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Puttonen M, Tynninen O, Salmikangas S, Vesterinen T, Sihto H, Böhling T. Fibroblast growth factor receptor expression in hemangioblastomas: A novel therapeutic target. PLoS One 2025; 20:e0323979. [PMID: 40393028 PMCID: PMC12092013 DOI: 10.1371/journal.pone.0323979] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2024] [Accepted: 04/17/2025] [Indexed: 05/22/2025] Open
Abstract
Hemangioblastoma is a highly vascularized, benign tumor in the central nervous system, frequently associated with von Hippel-Lindau (VHL) disease. Hemangioblastoma may cause tumor-associated hemorrhage or exert pressure on nearby structures, leading to life-threatening complications. Although surgical resection is the primary treatment, complete removal is not always feasible. Accordingly, there is a need to explore targeted or anti-angiogenic therapies. The fibroblast growth factor receptor (FGFR) family has roles in tumorigenesis and angiogenesis, making it a potential target in personalized therapy. The distribution and significance of FGFRs in hemangioblastoma have yet to be investigated. We examined 139 formalin-fixed, paraffin-embedded hemangioblastoma samples from 111 patients, including sporadic cases and those associated with VHL disease. Immunohistochemistry revealed positive staining for FGFR2 (95%) and FGFR4 (61%), while FGFR1 (0%) and FGFR3 (12%) were mainly negative. FGFR2 expression was significantly increased in VHL-mutated tumors (75%, p = 0.034) and in male patients (68%, p = 0.020). Tumors located in the cerebrum (n = 6, 5%) had a higher likelihood of positive FGFR4 staining (100%, p = 0.009). Additionally, a larger tumor diameter was associated with a higher likelihood of FGFR4 expression (median 12.0 mm vs 17.5 mm, p = 0.018), suggesting its contribution in tumor growth. Our study revealed the expression of FGFR2 and FGFR4 in a significant number of hemangioblastomas. This finding demonstrates the potential of FGFRs as promising therapeutic targets for patients with hemangioblastoma.
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Affiliation(s)
- Maya Puttonen
- Department of Pathology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Olli Tynninen
- Department of Pathology, HUSLAB, HUS Diagnostic Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Sami Salmikangas
- Department of Pathology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Tiina Vesterinen
- Department of Pathology, HUSLAB, HUS Diagnostic Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Harri Sihto
- Department of Pathology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Tom Böhling
- Department of Pathology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
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Perona-Moratalla AB, Carrión B, Villar Gómez de las Heras K, Arias-Salazar L, Yélamos-Sanz B, Segura T, Serrano-Heras G. Dual Inhibition of HIF-1α and HIF-2α as a Promising Treatment for VHL-Associated Hemangioblastomas: A Pilot Study Using Patient-Derived Primary Cell Cultures. Biomedicines 2025; 13:1234. [PMID: 40427061 PMCID: PMC12108798 DOI: 10.3390/biomedicines13051234] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2025] [Revised: 05/12/2025] [Accepted: 05/14/2025] [Indexed: 05/29/2025] Open
Abstract
Background: Von Hippel-Lindau (VHL) disease, a hereditary cancer syndrome, is characterized by mutations in the VHL gene, which result in the stabilization of hypoxia-inducible factors (HIF)-1α and -2α, ultimately leading to the development of highly vascularized tumors, such as hemangioblastomas of the central nervous system (CNS-HBs). The standard treatment for these brain tumors is neurosurgical resection. However, multiple surgeries are often necessary due to tumor recurrence, which increases the risk of neurological sequelae. Thus, elucidation of the proliferative behavior of hemangioblastomas (with the aim of identifying biomarkers associated with tumor progression) and the development of pharmacological therapies could reduce the need for repeated surgical interventions and provide alternative treatment options for unresectable CNS-HBs. Belzutifan (Welireg™), a selective HIF-2α inhibitor and the only FDA-approved non-surgical option, has shown limited efficacy in CNS-HBs, highlighting the need for alternative therapeutic strategies. Results: In this study, primary cell cultures were successfully established from CNS-HB tissue samples of VHL patients, achieving a 75% success rate. These cultures were predominantly composed of stromal cells and pericytes. The proliferative patterns of patient-derived HB cell cultures significantly correlated with tumor burden and recurrence in VHL patients. Furthermore, flow cytometry, reverse transcription-PCR, and Western blot analyses revealed marked overexpression of both HIF-1α and HIF-2α isoforms in primary HB cells. In addition, evaluation of the therapeutic potential of acriflavine, a dual HIF-1α/HIF-2α inhibitor, demonstrated reduced HB cells viability, induced G2/M cell cycle arrest, and predominantly triggered necrotic cell death in patient-derived HB cultures. Conclusions: These results suggest that the in vitro proliferative dynamics of HB cell cultures may reflect clinical characteristics associated with CNS-HB progression, potentially serving as indicators to predict tumor development in patients with VHL. Furthermore, our findings support the simultaneous targeting of both HIF-1α and HIF-2α isoforms as a promising non-invasive therapeutic strategy.
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Affiliation(s)
- Ana B. Perona-Moratalla
- Department of Neurology, General University Hospital of Albacete, Hermanos Falcó, 37, 02008 Albacete, Spain;
| | - Blanca Carrión
- Research Unit, General University Hospital of Albacete, Laurel, s/n, 02008 Albacete, Spain; (B.C.); (L.A.-S.); (B.Y.-S.)
- Department of Medicine, Faculty of Medicine, Health and Sports, Universidad Europea de Madrid, 28670 Villaviciosa de Odón, Spain
| | | | - Lourdes Arias-Salazar
- Research Unit, General University Hospital of Albacete, Laurel, s/n, 02008 Albacete, Spain; (B.C.); (L.A.-S.); (B.Y.-S.)
- Neuroscience Section, Institute of Health Research of Castilla-La Mancha (IDISCAM), 45071 Toledo, Spain
| | - Blanca Yélamos-Sanz
- Research Unit, General University Hospital of Albacete, Laurel, s/n, 02008 Albacete, Spain; (B.C.); (L.A.-S.); (B.Y.-S.)
- Neuroscience Section, Institute of Health Research of Castilla-La Mancha (IDISCAM), 45071 Toledo, Spain
| | - Tomás Segura
- Department of Neurology, General University Hospital of Albacete, Hermanos Falcó, 37, 02008 Albacete, Spain;
- Neuroscience Section, Institute of Health Research of Castilla-La Mancha (IDISCAM), 45071 Toledo, Spain
- Biomedicine Institute of UCLM (IB-UCLM), Faculty of Medicine, University of Castilla-La Mancha, 02008 Albacete, Spain
| | - Gemma Serrano-Heras
- Research Unit, General University Hospital of Albacete, Laurel, s/n, 02008 Albacete, Spain; (B.C.); (L.A.-S.); (B.Y.-S.)
- Neuroscience Section, Institute of Health Research of Castilla-La Mancha (IDISCAM), 45071 Toledo, Spain
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Lozano LP, Jensen R, Jennisch M, Pandala NG, Jamshidi F, Boldt HC, Tucker BA, Binkley EM. Genetics and current research models of Mendelian tumor predisposition syndromes with ocular involvement. Prog Retin Eye Res 2025; 106:101359. [PMID: 40274012 DOI: 10.1016/j.preteyeres.2025.101359] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2025] [Revised: 04/17/2025] [Accepted: 04/18/2025] [Indexed: 04/26/2025]
Abstract
In this review, we aim to provide a survey of hereditable tumor predisposition syndromes with a Mendelian inheritance pattern and ocular involvement. We focus our discussion on von Hippel-Lindau disease, neurofibromatosis type 1, NF2-related schwannomatosis, tuberous sclerosis complex, retinoblastoma, and the BAP1 tumor predisposition syndrome. For each of the six diseases, we discuss the clinical presentation and the molecular pathophysiology. We emphasize the genetics, current research models, and therapeutic developments. After reading each disease section, readers should possess an understanding of the clinical presentation, genetic causes and inheritance patterns, and current state of research in disease modeling and treatment.
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Affiliation(s)
- Lola P Lozano
- Institute for Vision Research, The University of Iowa, Iowa City, IA, 52242, USA.
| | - Renato Jensen
- Institute for Vision Research, The University of Iowa, Iowa City, IA, 52242, USA.
| | - Madeleine Jennisch
- Institute for Vision Research, The University of Iowa, Iowa City, IA, 52242, USA.
| | - Narendra G Pandala
- Institute for Vision Research, The University of Iowa, Iowa City, IA, 52242, USA.
| | - Farzad Jamshidi
- Department of Ophthalmology, University of Pittsburgh/UPMC, Pittsburgh, PA, 15213, USA.
| | - H Culver Boldt
- Institute for Vision Research, The University of Iowa, Iowa City, IA, 52242, USA; Department of Ophthalmology and Visual Sciences, The University of Iowa Carver College of Medicine, Iowa City, IA, 52242, USA.
| | - Budd A Tucker
- Institute for Vision Research, The University of Iowa, Iowa City, IA, 52242, USA; Department of Ophthalmology and Visual Sciences, The University of Iowa Carver College of Medicine, Iowa City, IA, 52242, USA.
| | - Elaine M Binkley
- Institute for Vision Research, The University of Iowa, Iowa City, IA, 52242, USA; Department of Ophthalmology and Visual Sciences, The University of Iowa Carver College of Medicine, Iowa City, IA, 52242, USA.
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Jung NY, Park JB. Von Hippel-Lindau Disease : A Comprehensive Review of Diagnosis, Genetics, Clinical Challenges, and Surveillance. J Korean Neurosurg Soc 2025; 68:338-349. [PMID: 40109021 PMCID: PMC12062539 DOI: 10.3340/jkns.2025.0018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2025] [Revised: 03/13/2025] [Accepted: 03/15/2025] [Indexed: 03/22/2025] Open
Abstract
von Hippel-Lindau (VHL) disease is a genetic condition predisposing individuals to the development of benign and malignant tumors across various organs. This review explores the intricate genetic underpinnings of VHL disease, its clinical manifestations, and the associated malignancy risks. The latest diagnostic criteria, surveillance guidelines, and advancements in therapeutic strategies, including the Food and Drug Administration-approved hypoxia-inducible factor-2α inhibitor, belzutifan, are focused on. Through a multidisciplinary approach, tailored surveillance programs aim to improve patient outcomes while balancing intervention risks. Emerging technologies such as wholebody magnetic resonance imaging and liquid biopsies hold promises for enhancing non-invasive surveillance. This review underscores the significance of ongoing research and interdisciplinary care in managing this complex syndrome.
