of the associated tumour suppressor gene and an autosomal dominant inheritance pattern. Familial small intestinal NET (SI NET) is a recently described condition which is also inherited in an autosomal dominant manner. There appears to be more than one causative gene; thus far, only the IPMK gene has been identified as a causative germline mutation. This was identified by carrying out whole-exome sequencing of germline and tumour DNA in a family with multiple members diagnosed with SI NET. Identification of NET predisposition genes in other families via these methods will allow the development of dedicated NET gene panels which can be used to screen NET patients and at-risk relatives for hereditary mutations. Close surveillance of at-risk individuals is important to detect NETs early when curative surgery can be offered and the morbidity and mortality of metastatic NETs can be avoided.
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Affiliation(s)
- Sarah Benafif
- The Institute of Cancer Research, Sutton, Surrey, UK
- Royal Marsden NHS Foundation Trust, Sutton, Surrey, UK
| | - Rosalind Eeles
- The Institute of Cancer Research, Sutton, Surrey, UK.
- Royal Marsden NHS Foundation Trust, Sutton, Surrey, UK.
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Circulating biomarkers in renal cell carcinoma: the link between microRNAs and extracellular vesicles, where are we now? J Kidney Cancer VHL 2014; 1:84-98. [PMID: 28326253 PMCID: PMC5345530 DOI: 10.15586/jkcvhl.2014.19] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2014] [Accepted: 12/23/2014] [Indexed: 11/18/2022] Open
Abstract
Renal cell carcinoma (RCC) is a lethal urological cancer, with incidence and mortality rates increasing by 2-3% per decade. The lack of standard screening tests contributes to the fact that one-third of patients are diagnosed with locally invasive or metastatic disease. Moreover, 20-40% of RCC patients submitted to surgical nephrectomy will develop metastasis. MicroRNAs (miRNAs) are small non-coding RNAs responsible for gene regulation at a post-transcriptional level. It is accepted that they are deregulated in cancer and can influence tumor development. Thus, miRNAs are promising RCC biomarkers, since they can be detected using non-invasive methods. They are highly stable and easier to quantify in circulating biofluids. The elevated miRNA stability in circulating samples may be the consequence of their capacity to circulate inside of extracellular microvesicles (EMVs), for example, the exosomes. The EMVs are bilayered membrane vesicles secreted by all cell types. They can be released in the interstitial space or into circulating biofluids, which allows the travelling, binding and entrance of these vesicles in receptor cells. This type of cell communication can shuttle bioactive molecules between cells, allowing the horizontal transference of genetic material. In this review, we focus on circulating miRNAs (miR-210, miR-1233, miR-221, miR-15a, miR-451, miR-508, miR-378) in the biofluids of RCC patients and attempt to establish the diagnostic and prognostic accuracy, their synergic effects, and the pathways involved in RCC biology.
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28
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Killion E, Mohan K, Lee EI. A review of vascular anomalies: genetics and common syndromes. Semin Plast Surg 2014; 28:64-8. [PMID: 25045331 DOI: 10.1055/s-0034-1376261] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Vascular tumors and malformations are unique in that affected cells exhibit disrupted angiogenesis. The current treatment options often yield suboptimal results. New insight into the genetics and molecular basis of vascular anomalies may pave the way for potential development of targeted therapy. The authors review the genetic and molecular basis of vascular anomalies and common associated syndromes.
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Affiliation(s)
- Elizabeth Killion
- Division of Plastic Surgery, Baylor College of Medicine, Houston, Texas
| | - Kriti Mohan
- Division of Plastic Surgery, Baylor College of Medicine, Houston, Texas
| | - Edward I Lee
- Division of Plastic Surgery, Baylor College of Medicine, Houston, Texas
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Dias F, Teixeira AL, Santos JI, Gomes M, Nogueira A, Assis J, Medeiros R. Renal cell carcinoma development and miRNAs: a possible link to the EGFR pathway. Pharmacogenomics 2014; 14:1793-803. [PMID: 24192126 DOI: 10.2217/pgs.13.184] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
Renal cell carcinoma (RCC) is the most common solid cancer of the adult kidney and the majority of RCC cases are detected accidentally. This reality and the nonexistence of a standard screening test contribute to the fact that one third of patients are diagnosed with local invasive disease or metastatic disease. miRNAs are a family of small ncRNAs that regulate gene expression and have been identified as key regulators in many biological processes including cell development, differentiation, apoptosis and proliferation. The EGF receptor signaling pathway is usually deregulated in cancer and it is suggested to have an important role in RCC. Further studies are needed to characterize deregulation of this pathway during RCC development. In this review we highlight some potential miRNAs that could be involved in the modulation of the EGF receptor pathway and consequently in RCC development.
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Affiliation(s)
- Francisca Dias
- Molecular Oncology Group, Portuguese Institute of Oncology, Rua Dr António Bernardino de Almeida, 4200-072 Porto, Portugal
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Complex molecular regulation of tyrosine hydroxylase. J Neural Transm (Vienna) 2014; 121:1451-81. [PMID: 24866693 DOI: 10.1007/s00702-014-1238-7] [Citation(s) in RCA: 85] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2014] [Accepted: 05/04/2014] [Indexed: 12/16/2022]
Abstract
Tyrosine hydroxylase, the rate-limiting enzyme in catecholamine biosynthesis, is strictly controlled by several interrelated regulatory mechanisms. Enzyme synthesis is controlled by epigenetic factors, transcription factors, and mRNA levels. Enzyme activity is regulated by end-product feedback inhibition. Phosphorylation of the enzyme is catalyzed by several protein kinases and dephosphorylation is mediated by two protein phosphatases that establish a sensitive process for regulating enzyme activity on a minute-to-minute basis. Interactions between tyrosine hydroxylase and other proteins introduce additional layers to the already tightly controlled production of catecholamines. Tyrosine hydroxylase degradation by the ubiquitin-proteasome coupled pathway represents yet another mechanism of regulation. Here, we revisit the myriad mechanisms that regulate tyrosine hydroxylase expression and activity and highlight their physiological importance in the control of catecholamine biosynthesis.
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