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Affiliation(s)
- Na Young Jung
- Department of Neurosurgery, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Korea
| | - Jun Bum Park
- Department of Neurosurgery, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Korea
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Oki R, Takemura K, Urasaki T, Fujiwara R, Numao N, Yonese J, Miura Y, Yuasa T. Prevailing challenges in personalized treatment for metastatic renal cell carcinoma: a narrative review. Expert Rev Anticancer Ther 2025:1-13. [PMID: 40210604 DOI: 10.1080/14737140.2025.2491647] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2025] [Revised: 04/05/2025] [Accepted: 04/07/2025] [Indexed: 04/12/2025]
Abstract
INTRODUCTION The management of metastatic renal cell carcinoma (mRCC) has advanced with recent therapies, yet optimizing treatment remains challenging due to disease heterogeneity and the growing number of options. Integrating systemic and local treatments requires a multidisciplinary approach to improve outcomes. AREA COVERED This review summarizes recent developments in treatment for mRCC. Upfront immuno-oncology (IO)-based combinations have improved survival, though concerns about overtreatment and toxicity persist. While the role of cytoreductive nephrectomy (CN) has declined to some extent, it may still benefit well-selected patients. Metastasis-directed therapies, including metastasectomy and stereotactic radiotherapy, provide prognostic value, particularly for oligometastatic lesions or brain metastases. Comprehensive genomic profiling (CGP) holds promise for personalized treatment but is currently limited by the lack of actionable mutations and predictive biomarkers. EXPERT OPINION A personalized, multimodal approach is essential for optimizing mRCC management. Careful patient selection is key to balancing the benefits of treatment with the risks of toxicity. While CN and metastasis-directed therapies remain useful in select cases, advancing individualized care requires the development of validated biomarkers and broader application of CGP.
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Affiliation(s)
- Ryosuke Oki
- Department of Medical Oncology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Kosuke Takemura
- Department of Genitourinary Oncology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Tetsuya Urasaki
- Department of Medical Oncology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Ryo Fujiwara
- Department of Genitourinary Oncology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Noboru Numao
- Department of Genitourinary Oncology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Junji Yonese
- Department of Genitourinary Oncology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Yuji Miura
- Department of Medical Oncology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Takeshi Yuasa
- Department of Genitourinary Oncology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
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Choi SH, Chen YW, Panian J, Yuen K, McKay RR. Emerging innovative treatment strategies for advanced clear cell renal cell carcinoma. Oncologist 2025; 30:oyae276. [PMID: 39401004 PMCID: PMC11954509 DOI: 10.1093/oncolo/oyae276] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2024] [Accepted: 09/10/2024] [Indexed: 10/15/2024] Open
Abstract
Dramatic advances in biological discoveries, since the 1990s, have continued to reshape the treatment paradigm of metastatic renal cell carcinoma (RCC). Von Hippel Lindau (VHL) gene alterations are associated with pro-angiogenic activity and are central to the pathogenesis of clear cell RCC (ccRCC), the most predominant histologic subtype of RCC. Antiangiogenic strategies revolving around this VHL/HIF/VEGF axis have been shown to improve survival in metastatic ccRCC. The discovery of immune checkpoints and agents that target their inhibition introduced a new treatment paradigm for patients with RCC. While initially approved as monotherapy, studies investigating immune checkpoint inhibitor combinations have led to their approval as the new standard of care, providing durable responses and unprecedented improvements in clinical outcome. Despite these advances, the projected 14 390 deaths in 2024 from RCC underscore the need to continue efforts in expanding and optimizing treatment options for patients with metastatic RCC. This article reviews key findings that have transformed the way we understand and treat metastatic RCC, in addition to highlighting novel treatment strategies that are currently under development.
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Affiliation(s)
- Sharon H Choi
- Division of Hematology Oncology, University of California San Diego, San Diego, CA, United States
| | - Yu-Wei Chen
- Division of Hematology Oncology, University of California San Diego, San Diego, CA, United States
| | - Justine Panian
- Division of Hematology Oncology, University of California San Diego, San Diego, CA, United States
| | - Kit Yuen
- Department of Urology, University of California San Diego, San Diego, CA, United States
| | - Rana R McKay
- Division of Hematology Oncology, University of California San Diego, San Diego, CA, United States
- Department of Urology, University of California San Diego, San Diego, CA, United States
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7
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Tesarova T, Fiala O, Hora M, Vaclavikova R. Non-coding transcriptome profiles in clear-cell renal cell carcinoma. Nat Rev Urol 2025; 22:151-174. [PMID: 39242964 DOI: 10.1038/s41585-024-00926-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/29/2024] [Indexed: 09/09/2024]
Abstract
Clear-cell renal cell carcinoma (ccRCC) is a common urological malignancy with an increasing incidence. The development of molecular biomarkers that can predict the response to treatment and guide personalized therapy selection would substantially improve patient outcomes. Dysregulation of non-coding RNA (ncRNA) has been shown to have a role in the pathogenesis of ccRCC. Thus, an increasing number of studies are being carried out with a focus on the identification of ncRNA biomarkers in ccRCC tissue samples and the connection of these markers with patients' prognosis, pathological stage and grade (including metastatic potential), and therapy outcome. RNA sequencing analysis led to the identification of several ncRNA biomarkers that are dysregulated in ccRCC and might have a role in ccRCC development. These ncRNAs have the potential to be prognostic and predictive biomarkers for ccRCC, with prospective applications in personalized treatment selection. Research on ncRNA biomarkers in ccRCC is advancing, but clinical implementation remains preliminary owing to challenges in validation, standardization and reproducibility. Comprehensive studies and integration of ncRNAs into clinical trials are essential to accelerate the clinical use of these biomarkers.
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Affiliation(s)
- Tereza Tesarova
- Toxicogenomics Unit, National Institute of Public Health, Prague, Czech Republic.
- Laboratory of Pharmacogenomics, Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech Republic.
| | - Ondrej Fiala
- Department of Oncology and Radiotherapeutics, Faculty of Medicine in Pilsen and University Hospital, Charles University, Pilsen, Czech Republic
- Laboratory of Cancer Treatment and Tissue Regeneration, Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech Republic
| | - Milan Hora
- Department of Urology, Faculty of Medicine in Pilsen and University Hospital, Charles University, Pilsen, Czech Republic
| | - Radka Vaclavikova
- Toxicogenomics Unit, National Institute of Public Health, Prague, Czech Republic
- Laboratory of Pharmacogenomics, Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech Republic
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Gómez-Virgilio L, Velazquez-Paniagua M, Cuazozon-Ferrer L, Silva-Lucero MDC, Gutierrez-Malacara AI, Padilla-Mendoza JR, Borbolla-Vázquez J, Díaz-Hernández JA, Jiménez-Orozco FA, Cardenas-Aguayo MDC. Genetics, Pathophysiology, and Current Challenges in Von Hippel-Lindau Disease Therapeutics. Diagnostics (Basel) 2024; 14:1909. [PMID: 39272694 PMCID: PMC11393980 DOI: 10.3390/diagnostics14171909] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2024] [Revised: 08/12/2024] [Accepted: 08/23/2024] [Indexed: 09/15/2024] Open
Abstract
This review article focuses on von Hippel-Lindau (VHL) disease, a rare genetic disorder characterized by the development of tumors and cysts throughout the body. It discusses the following aspects of the disease. GENETICS VHL disease is caused by mutations in the VHL tumor suppressor gene located on chromosome 3. These mutations can be inherited or occur spontaneously. This article details the different types of mutations and their associated clinical features. PATHOPHYSIOLOGY The underlying cause of VHL disease is the loss of function of the VHL protein (pVHL). This protein normally regulates hypoxia-inducible factors (HIFs), which are involved in cell growth and survival. When pVHL is dysfunctional, HIF levels become elevated, leading to uncontrolled cell growth and tumor formation. CLINICAL MANIFESTATIONS VHL disease can affect various organs, including the brain, spinal cord, retina, kidneys, pancreas, and adrenal glands. Symptoms depend on the location and size of the tumors. DIAGNOSIS Diagnosis of VHL disease involves a combination of clinical criteria, imaging studies, and genetic testing. TREATMENT Treatment options for VHL disease depend on the type and location of the tumors. Surgery is the mainstay of treatment, but other options like radiation therapy may also be used. CHALLENGES This article highlights the challenges in VHL disease management, including the lack of effective therapies for some tumor types and the need for better methods to monitor disease progression. In conclusion, we emphasize the importance of ongoing research to develop new and improved treatments for VHL disease.
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Affiliation(s)
- Laura Gómez-Virgilio
- Laboratory of Cellular Reprogramming, Department of Physiology, Facultad de Medicina, Universidad Nacional Autónoma de México, Av. Universidad No. 3000, Coyoacan CDMX 04510, Mexico
| | - Mireya Velazquez-Paniagua
- Laboratory of Cellular Reprogramming, Department of Physiology, Facultad de Medicina, Universidad Nacional Autónoma de México, Av. Universidad No. 3000, Coyoacan CDMX 04510, Mexico
| | - Lucero Cuazozon-Ferrer
- Laboratory of Cellular Reprogramming, Department of Physiology, Facultad de Medicina, Universidad Nacional Autónoma de México, Av. Universidad No. 3000, Coyoacan CDMX 04510, Mexico
- Ingenieria en Biotecnología, Universidad Politécnica de Quintana Roo, Av. Arco Bicentenario, MZ. 11, Lote 1119-33 SM 255, Cancún Quintana Roo 77500, Mexico
| | - Maria-Del-Carmen Silva-Lucero
- Laboratory of Cellular Reprogramming, Department of Physiology, Facultad de Medicina, Universidad Nacional Autónoma de México, Av. Universidad No. 3000, Coyoacan CDMX 04510, Mexico
| | - Andres-Ivan Gutierrez-Malacara
- Laboratory of Cellular Reprogramming, Department of Physiology, Facultad de Medicina, Universidad Nacional Autónoma de México, Av. Universidad No. 3000, Coyoacan CDMX 04510, Mexico
| | - Juan-Ramón Padilla-Mendoza
- Laboratory of Cellular Reprogramming, Department of Physiology, Facultad de Medicina, Universidad Nacional Autónoma de México, Av. Universidad No. 3000, Coyoacan CDMX 04510, Mexico
| | - Jessica Borbolla-Vázquez
- Ingenieria en Biotecnología, Universidad Politécnica de Quintana Roo, Av. Arco Bicentenario, MZ. 11, Lote 1119-33 SM 255, Cancún Quintana Roo 77500, Mexico
| | - Job-Alí Díaz-Hernández
- Ingenieria en Biotecnología, Universidad Politécnica de Quintana Roo, Av. Arco Bicentenario, MZ. 11, Lote 1119-33 SM 255, Cancún Quintana Roo 77500, Mexico
| | | | - Maria-Del-Carmen Cardenas-Aguayo
- Laboratory of Cellular Reprogramming, Department of Physiology, Facultad de Medicina, Universidad Nacional Autónoma de México, Av. Universidad No. 3000, Coyoacan CDMX 04510, Mexico
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Wang T, Liu L, Rampisela D, Dong X, Keith KA, Benardete EA, Shan FY. A Cerebellar Tumor-to-Tumor Metastasis in a Patient With Von Hippel-Lindau Disease. Appl Immunohistochem Mol Morphol 2024; 32:244-248. [PMID: 38712587 DOI: 10.1097/pai.0000000000001197] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2023] [Accepted: 03/15/2024] [Indexed: 05/08/2024]
Abstract
Tumor-to-tumor metastasis in the central nerve system is uncommon in our routine practice. Most reports include metastatic breast cancer into meningioma. Here we report a metastatic clear cell renal cell carcinoma (ccRCC) into a cerebellar hemangioblastoma in a patient with von Hippel-Lindau (VHL) disease. Imaging cannot distinguish metastatic ccRCC from primary cerebellar hemangioblastoma. Immuno-molecular studies are proven to be diagnostic. We also reviewed previously documented tumor-to-tumor metastasis of ccRCC to cerebellar hemangioblastoma in VHL disease. Lastly, we discussed potential mechanisms involved in the metastasis of ccRCC to hemangioblastoma in the cerebellum in patients with VHL.
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Affiliation(s)
| | | | | | | | | | - Ethan A Benardete
- Department of Neurosurgery, Baylor Scott and White Health, Temple, TX
| | - Frank Y Shan
- Department of Pathology
- Department of Neurosurgery, Baylor Scott and White Health, Temple, TX
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10
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Kubala JM, Laursen KB, Schreiner R, Williams RM, van der Mijn JC, Crowley MJ, Mongan NP, Nanus DM, Heller DA, Gudas LJ. NDUFA4L2 reduces mitochondrial respiration resulting in defective lysosomal trafficking in clear cell renal cell carcinoma. Cancer Biol Ther 2023; 24:2170669. [PMID: 36722045 PMCID: PMC9897797 DOI: 10.1080/15384047.2023.2170669] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Accepted: 12/23/2022] [Indexed: 02/02/2023] Open
Abstract
In clear cell renal cell carcinoma (ccRCC), activation of hypoxic signaling induces NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 4-like 2 (NDUFA4L2) expression. Over 90% of ccRCCs exhibit overexpression of NDUFA4L2, which we previously showed contributes to ccRCC proliferation and survival. The function of NDUFA4L2 in ccRCC has not been fully elucidated. NDUFA4L2 was reported to reduce mitochondrial respiration via mitochondrial complex I inhibition. We found that NDUFA4L2 expression in human ccRCC cells increases the extracellular acidification rate, indicative of elevated glycolysis. Conversely, NDUFA4L2 expression in non-cancerous kidney epithelial cells decreases oxygen consumption rate while increasing extracellular acidification rate, suggesting that a Warburg-like effect is induced by NDUFA4L2 alone. We performed mass-spectrometry (MS)-based proteomics of NDUFA4L2 associated complexes. Comparing RCC4-P (parental) ccRCC cells with RCC4 in which NDUFA4L2 is knocked out by CRISPR-Cas9 (RCC4-KO-643), we identified 3,215 proteins enriched in the NDUFA4L2 immunoprecipitates. Among the top-ranking pathways were "Metabolic Reprogramming in Cancer" and "Glycolysis Activation in Cancer (Warburg Effect)." We also show that NDUFA4L2 enhances mitochondrial fragmentation, interacts with lysosomes, and increases mitochondrial-lysosomal associations, as assessed by high-resolution fluorescence microscopy and live cell imaging. We identified 161 lysosomal proteins, including Niemann-Pick Disease Type C Intracellular Cholesterol Transporters 1 and 2 (NPC1, NPC2), that are associated with NDUFA4L2 in RCC4-P cells. RCC4-P cells have larger and decreased numbers of lysosomes relative to RCC4 NDUFA4L2 knockout cells. These findings suggest that NDUFA4L2 regulates mitochondrial-lysosomal associations and potentially lysosomal size and abundance. Consequently, NDUFA4L2 may regulate not only mitochondrial, but also lysosomal functions in ccRCC.
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Affiliation(s)
- Jaclyn M. Kubala
- Department of Pharmacology, Weill Cornell Medicine, New York, NY, USA
- Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA
| | | | - Ryan Schreiner
- Division of Regenerative Medicine Research, Department of Medicine, Weill Cornell Medicine, New York, NY, USA
| | - Ryan M. Williams
- Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Biomedical Engineering, the City College of New York, New York, NY, USA
| | | | - Michael J. Crowley
- Department of Physiology, Biophysics, and Systems Biology, Weill Cornell Medicine, New York, NY, USA
| | - Nigel P. Mongan
- Department of Pharmacology, Weill Cornell Medicine, New York, NY, USA
- Faculty of Medicine and Health Sciences, Center for Cancer Sciences, University of Nottingham, Sutton Bonington Campus, Loughborough, UK
| | - David M. Nanus
- Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA
- Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medicine, New York, NY, USA
- Department of Urology; New York Presbyterian Hospital, Weill Cornell Medicine, New York, NY, USA
| | - Daniel A. Heller
- Department of Pharmacology, Weill Cornell Medicine, New York, NY, USA
- Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Physiology, Biophysics, and Systems Biology, Weill Cornell Medicine, New York, NY, USA
| | - Lorraine J. Gudas
- Department of Pharmacology, Weill Cornell Medicine, New York, NY, USA
- Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA
- Department of Urology; New York Presbyterian Hospital, Weill Cornell Medicine, New York, NY, USA
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Morlacchi LC, Zanini U, Gramegna A, Faverio P, Blasi F, Luppi F. Idiopathic interstitial pneumonia in a patient with von Hippel-Lindau syndrome: a first case. ERJ Open Res 2023; 9:00504-2023. [PMID: 38020566 PMCID: PMC10680027 DOI: 10.1183/23120541.00504-2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Accepted: 10/11/2023] [Indexed: 12/01/2023] Open
Abstract
Although the mechanisms are not known, this is a case of progressive interstitial lung involvement, with a NSIP radiological pattern, evolving in pulmonary fibrosis in a patient with von Hippel-Lindau syndrome, without extrapulmonary fibrosis. https://bit.ly/3QlNStu.
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Affiliation(s)
- Letizia Corinna Morlacchi
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy
- Internal Medicine Department, Respiratory Unit and Cystic Fibrosis Center, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy
- These authors contributed equally
| | - Umberto Zanini
- UOC Pneumologia, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy
- School of Medicine and Surgery, University of Milano Bicocca, Milan, Italy
- These authors contributed equally
| | - Andrea Gramegna
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy
- Internal Medicine Department, Respiratory Unit and Cystic Fibrosis Center, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Paola Faverio
- UOC Pneumologia, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy
- School of Medicine and Surgery, University of Milano Bicocca, Milan, Italy
| | - Francesco Blasi
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy
- Internal Medicine Department, Respiratory Unit and Cystic Fibrosis Center, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Fabrizio Luppi
- UOC Pneumologia, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy
- School of Medicine and Surgery, University of Milano Bicocca, Milan, Italy
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12
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Shirole NH, Kaelin WG. von-Hippel Lindau and Hypoxia-Inducible Factor at the Center of Renal Cell Carcinoma Biology. Hematol Oncol Clin North Am 2023; 37:809-825. [PMID: 37270382 PMCID: PMC11315268 DOI: 10.1016/j.hoc.2023.04.011] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/05/2023]
Abstract
The most common form of kidney cancer is clear cell renal cell carcinoma (ccRCC). Biallelic VHL tumor suppressor gene inactivation is the usual initiating event in both hereditary (VHL Disease) and sporadic ccRCCs. The VHL protein, pVHL, earmarks the alpha subunits of the HIF transcription factor for destruction in an oxygen-dependent manner. Deregulation of HIF2 drives ccRCC pathogenesis. Drugs inhibiting the HIF2-responsive growth factor VEGF are now mainstays of ccRCC treatment. A first-in-class allosteric HIF2 inhibitor was recently approved for treating VHL Disease-associated neoplasms and appears active against sporadic ccRCC in early clinical trials.
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Affiliation(s)
- Nitin H Shirole
- Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA
| | - William G Kaelin
- Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA; Brigham and Women's Hospital, Harvard Medical School; Howard Hughes Medical Institute.
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13
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Gross C, Guérin LP, Socol BG, Germain L, Guérin SL. The Ins and Outs of Clusterin: Its Role in Cancer, Eye Diseases and Wound Healing. Int J Mol Sci 2023; 24:13182. [PMID: 37685987 PMCID: PMC10488069 DOI: 10.3390/ijms241713182] [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: 06/30/2023] [Revised: 08/17/2023] [Accepted: 08/21/2023] [Indexed: 09/10/2023] Open
Abstract
Clusterin (CLU) is a glycoprotein originally discovered in 1983 in ram testis fluid. Rapidly observed in other tissues, it was initially given various names based on its function in different tissues. In 1992, it was finally named CLU by consensus. Nearly omnipresent in human tissues, CLU is strongly expressed at fluid-tissue interfaces, including in the eye and in particular the cornea. Recent research has identified different forms of CLU, with the most prominent being a 75-80 kDa heterodimeric protein that is secreted. Another truncated version of CLU (55 kDa) is localized to the nucleus and exerts pro-apoptotic activities. CLU has been reported to be involved in various physiological processes such as sperm maturation, lipid transportation, complement inhibition and chaperone activity. CLU was also reported to exert important functions in tissue remodeling, cell-cell adhesion, cell-substratum interaction, cytoprotection, apoptotic cell death, cell proliferation and migration. Hence, this protein is sparking interest in tissue wound healing. Moreover, CLU gene expression is finely regulated by cytokines, growth factors and stress-inducing agents, leading to abnormally elevated levels of CLU in many states of cellular disturbance, including cancer and neurodegenerative conditions. In the eye, CLU expression has been reported as being severely increased in several pathologies, such as age-related macular degeneration and Fuch's corneal dystrophy, while it is depleted in others, such as pathologic keratinization. Nevertheless, the precise role of CLU in the development of ocular pathologies has yet to be deciphered. The question of whether CLU expression is influenced by these disorders or contributes to them remains open. In this article, we review the actual knowledge about CLU at both the protein and gene expression level in wound healing, and explore the possibility that CLU is a key factor in cancer and eye diseases. Understanding the expression and regulation of CLU could lead to the development of novel therapeutics for promoting wound healing.
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Affiliation(s)
- Christelle Gross
- Centre de Recherche en Organogénèse Expérimentale de l’Université Laval/LOEX, Québec City, QC G1V 0A6, Canada; (C.G.); (B.G.S.); (L.G.)
- Centre de Recherche du CHU de Québec, Axe Médecine Régénératrice, Québec City, QC G1J 1Z4, Canada
- Département d’Ophtalmologie, Faculté de Médecine, Université Laval, Québec City, QC G1V 0A6, Canada
| | | | - Bianca G. Socol
- Centre de Recherche en Organogénèse Expérimentale de l’Université Laval/LOEX, Québec City, QC G1V 0A6, Canada; (C.G.); (B.G.S.); (L.G.)
| | - Lucie Germain
- Centre de Recherche en Organogénèse Expérimentale de l’Université Laval/LOEX, Québec City, QC G1V 0A6, Canada; (C.G.); (B.G.S.); (L.G.)
- Centre de Recherche du CHU de Québec, Axe Médecine Régénératrice, Québec City, QC G1J 1Z4, Canada
- Département d’Ophtalmologie, Faculté de Médecine, Université Laval, Québec City, QC G1V 0A6, Canada
- Département de Chirurgie, Faculté de Médecine, Université Laval, Québec City, QC G1V 0A6, Canada
| | - Sylvain L. Guérin
- Centre de Recherche en Organogénèse Expérimentale de l’Université Laval/LOEX, Québec City, QC G1V 0A6, Canada; (C.G.); (B.G.S.); (L.G.)
- Centre de Recherche du CHU de Québec, Axe Médecine Régénératrice, Québec City, QC G1J 1Z4, Canada
- Département d’Ophtalmologie, Faculté de Médecine, Université Laval, Québec City, QC G1V 0A6, Canada
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14
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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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15
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Chittiboina P, Mandal D, Bugarini A, Asuzu DT, Mullaney D, Mastorakos P, Stoica S, Alvarez R, Scott G, Maric D, Elkahloun A, Zhuang Z, Chew EY, Yang C, Linehan M, Lonser RR. Proteostasis Modulation in Germline Missense von Hippel Lindau Disease. Clin Cancer Res 2023; 29:2199-2209. [PMID: 37018064 PMCID: PMC10330138 DOI: 10.1158/1078-0432.ccr-22-3651] [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: 11/29/2022] [Revised: 02/06/2023] [Accepted: 04/03/2023] [Indexed: 04/06/2023]
Abstract
PURPOSE Missense mutated von Hippel Lindau (VHL) protein (pVHL) maintains intrinsic function but undergoes proteasomal degradation and tumor initiation and/or progression in VHL disease. Vorinostat can rescue missense mutated pVHL and arrest tumor growth in preclinical models. We asked whether short-term oral vorinostat could rescue pVHL in central nervous system hemangioblastomas in patients with germline missense VHL. PATIENTS AND METHODS We administered oral vorinostat to 7 subjects (ages 46.0 ± 14.5 years) and then removed symptomatic hemangioblastomas surgically (ClinicalTrials.gov identifier NCT02108002). RESULTS Vorinostat was tolerated without serious adverse events by all patients. pVHL expression was elevated in neoplastic stromal cells compared with untreated hemangioblastomas from same patients. We found transcriptional suppression of downstream hypoxia-inducible factor (HIF) effectors. Mechanistically, vorinostat prevented Hsp90 recruitment to mutated pVHL in vitro. The effects of vorinostat on the Hsp90-pVHL interaction, pVHL rescue, and transcriptional repression of downstream HIF effectors was independent of the location of the missense mutation on the VHL locus. We confirmed a neoplastic stromal cell-specific effect in suppression of protumorigenic pathways with single-nucleus transcriptomic profiling. CONCLUSIONS We found that oral vorinostat treatment in patients with germline missense VHL mutations has a potent biologic effect that warrants further clinical study. These results provide biologic evidence to support the use of proteostasis modulation for the treatment of syndromic solid tumors involving protein misfolding. Proteostasis modulation with vorinostat rescues missense mutated VHL protein. Further clinical trials are needed to demonstrate tumor growth arrest.
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Affiliation(s)
- Prashant Chittiboina
- Neurosurgery Unit for Pituitary and Inheritable Diseases, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD
- Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD
| | - Debjani Mandal
- Neurosurgery Unit for Pituitary and Inheritable Diseases, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD
| | - Alejandro Bugarini
- Neurosurgery Unit for Pituitary and Inheritable Diseases, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD
- Department of Neurological Surgery, Geisinger Health System, Danville, PA
| | - David T. Asuzu
- Neurosurgery Unit for Pituitary and Inheritable Diseases, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD
- Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD
- Department of Neurological Surgery, University of Virginia Health Science Center, University of Virginia, Charlottesville, VA
| | - Dustin Mullaney
- Neurosurgery Unit for Pituitary and Inheritable Diseases, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD
| | - Panagiotis Mastorakos
- Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD
- Department of Neurological Surgery, University of Virginia Health Science Center, University of Virginia, Charlottesville, VA
| | - Stefan Stoica
- Neurosurgery Unit for Pituitary and Inheritable Diseases, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD
| | - Reinier Alvarez
- Department of Neurological Surgery, University of Colorado, Aurora, CO
| | - Gretchen Scott
- Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD
| | - Dragan Maric
- Flow and Imaging Cytometry Core Facility, National Institute of Neurological Disorders and Stroke, Bethesda, MD
| | - Abdel Elkahloun
- Cancer Genetics and Comparative Genomics Branch, National Human Genome Research Institute, Bethesda, MD
| | - Zhengping Zhuang
- Neuro-Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | - Emily Y. Chew
- Division of Epidemiology and Clinical Applications, National Eye Institute, National Institutes of Health, Bethesda, MD
| | - Chunzhang Yang
- Neuro-Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | - Marston Linehan
- Urologic Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | - Russell R. Lonser
- Department of Neurological Surgery, The Ohio State University Wexner Medical Center, The Ohio State University, Columbus, OH
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16
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Vergauwen E, Forsyth R, Vortmeyer A, Gläsker S. Expression of Hemangioblast Proteins in von Hippel-Lindau Disease Related Tumors. Cancers (Basel) 2023; 15:cancers15092551. [PMID: 37174017 PMCID: PMC10177177 DOI: 10.3390/cancers15092551] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Revised: 04/23/2023] [Accepted: 04/27/2023] [Indexed: 05/15/2023] Open
Abstract
Von Hippel-Lindau (VHL) disease is a hereditary tumor syndrome that targets a highly selective subset of organs causing specific types of tumors. The biological basis for this principle of organ selectivity and tumor specificity is not well understood. VHL-associated hemangioblastomas share similar molecular and morphological features with embryonic blood and vascular precursor cells. Therefore, we suggest that VHL hemangioblastomas are derived from developmentally arrested hemangioblastic lineage keeping their potential of further differentiation. Due to these common features, it is of major interest to investigate whether VHL-associated tumors other than hemangioblastoma also share these pathways and molecular features. The expression of hemangioblast proteins has not yet been assessed in other VHL-related tumors. To gain a better understanding of VHL tumorigenesis, the expression of hemangioblastic proteins in different VHL-associated tumors was investigated. The expression of embryonic hemangioblast proteins Brachyury and TAL1 (T-cell acute lymphocytic leukemia protein 1) was assessed by immunohistochemistry staining on 75 VHL-related tumors of 51 patients: 47 hemangioblastomas, 13 clear cell renal cell carcinomas, 8 pheochromocytomas, 5 pancreatic neuroendocrine tumors, and 2 extra-adrenal paragangliomas. Brachyury and TAL1 expression was, respectively, observed in 26% and 93% of cerebellar hemangioblastomas, 55% and 95% of spinal hemangioblastomas, 23% and 92% of clear cell renal cell carcinomas, 38% and 88% of pheochromocytomas, 60% and 100% of pancreatic neuroendocrine tumors, and 50% and 100% of paragangliomas. We concluded that the expression of hemangioblast proteins in different VHL-associated tumors indicates a common embryological origin of these lesions. This may also explain the specific topographic distribution of VHL-associated tumors.
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Affiliation(s)
- Evelynn Vergauwen
- Department of Neurosurgery, Vrije Universiteit Brussel, Laarbeeklaan 101, 1090 Jette, Belgium
- Department of Neurology, Universiteit Antwerpen, Universiteitsplein 1, 2610 Antwerpen, Belgium
| | - Ramses Forsyth
- Department of Pathology, Universitair Ziekenhuis Brussel, Laarbeeklaan 101, 1090 Jette, Belgium
- Experimental Pathology Research Group, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Jette, Belgium
| | - Alexander Vortmeyer
- Department of Pathology, Indiana University-Purdue University, 420 University Blvd, Indianapolis, IN 46202, USA
| | - Sven Gläsker
- Department of Neurosurgery, Vrije Universiteit Brussel, Laarbeeklaan 101, 1090 Jette, Belgium
- Neurosurgery Section, Gesundheitsverbund Landkreis Konstanz (GLKN), 78224 Singen am Hohentwiel, Germany
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17
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Kase AM, George DJ, Ramalingam S. Clear Cell Renal Cell Carcinoma: From Biology to Treatment. Cancers (Basel) 2023; 15:665. [PMID: 36765622 PMCID: PMC9913203 DOI: 10.3390/cancers15030665] [Citation(s) in RCA: 36] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2022] [Revised: 01/13/2023] [Accepted: 01/17/2023] [Indexed: 01/25/2023] Open
Abstract
The majority of kidney cancers are detected incidentally and typically diagnosed at a localized stage, however, the development of regional or distant disease occurs in one-third of patients. Over 90% of kidney tumors are renal cell carcinomas, of which, clear cell is the most predominate histologic subtype. Von Hippel Lindau (VHL) gene alterations result in the overexpression of growth factors that are central to the pathogenesis of clear cell carcinoma. The therapeutic strategies have revolved around this tumor suppressor gene and have led to the approval of tyrosine kinase inhibitors (TKI) targeting the vascular endothelial growth factor (VEGF) axis. The treatment paradigm shifted with the introduction of immune checkpoint inhibitors (ICI) and programed death-1 (PD-1) inhibition, leading to durable response rates and improved survival. Combinations of TKI and/or ICIs have become the standard of care for advanced clear cell renal cell carcinoma (ccRCC), changing the outlook for patients, with several new and promising therapeutic targets under development.
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Affiliation(s)
- Adam M. Kase
- Mayo Clinic, Division of Hematology Oncology, Jacksonville, FL 32224, USA
| | - Daniel J. George
- Duke Cancer Institute, Duke University School of Medicine, Durham, NC 27710, USA
| | - Sundhar Ramalingam
- Duke Cancer Institute, Duke University School of Medicine, Durham, NC 27710, USA
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18
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Fields BKK, Demirjian NL, Ahmadzadehfar H, Yordanova A, Nabipour I, Jokar N, Assadi M, Joyce P, Gholamrezanezhad A. Imaging Approach to Pediatric and Adolescent Familial Cancer Syndromes. FAMILIAL ENDOCRINE CANCER SYNDROMES 2023:127-148. [DOI: 10.1007/978-3-031-37275-9_7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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19
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Matloob SA, Paraskevopoulos D, O'Toole SM, Drake W, Plowman N, Foroglou N. VHL: Trends and Insight into a Multi-Modality, Interdisciplinary Approach for Management of Central Nervous System Hemangioblastoma. ACTA NEUROCHIRURGICA. SUPPLEMENT 2023; 135:81-88. [PMID: 38153453 DOI: 10.1007/978-3-031-36084-8_14] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/29/2023]
Abstract
Von Hippel-Lindau (VHL) is a multi-system disease which results in significant morbidity from central nervous system (CNS) involvement as well as ocular, renal and neuro-endocrine effects. Haemangioblastomas of the CNS present a number of challenges. The natural history of these lesions is varied, as is the size and location within the CNS. Whilst surgery is considered the mainstay of treatment and best chance at curing these lesions, this is also often associated with significant risks due to the anatomical location of these lesions, most commonly the posterior fossa and spinal cord.We review the literature and describe our experience across two separate European VHL referral centres. Alternative treatment options and combined modalities are increasingly being used in the context of managing CNS haemangioblastomas. We analyse the increasing use of stereotactic radiosurgery and the evolution of medical treatments as potential future adjuncts to surgery. The availability of multiple modalities in our armamentarium is essential in tailoring a personalised treatment approach to these patients. Owing to the multi-systemic nature of the disease, in our experience, managing the care of patients with VHL is best delivered using an interdisciplinary approach utilising multiple specialties and adopting an individually tailored holistic approach.
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Affiliation(s)
- S A Matloob
- Department of Neurosurgery, Barts Health NHS Trust, London, UK.
- Department of Neurosurgery, Royal London Hospital, London, UK.
| | | | - S M O'Toole
- Department of Endocrinology, The Royal Hallamshire Hospital, Sheffield, UK
| | - W Drake
- Department of Endocrinology, Barts Health NHS Trust, London, UK
| | - N Plowman
- Department of Oncology, Barts Health NHS Trust, London, UK
| | - N Foroglou
- Department of Neurosurgery, AHEPA University Hospital, Thessaloniki, Greece
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20
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Advances in Adrenal and Extra-adrenal Paraganglioma: Practical Synopsis for Pathologists. Adv Anat Pathol 2023; 30:47-57. [PMID: 36136370 DOI: 10.1097/pap.0000000000000365] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Adrenal paraganglioma (or "pheochromocytoma") and extra-adrenal paraganglioma, collectively abbreviated PPGL, are rare but spectacular nonepithelial neuroendocrine neoplasms. These are the most inheritable neoplasia of all, with a metastatic potential in a varying degree. As of such, these lesions demand careful histologic, immunohistochemical, and genetic characterization to provide the clinical team with a detailed report taking into account the anticipated prognosis and risk of syndromic/inherited disease. While no histologic algorithm, immunohistochemical biomarker, or molecular aberration single-handedly can identify potentially lethal cases upfront, the combined analysis of various risk parameters may stratify PPGL patients more stringently than previously. Moreover, the novel 2022 WHO Classification of Endocrine and Neuroendocrine Tumors also brings some new concepts into play, not least the reclassification of special neuroendocrine neoplasms (cauda equina neuroendocrine tumor and composite gangliocytoma/neuroma-neuroendocrine tumor) previously thought to belong to the spectrum of PPGL. This review focuses on updated key diagnostic and prognostic concepts that will aid when facing this rather enigmatic tumor entity in clinical practice.
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21
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Characterization of Microscopic Multicellular Foci in Grossly Normal Renal Parenchyma of Von Hippel-Lindau Kidney. MEDICINA (KAUNAS, LITHUANIA) 2022; 58:medicina58121725. [PMID: 36556926 PMCID: PMC9782033 DOI: 10.3390/medicina58121725] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Revised: 11/06/2022] [Accepted: 11/16/2022] [Indexed: 11/26/2022]
Abstract
Background and Objectives: This study aims to describe the earliest renal lesions in patients with von Hippel-Lindau (VHL) disease, especially the multicellular microscopic pathologic events, to get information into the genesis of renal neoplasms in this condition. Materials and Methods: Multicellular events were identified, and 3dimensional reconstruction was performed in grossly normal kidney parenchyma from VHL disease patients by using H&E-stained slides previously prepared. Results: The lesions were measured and the volume of clusters was calculated. Immunohistochemistry was performed for downstream HIF-target protein carbonic anhydrase 9 (CAIX) as well as CD34 for assessment of angiogenesis. We divided lesions into four types according to lesion height/size. The number of lesions was markedly decreased from lesion 1 (smallest) to lesion 2, then from lesions 2 to 3, and again from lesion 3 to 4. Distribution was highly consistent in the four cases, and the same decrement pattern was seen in all blocks studied. The volumes of clusters were measured and divided into three categories according to their volume. The most frequent pathologic event in VHL kidneys was category 1 (smallest volume), then category 2, and then category 3. Conclusion: We demonstrate that tracking histologic and morphologic changes in 3 dimensions of multicellular microscopic pathologic events enabled us to confirm a protracted sequence of events from smaller to larger cellular amplification events in VHL kidney.
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22
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Cinque A, Minnei R, Floris M, Trevisani F. The Clinical and Molecular Features in the VHL Renal Cancers; Close or Distant Relatives with Sporadic Clear Cell Renal Cell Carcinoma? Cancers (Basel) 2022; 14:5352. [PMID: 36358771 PMCID: PMC9657498 DOI: 10.3390/cancers14215352] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2022] [Accepted: 10/27/2022] [Indexed: 11/24/2022] Open
Abstract
Von Hippel-Lindau (VHL) disease is an autosomal dominant inherited cancer syndrome caused by germline mutations in the VHL tumor suppressor gene, characterized by the susceptibility to a wide array of benign and malign neoplasms, including clear-cell renal cell carcinoma. Moreover, VHL somatic inactivation is a crucial molecular event also in sporadic ccRCCs tumorigenesis. While systemic biomarkers in the VHL syndrome do not currently play a role in clinical practice, a new promising class of predictive biomarkers, microRNAs, has been increasingly studied. Lots of pan-genomic studies have deeply investigated the possible biological role of microRNAs in the development and progression of sporadic ccRCC; however, few studies have investigated the miRNA profile in VHL patients. Our review summarize all the new insights related to clinical and molecular features in VHL renal cancers, with a particular focus on the overlap with sporadic ccRCC.
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Affiliation(s)
- Alessandra Cinque
- Biorek S.r.l., San Raffaele Scientific Institute, 20132 Milan, Italy
| | - Roberto Minnei
- Nephrology, Dialysis, and Transplantation, G. Brotzu Hospital, University of Cagliari, 09134 Cagliari, Italy
| | - Matteo Floris
- Nephrology, Dialysis, and Transplantation, G. Brotzu Hospital, University of Cagliari, 09134 Cagliari, Italy
| | - Francesco Trevisani
- Biorek S.r.l., San Raffaele Scientific Institute, 20132 Milan, Italy
- Urological Research Institute, San Raffaele Scientific Institute, 20132 Milan, Italy
- Unit of Urology, San Raffaele Scientific Institute, 20132 Milan, Italy
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23
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Kirste S, Rühle A, Zschiedrich S, Schultze-Seemann W, Jilg CA, Neumann-Haefelin E, Lo SS, Grosu AL, Kim E. Stereotactic Body Radiotherapy for Renal Cell Carcinoma in Patients with Von Hippel-Lindau Disease-Results of a Prospective Trial. Cancers (Basel) 2022; 14:5069. [PMID: 36291853 PMCID: PMC9599838 DOI: 10.3390/cancers14205069] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Revised: 10/04/2022] [Accepted: 10/12/2022] [Indexed: 11/18/2022] Open
Abstract
Von Hippel-Lindau disease (VHL) is a hereditary disorder associated with malignant tumors including clear cell renal cell carcinoma (ccRCC). Partial nephrectomy is complicated by multilocular tumor occurrence and a high recurrence rate. The aim of this study was to evaluate the potential of stereotactic body radiotherapy (SBRT) as an alternative treatment approach in VHL patients with multiple ccRCC. Patients with VHL and a diagnosis of ccRCC were enrolled. SBRT was conducted using five fractions of 10 Gy or eight fractions of 7.5 Gy. The primary endpoint was local control (LC). Secondary endpoints included alteration of renal function and adverse events. Seven patients with a total of eight treated lesions were enrolled. Median age was 44 years. Five patients exhibited multiple bilateral kidney cysts in addition to ccRCC. Three patients underwent at least one partial nephrectomy in the past. After a median follow-up of 43 months, 2-year LC was 100%, while 2-year CSS, 2-year PFS and 2-year OS was 100%, 85.7% and 85.7%, respectively. SBRT was very well tolerated with no acute or chronic toxicities grade ≥ 2. Mean estimated glomerular filtration rate (eGFR) at baseline was 83.7 ± 13.0 mL/min/1.73 m2, which decreased to 76.6 ± 8.0 mL/min/1.73 m2 after 1 year. Although the sample size was small, SBRT resulted in an excellent LC rate and was very well tolerated with preservation of kidney function in patients with multiple renal lesions and cysts.
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Affiliation(s)
- Simon Kirste
- Department of Radiation Oncology, Medical Center—University of Freiburg, Faculty of Medicine, 79106 Freiburg, Germany
- German Cancer Consortium (DKTK) Partner Site Freiburg, German Cancer Research Center (dkfz), 69120 Heidelberg, Germany
| | - Alexander Rühle
- Department of Radiation Oncology, Medical Center—University of Freiburg, Faculty of Medicine, 79106 Freiburg, Germany
- German Cancer Consortium (DKTK) Partner Site Freiburg, German Cancer Research Center (dkfz), 69120 Heidelberg, Germany
| | - Stefan Zschiedrich
- Renal Division, Department of Internal Medicine, Bürgerspital Solothurn, 4500 Solothurn, Switzerland
- Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
| | - Wolfgang Schultze-Seemann
- Department of Urology, Medical Center—University of Freiburg, Faculty of Medicine, 79106 Freiburg, Germany
| | - Cordula A. Jilg
- Department of Urology, Medical Center—University of Freiburg, Faculty of Medicine, 79106 Freiburg, Germany
| | - Elke Neumann-Haefelin
- Renal Division, Department of Medicine, Medical Center—University of Freiburg, Faculty of Medicine, 79106 Freiburg, Germany
| | - Simon S. Lo
- Department of Radiation Oncology, University of Washington School of Medicine, Seattle, WA 98195, USA
| | - Anca-Ligia Grosu
- Department of Radiation Oncology, Medical Center—University of Freiburg, Faculty of Medicine, 79106 Freiburg, Germany
- German Cancer Consortium (DKTK) Partner Site Freiburg, German Cancer Research Center (dkfz), 69120 Heidelberg, Germany
| | - Emily Kim
- Department of Radiation Oncology, Medical Center—University of Freiburg, Faculty of Medicine, 79106 Freiburg, Germany
- German Cancer Consortium (DKTK) Partner Site Freiburg, German Cancer Research Center (dkfz), 69120 Heidelberg, Germany
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24
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Raghubar AM, Roberts MJ, Wood S, Healy HG, Kassianos AJ, Mallett AJ. Cellular milieu in clear cell renal cell carcinoma. Front Oncol 2022; 12:943583. [PMID: 36313721 PMCID: PMC9614096 DOI: 10.3389/fonc.2022.943583] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Accepted: 09/21/2022] [Indexed: 11/13/2022] Open
Abstract
Clear cell renal cell carcinoma (ccRCC) is globally the most prevalent renal cancer. The cells of origin in ccRCC have been identified as proximal tubular epithelial cells (PTEC); however, the transcriptomic pathways resulting in the transition from normal to malignant PTEC state have remained unclear. Immunotherapy targeting checkpoints have revolutionized the management of ccRCC, but a sustained clinical response is achieved in only a minority of ccRCC patients. This indicates that our understanding of the mechanisms involved in the malignant transition and resistance to immune checkpoint therapy in ccRCC is unclear. This review examines recent single-cell transcriptomics studies of ccRCC to clarify the transition of PTEC in ccRCC development, and the immune cell types, states, and interactions that may limit the response to targeted immune therapy, and finally suggests stromal cells as key drivers in recurrent and locally invasive ccRCC. These and future single-cell transcriptomics studies will continue to clarify the cellular milieu in the ccRCC microenvironment, thus defining actional clinical, therapeutic, and prognostic characteristics of ccRCC.
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Affiliation(s)
- Arti M. Raghubar
- Kidney Health Service, Royal Brisbane and Women’s Hospital, Herston, QLD, Australia
- Conjoint Internal Medicine Laboratory, Chemical Pathology, Pathology Queensland, Health Support Queensland, Herston, QLD, Australia
- Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia
- Anatomical Pathology, Pathology Queensland, Health Support Queensland, Herston, QLD, Australia
- Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, Australia
| | - Matthew J. Roberts
- Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia
- Department of Urology, Royal Brisbane and Women’s Hospital, Brisbane, QLD, Australia
- Department of Urology, Redcliffe Hospital, Redcliffe, QLD, Australia
- Centre for Clinical Research, The University of Queensland, Brisbane, QLD, Australia
| | - Simon Wood
- Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia
- Department of Urology, Princess Alexandra Hospital, Brisbane, QLD, Australia
| | - Helen G. Healy
- Kidney Health Service, Royal Brisbane and Women’s Hospital, Herston, QLD, Australia
- Conjoint Internal Medicine Laboratory, Chemical Pathology, Pathology Queensland, Health Support Queensland, Herston, QLD, Australia
- Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia
| | - Andrew J. Kassianos
- Kidney Health Service, Royal Brisbane and Women’s Hospital, Herston, QLD, Australia
- Conjoint Internal Medicine Laboratory, Chemical Pathology, Pathology Queensland, Health Support Queensland, Herston, QLD, Australia
- Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia
| | - Andrew J. Mallett
- Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia
- Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, Australia
- College of Medicine & Dentistry, James Cook University, Townsville, QLD, Australia
- Department of Renal Medicine, Townsville University Hospital, Townsville, QLD, Australia
- *Correspondence: Andrew J. Mallett,
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25
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De Jesus O, Rosado-Philippi J. Spinal leptomeningeal hemangioblastomatosis occurring without craniospinal surgery in von Hippel-Lindau disease. BMJ Case Rep 2022; 15:e249758. [PMID: 36038156 PMCID: PMC9438049 DOI: 10.1136/bcr-2022-249758] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/14/2022] [Indexed: 11/03/2022] Open
Abstract
Hemangioblastomatosis represents an unusual and malignant leptomeningeal dissemination of hemangioblastoma (HB). It has been reported in patients with sporadic HB or von Hippel-Lindau (VHL) disease. Hemangioblastomatosis had been reported following resection of a primary HB lesion in all cases except one patient with a sporadic HB. We present a patient with VHL with several HBs at the brainstem, cerebellum, pituitary stalk and retina who developed spinal hemangioblastomatosis without previous craniospinal surgery. A whole spine MRI showed the spinal dissemination from the primary lesions. The patient received craniospinal radiotherapy due to the extensive spinal leptomeningeal dissemination and multiple HBs. MRI performed 12 months after the radiotherapy showed stability of the lesions.
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Affiliation(s)
- Orlando De Jesus
- Neurosurgery, University of Puerto Rico Medical Sciences Campus, San Juan, Puerto Rico
| | - Julio Rosado-Philippi
- Neurosurgery, University of Puerto Rico Medical Sciences Campus, San Juan, Puerto Rico
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26
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Schönbach EM, Trichonas G. JUXTAPAPILLARY CAPILLARY RETINAL ANGIOMA AND EPIRETINAL MEMBRANE MANAGEMENT IN A MONOCULAR PATIENT WITH VON HIPPEL-LINDAU SYNDROME. Retin Cases Brief Rep 2022; 16:520-522. [PMID: 32541428 DOI: 10.1097/icb.0000000000001021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/11/2023]
Abstract
PURPOSE To report a case of von Hippel-Lindau syndrome in a monocular patient with progressive vision loss due to a juxtapapillary capillary retinal angioma and an epiretinal membrane (ERM) formation. PATIENT We describe a 37-year-old white male patient with von Hippel-Lindau syndrome who presented for retinal evaluation. The right eye was blind with no light perception vision. The left eye had a best-corrected visual acuity of 20/30 and exhibited a peripheral capillary hemangioblastoma at 12 o'clock and a juxtapapillary capillary hemangioma with an ERM covering the fovea. The patient underwent two sessions of fluorescein-potentiated argon laser treatment to the peripheral capillary hemangioblastoma with initial stabilization of vision. After 18 months of follow-up, the ERM contracted causing decline in vision to 20/50. Intravitreal injection of bevacizumab was given without improvement in vision or distortion. Twenty-five-gauge pars plana vitrectomy with ERM peeling and internal limiting membrane removal was performed with immediate improvement in vision and distortion. CONCLUSION This case suggests that pars plana vitrectomy is a reasonable treatment option for vision loss due to a juxtapapillary capillary retinal angioma and ERM formation.
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Affiliation(s)
- Etienne M Schönbach
- Department of Ophthalmology, University Hospitals Eye Institute, Case Western Reserve University, Cleveland, Ohio
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Yoda RA, Cimino PJ. Neuropathologic features of central nervous system hemangioblastoma. J Pathol Transl Med 2022; 56:115-125. [PMID: 35501672 PMCID: PMC9119802 DOI: 10.4132/jptm.2022.04.13] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2022] [Accepted: 04/13/2022] [Indexed: 12/04/2022] Open
Abstract
Hemangioblastoma is a benign, highly vascularized neoplasm of the central nervous system (CNS). This tumor is associated with loss of function of the VHL gene and demonstrates frequent occurrence in von Hippel-Lindau (VHL) disease. While this entity is designated CNS World Health Organization grade 1, due to its predilection for the cerebellum, brainstem, and spinal cord, it is still an important cause of morbidity and mortality in affected patients. Recognition and accurate diagnosis of hemangioblastoma is essential for the practice of surgical neuropathology. Other CNS neoplasms, including several tumors associated with VHL disease, may present as histologic mimics, making diagnosis challenging. We outline key clinical and radiologic features, pathophysiology, treatment modalities, and prognostic information for hemangioblastoma, and provide a thorough review of the gross, microscopic, immunophenotypic, and molecular features used to guide diagnosis.
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Affiliation(s)
- Rebecca A. Yoda
- Department of Laboratory Medicine and Pathology, Division of Neuropathology, University of Washington, Seattle, WA, USA
- Department of Laboratory Medicine and Pathology, Division of Cytopathology, University of Washington, Seattle, WA, USA
- Corresponding Author: Rebecca A. Yoda, MD, Department of Laboratory Medicine and Pathology, University of Washington, 325 9th Avenue, Box 359791, Seattle, WA 98104-2499, USA Tel: +1-206-744-3145, Fax: +1-206-744-8240, E-mail:
| | - Patrick J. Cimino
- Department of Laboratory Medicine and Pathology, Division of Neuropathology, University of Washington, Seattle, WA, USA
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28
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Chakiryan NH, Hajiran A, Kim Y, Aydin AM, Zemp L, Katende E, Nguyen J, Fan W, Cheng CH, Lopez-Blanco N, Chahoud J, Spiess PE, Fournier M, Dhillon J, Wang L, Moran-Segura C, Mulé J, Du D, Yoder SJ, Berglund A, Teer JK, Manley BJ. Correlating Immune Cell Infiltration Patterns with Recurrent Somatic Mutations in Advanced Clear Cell Renal Cell Carcinoma. Eur Urol Focus 2022; 8:784-793. [PMID: 33994165 PMCID: PMC11091541 DOI: 10.1016/j.euf.2021.04.014] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Revised: 03/24/2021] [Accepted: 04/15/2021] [Indexed: 02/01/2023]
Abstract
BACKGROUND Clear cell renal cell carcinoma (ccRCC) tumors have low frequencies of genetic alterations compared with other malignancies, but very high levels of immune cell infiltration and favorable response rates to immunotherapy. Currently, the interplay between specific ccRCC somatic mutations and immune infiltration pattern is unclear. OBJECTIVE To analyze the associations between common ccRCC somatic mutations and immune cell infiltration patterns within the tumor immune microenvironment (TIME). DESIGN, SETTING, AND PARTICIPANTS The study included tumor samples (24 primary and 24 metastatic) from 48 patients with stage IV ccRCC. Targeted sequencing was performed for well-characterized recurrent somatic mutations in ccRCC, with the analysis focusing on the six most common ones: VHL, BAP1, PBRM1, SETD2, TP53, and KDM5C. For each sample, multiplex immunofluorescence (IF) was performed in lymphoid and myeloid panels, for seven regions of interest in three zones (tumor core, stroma, and tumor-stroma interface). IF-derived cellular densities were compared across patients, stratified by their somatic mutation status, using a linear mixed-model analysis. External validation was pursued using RNA-seq enrichment scoring from three large external data sources. RESULTS AND LIMITATIONS Tumors with SETD2 mutations demonstrated significantly decreased levels of FOXP3+ T cells in the tumor core, stroma, and tumor-stroma interface. PBRM1 mutations were associated with decreased FOXP3+ T cells in the tumor core. Primary KDM5C mutations were associated with significantly increased CD206+ macrophage tumor infiltration in the tumor core. A computational method estimating immune cell types in the TIME using bulk RNA-seq data, xCell scoring, failed to validate associations from the IF analysis in large external data sets. A major limitation of the study is the relatively small patient population studied. CONCLUSIONS This study provides evidence that common somatic mutations in ccRCC, such as SETD2, PBRM1, and KDM5C, are associated with distinct immune infiltration patterns within the TIME. PATIENT SUMMARY In this study, we analyzed tumor samples from patients with metastatic kidney cancer to determine whether common genetic mutations that arise from the cancer cells are associated with the density of immune cells found within those tumors. We found several distinct immune cell patterns that were associated with specific genetic mutations. These findings provide insight into the interaction between cancer genetics and the immune system in kidney cancer.
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Affiliation(s)
- Nicholas H Chakiryan
- Department of Genitourinary Oncology, H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA; Integrated Mathematical Oncology Department, H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
| | - Ali Hajiran
- Department of Genitourinary Oncology, H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA; Integrated Mathematical Oncology Department, H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
| | - Youngchul Kim
- Department of Biostatistics and Bioinformatics, H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA; Integrated Mathematical Oncology Department, H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
| | - Ahmet M Aydin
- Department of Genitourinary Oncology, H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA; Integrated Mathematical Oncology Department, H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
| | - Logan Zemp
- Department of Genitourinary Oncology, H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA; Integrated Mathematical Oncology Department, H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
| | - Esther Katende
- Department of Genitourinary Oncology, H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA; Integrated Mathematical Oncology Department, H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
| | - Jonathan Nguyen
- Department of Pathology, H Lee Moffitt Cancer Center, Tampa, FL, USA; Integrated Mathematical Oncology Department, H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
| | - Wenyi Fan
- Biostatistics and Bioinformatics Shared Resource, H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA; Integrated Mathematical Oncology Department, H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
| | - Chia-Ho Cheng
- Biostatistics and Bioinformatics Shared Resource, H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA; Integrated Mathematical Oncology Department, H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
| | - Neale Lopez-Blanco
- Department of Pathology, H Lee Moffitt Cancer Center, Tampa, FL, USA; Integrated Mathematical Oncology Department, H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
| | - Jad Chahoud
- Department of Genitourinary Oncology, H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA; Integrated Mathematical Oncology Department, H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
| | - Philippe E Spiess
- Department of Genitourinary Oncology, H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA; Integrated Mathematical Oncology Department, H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
| | - Michelle Fournier
- Department of Genitourinary Oncology, H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA; Integrated Mathematical Oncology Department, H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
| | - Jasreman Dhillon
- Department of Pathology, H Lee Moffitt Cancer Center, Tampa, FL, USA; Integrated Mathematical Oncology Department, H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
| | - Liang Wang
- Department of Tumor Biology, H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA; Integrated Mathematical Oncology Department, H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
| | - Carlos Moran-Segura
- Department of Pathology, H Lee Moffitt Cancer Center, Tampa, FL, USA; Integrated Mathematical Oncology Department, H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
| | - James Mulé
- Immunology Department, H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA; Integrated Mathematical Oncology Department, H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
| | - Dongliang Du
- Department of Biostatistics and Bioinformatics, H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA; Integrated Mathematical Oncology Department, H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
| | - Sean J Yoder
- Molecular Genomics Shared Resource, H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA; Integrated Mathematical Oncology Department, H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
| | - Anders Berglund
- Department of Biostatistics and Bioinformatics, H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA; Integrated Mathematical Oncology Department, H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
| | - Jamie K Teer
- Department of Biostatistics and Bioinformatics, H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA; Integrated Mathematical Oncology Department, H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
| | - Brandon J Manley
- Department of Genitourinary Oncology, H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA; Department of Biostatistics and Bioinformatics, H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA; Integrated Mathematical Oncology Department, H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
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29
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Andreou A, Yngvadottir B, Bassaganyas L, Clark G, Martin E, Whitworth J, Cornish AJ, Genomics England Research Consortium, Houlston RS, Rich P, Egan C, Hodgson SV, Warren AY, Snape K, Maher ER. Elongin C (ELOC/TCEB1)-associated von Hippel-Lindau disease. Hum Mol Genet 2022; 31:2728-2737. [PMID: 35323939 PMCID: PMC9402235 DOI: 10.1093/hmg/ddac066] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Revised: 03/15/2022] [Accepted: 03/16/2022] [Indexed: 12/02/2022] Open
Abstract
Around 95% of patients with clinical features that meet the diagnostic criteria for von Hippel-Lindau disease (VHL) have a detectable inactivating germline variant in VHL. The VHL protein (pVHL) functions as part of the E3 ubiquitin ligase complex comprising pVHL, elongin C, elongin B, cullin 2 and ring box 1 (VCB-CR complex), which plays a key role in oxygen sensing and degradation of hypoxia-inducible factors. To date, only variants in VHL have been shown to cause VHL disease. We undertook trio analysis by whole-exome sequencing in a proband with VHL disease but without a detectable VHL mutation. Molecular studies were also performed on paired DNA extracted from the proband's kidney tumour and blood and bioinformatics analysis of sporadic renal cell carcinoma (RCC) dataset was undertaken. A de novo pathogenic variant in ELOC NM_005648.4(ELOC):c.236A>G (p.Tyr79Cys) gene was identified in the proband. ELOC encodes elongin C, a key component [C] of the VCB-CR complex. The p.Tyr79Cys substitution is a mutational hotspot in sporadic VHL-competent RCC and has previously been shown to mimic the effects of pVHL deficiency on hypoxic signalling. Analysis of an RCC from the proband showed similar findings to that in somatically ELOC-mutated RCC (expression of hypoxia-responsive proteins, no somatic VHL variants and chromosome 8 loss). These findings are consistent with pathogenic ELOC variants being a novel cause for VHL disease and suggest that genetic testing for ELOC variants should be performed in individuals with suspected VHL disease with no detectable VHL variant.
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Affiliation(s)
- Avgi Andreou
- Department of Medical Genetics, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK
| | - Bryndis Yngvadottir
- Department of Medical Genetics, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK
| | - Laia Bassaganyas
- Department of Medical Genetics, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK
| | - Graeme Clark
- Department of Medical Genetics, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK,Stratified Medicine Core Laboratory NGS Hub, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK
| | - Ezequiel Martin
- Department of Medical Genetics, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK,Stratified Medicine Core Laboratory NGS Hub, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK
| | - James Whitworth
- Department of Medical Genetics, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK
| | - Alex J Cornish
- Division of Genetics and Epidemiology, The Institute of Cancer Research, Sutton, Surrey SM2 5NG, UK
| | | | - Richard S Houlston
- Division of Genetics and Epidemiology, The Institute of Cancer Research, Sutton, Surrey SM2 5NG, UK
| | - Philip Rich
- Department of Neuroradiology, St. George’s University Hospitals NHS Foundation Trust, London SW17 0QT, UK
| | - Catherine Egan
- NIHR Biomedical Research Center at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, London, UK
| | - Shirley V Hodgson
- South West Thames Regional Genetics Service, St George's University Hospitals NHS Foundation Trust, London, UK
| | - Anne Y Warren
- Department of Histopathology, Cambridge University NHS Foundation Trust, Cambridge CB2 OQQ, UK
| | - Katie Snape
- South West Thames Regional Genetics Service, St George's University Hospitals NHS Foundation Trust, London, UK,St George's University of London, UK
| | - Eamonn R Maher
- To whom correspondence should be addressed at: Department of Medical Genetics, University of Cambridge, Box 238, Cambridge Biomedical Campus, Cambridge, CB2 0QQ, UK. Tel: +44 01223746715; Fax: +44 01223746777;
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30
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Von Hippel-Lindau Syndrome: Medical Syndrome or Surgical Syndrome? A Surgical Perspective. J Kidney Cancer VHL 2021; 9:27-32. [PMID: 34963877 PMCID: PMC8652351 DOI: 10.15586/jkcvhl.v9i1.206] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2021] [Accepted: 10/24/2021] [Indexed: 01/29/2023] Open
Abstract
Von Hippel-Lindau syndrome (VHL) is an autosomal dominant disease caused by a genetic aberration of the tumor suppressor gene VHL and characterized by multi-organ tumors. The most common neoplasm is retinal or cerebral hemangioblastoma, although spinal hemangioblastomas, Renal Clear Cell Carcinoma (RCCC), pheochromocytomas (Pheo), paragangliomas, Pancreatic Neuroendocrine Tumors (PNETs), cystadenomas of the epididymis, and tumors of the lymphatic sac can also be found. Neurological complications from retinal or CNS hemangioblastoma and metastases of RCCC are the most common causes of death. There is a strong association between pheochromocytoma and VHL syndrome, and pheochromocytoma is often a classic manifestation of the syndrome. RCCCs are often incidental and identified during other tests. Between 35 and 70% of patients with VHL have pancreatic cysts. These can manifest as simple cysts, serous cysto-adenomas, or PNETs with a risk of malignant degeneration or metastasis of no more than 8%. The objective of this retrospective study is to analyze abdominal manifestations of VHL from a surgical point of view.
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31
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Fuhrmann C, Czerner CP, Ripperger T, Imkamp F. [Hereditary kidney cancer - easily clarified and diagnosed with ToSCaNA]. Aktuelle Urol 2021; 53:416-422. [PMID: 34670316 DOI: 10.1055/a-1466-9326] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
BACKGROUND In recent years great improvements in the diagnosis and differentiation of hereditary syndroms with predisposition for kidney cancer have been achieved. It has been assumed that 5-8% of all kidney cancer have a hereditary origin. In reality, this number will probably be much higher as many genetic aspects of kidney cancer are still not entirely known. Hereditary kidney cancer usually shows two characteristic properties: While the median age of diagnosis of sporadic renal cell carcinoma is 64 years, patients with a hereditary tumor predisposition are about 20 years younger at the time of diagnosis. Additionally, their tumors often occur multifocal/bilateral. Therefore, a special management with extended diagnostics is necessary for these young kidney cancer patients. In literature many reports on hereditary syndromes with kidney cancer predisposition exist. Though, these papers usually put their focus on single syndromes rather than on the aspects of kidney cancer. The goal of this article is to present the practicing urologist with a compact overview of the most important hereditary syndromes with kidney cancer predisposition and by this improve the primary diagnostic and treatment of renal cancer patients and their relatives. MATERIAL/METHODS We conducted a literature search on the five most important hereditary syndromes with kidney cancer association and summarized the results in a chart. Additionally, we formed the acronym ToSCaNA combining the most important extrarenal manifestations of the syndromes. Based on this data, a diagnostic workflow and treatment path was established. RESULTS All in all, hereditary kidney cancer is a rare entity, which nonetheless could present as a significant number in high-volume centers. For doctors who scarcely get in contact with these types of tumors, the acronym and workflow could pose a valuable asset for their clinical diagnostic portfolio. An early identification and diagnostic work-up of affected patients and their relatives is crucial for appropriate treatment and surveillance and allows the identification/treatment of additionally affected relatives. CONCLUSION In patients with young age of onset and multifocal/bilateral occurrence of kidney cancer, hereditary syndromes should always be considered. The initial suspicion of a hereditary genesis of the cancer can be further evaluated by the acronym ToSCaNA and the presented workflow.
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Affiliation(s)
- Christian Fuhrmann
- Klinik für Urologie und urologische Onkologie, Medizinische Hochschule Hannover, Hannover, Germany
| | - Christoph P. Czerner
- Institut für Diagnostische und Interventionelle Radiologie, Medizinische Hochschule Hannover, Hannover, Germany
| | - Tim Ripperger
- Institut für Humangenetik, Medizinische Hochschule Hannover, Hannover, Germany
| | - Florian Imkamp
- Urologische Klinik, Vinzenzkrankenhaus Hannover GmbH, Hannover, Germany
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Poly(ADP)-Ribosylation Inhibition: A Promising Approach for Clear Cell Renal Cell Carcinoma Therapy. Cancers (Basel) 2021; 13:cancers13194973. [PMID: 34638458 PMCID: PMC8507656 DOI: 10.3390/cancers13194973] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2021] [Revised: 09/28/2021] [Accepted: 09/28/2021] [Indexed: 01/11/2023] Open
Abstract
Poly(ADP-ribose) polymerase 1 (PARP-1) and glycohydrolase (PARG) enzymes regulate chromatin structure, transcription activation, and DNA repair by modulating poly(ADP-ribose) (pADPr) level. Interest in PARP-1 inhibitors has soared recently with the recognition of their antitumor efficacy. We have shown that the development of clear cell renal cell carcinoma (ccRCC) is associated with extreme accumulation of pADPr caused by the enhanced expression of PARP-1 and decreased PARG levels. The most severe misregulation of pADPr turnover is found in ccRCC specimens from metastatic lesions. Both, classical NAD-like and non-NAD-like PARP-1 inhibitors reduced viability and clonogenic potential of ccRCC cell lines and suppressed growth of ccRCC xenograft tumors. However, classical NAD-like PARP-1 inhibitors affected viability of normal kidney epithelial cells at high concentrations, while novel non-NAD-like PARP-1 inhibitors exhibited activity against malignant cells only. We have also utilized different approaches to reduce the pADPr level in ccRCC cells by stably overexpressing PARG and demonstrated the prominent antitumor effect of this "back-to-normal" intervention. We also generated ccRCC cell lines with stable overexpression of PARG under doxycycline induction. This genetic approach demonstrated significantly affected malignancy of ccRCC cells. Transcriptome analysis linked observed phenotype with changes in gene expression levels for lipid metabolism, interferon signaling, and angiogenesis pathways along with the changes in expression of key cancer-related genes.
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Abstract
Abdominal paragangliomas and pheochromocytomas (PPGLs) are rare neuroendocrine tumors of the infradiaphragmatic paraganglia and adrenal medulla, respectively. Although few pathologists outside of endocrine tertiary centers will ever diagnose such a lesion, the tumors are well known through the medical community-possible due to a combination of the sheer rarity, their often-spectacular presentation due to excess catecholamine secretion as well as their unrivaled coupling to constitutional susceptibility gene mutations and hereditary syndromes. All PPGLs are thought to harbor malignant potential, and therefore pose several challenges to the practicing pathologist. Specifically, a responsible diagnostician should recognize both the capacity and limitations of histological, immunohistochemical, and molecular algorithms to pinpoint high risk for future metastatic disease. This focused review aims to provide the surgical pathologist with a condensed update regarding the current strategies available in order to deliver an accurate prognostication of these enigmatic lesions.
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Affiliation(s)
- C Christofer Juhlin
- Department of Oncology-Pathology, Karolinska Institutet, Solna, Sweden.
- Department of Pathology and Cytology, Karolinska University Hospital, Stockholm, Sweden.
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Mir Saeid Ghazi AA, Amouzegar A, Zadeh-Vakili A, Sheikh Rezaei A, Amirbaigloo A, Zarif Yeganeh M, Hashemi H, Azizi F. Clinical and Laboratory Characteristics of a Large Iranian Kindred Afflicted with Von Hippel Lindau Disease. Int J Endocrinol Metab 2021; 19:e105189. [PMID: 34149843 PMCID: PMC8198607 DOI: 10.5812/ijem.105189] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2020] [Revised: 11/16/2020] [Accepted: 01/06/2021] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND Von Hippel Lindau (VHL) disease is a hereditary disorder characterized by the development of benign or malignant tumors in the brain, spinal cord, eyes, adrenal medulla, kidney, pancreas, and many other organs. Advances in molecular diagnosis have led to the identification of the affected members of families at earlier stages. We present the clinical, laboratory, and genetic characteristics of five generations of a large Iranian kindred with VHL. METHODS The proband, a 52-year-old Iranian man, was recognized with VHL. All family members underwent clinical, laboratory, imaging, and genetic evaluation. Medical files and histopathology reports of patients who had been operated on before were also reviewed. Diagnosis of the disease was based on clinical findings, positive family history of VHL, and development of a central nervous system or retinal hemangioblastoma or pheochromocytoma. RESULTS Based on diagnostic criteria, our initial evaluations revealed that 10 members of the family had already been affected by the disease. Among them, nine had pheochromocytoma, and one had retinal hemangioblastoma. There was no case of kidney tumors among the kindred. CONCLUSIONS Study results show the high penetrance of the disease and focus on the large burden imposed by the disease on the health and quality of life of patients afflicted with the disease, emphasizing the importance of surveillance from early childhood for detection and management of the disease as early as possible.
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Affiliation(s)
- Ali Asghar Mir Saeid Ghazi
- Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Corresponding Author: Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Atieh Amouzegar
- Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Azita Zadeh-Vakili
- Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | | | | | - Marjan Zarif Yeganeh
- Cellular and Molecular Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | | | - Fereidoun Azizi
- Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Relationship between visceral adipose tissue and genetic mutations (VHL and KDM5C) in clear cell renal cell carcinoma. Radiol Med 2021; 126:645-651. [PMID: 33400184 DOI: 10.1007/s11547-020-01310-y] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Accepted: 11/15/2020] [Indexed: 02/06/2023]
Abstract
BACKGROUND The sequencing of the renal cell carcinoma (RCC) genome has detected several mutations with prognostic meaning. The association between visceral adipose tissue (VAT) and clear cell renal cell carcinoma (ccRCC) is well known. The relationship among abdominal adipose tissue distribution and ccRCC-VHL and KDM5C genetic mutations is, to the knowledge of the authors, not known. METHODS In this retrospective study, we enrolled 97 Caucasian male patients divided into three groups: the control group (n = 35), the ccRCC-VHL group (n = 52) composed of ccRCC patients with VHL mutations and ccRCC-KDM5C group (n = 10) composed of ccRCC patients with KDM5C mutation. Total adipose tissue (TAT) area, VAT area and subcutaneous adipose tissue (SAT) area were measured in the groups. VAT/SAT ratio was calculated for each subject. RESULTS Statistically significant differences between ccRCC-KDM5C group and ccRCC-VHL group were obtained for TAT area (p < 0.05), VAT area (p < 0.05) and VAT/SAT ratio (p < 0.05); between ccRCC-VHL group and control group for TAT area (p < 0.001) and VAT area (p < 0.01); and between ccRCC-KDM5C group and control group for TAT area (p < 0.0001), VAT area (p < 0.0001) and SAT area (p < 0.01). CONCLUSIONS This study demonstrates for the first time an increased amount of TAT, especially VAT, in the ccRCC-VHL and ccRCC-KDM5C groups. The effect was greater for the ccRCC-KDM5C group.
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36
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Eble JN. Contributions of genetics to the evolution of the diagnostic classification of renal cell neoplasia: a personal perspective. Pathology 2020; 53:96-100. [PMID: 33234231 DOI: 10.1016/j.pathol.2020.10.004] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2020] [Accepted: 10/22/2020] [Indexed: 12/16/2022]
Abstract
The classification system for neoplasms of the cells lining the renal tubules (renal cell neoplasms) has expanded greatly over the last five decades. The criteria for recognising an entity and including it in the classification have changed from being purely morphological and clinical to include genetics; presently, some are defined purely on genetics. Expansion of the number of entities included in the classification has many of the newly included entities and those under consideration for inclusion being very rare. The clinical utility of including entities which are extremely rare, based mainly upon genetic information, is unclear.
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Affiliation(s)
- John N Eble
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
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Heller MT, Furlan A, Kawashima A. Multiparametric MR for Solid Renal Mass Characterization. Magn Reson Imaging Clin N Am 2020; 28:457-469. [PMID: 32624162 DOI: 10.1016/j.mric.2020.03.008] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Multiparametric MR provides a noninvasive means for improved differentiation between benign and malignant solid renal masses. Although most large, heterogeneous renal masses are due to renal cell carcinoma, smaller "indeterminate" renal masses are being identified on cross-sectional imaging. Although definitive diagnosis of a solid renal mass may not always be possible by MR imaging, integrated evaluation of multiple MR imaging parameters can result in concise differential diagnosis. Multiparametric MR should be considered a critical step in the triage of patients with a solid renal mass for whom treatment options are being considered in the context of morbidity, prognosis, and mortality.
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Affiliation(s)
- Matthew T Heller
- Department of Radiology, Mayo Clinic, Mayo Clinic Hospital, 5777 East Mayo Boulevard, PX SS 01 RADLGY, Phoenix, AZ 85054, USA.
| | - Alessandro Furlan
- Department of Radiology, University of Pittsburgh, University of Pittsburgh Medical Center, 200 Lothrop Street, Pittsburgh, PA 15213, USA
| | - Akira Kawashima
- Department of Radiology, Mayo Clinic, Mayo Clinic Hospital, 5777 East Mayo Boulevard, PX SS 01 RADLGY, Phoenix, AZ 85054, USA
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Abstract
The treatment landscape of metastatic renal cell carcinoma (RCC) has been revolutionized over the past two decades, bringing forth an era in which more than a dozen therapeutic agents are now available to treat patients. As a consequence, personalized care has become a critical part of developing effective treatment guidelines and improving patient outcomes. One of the most important emerging aspects of precision medicine in cancer is matching patients and treatments based on the genomic characteristics of an individual and their tumour. Despite the lack of a single genomic predictor of treatment response or prognostication feature in RCC, emerging research suggests that the identification of such markers remains promising. Mutations in VHL and alterations in its downstream pathways are the mainstay of RCC development and progression. However, the predictive value of VHL mutations has been questioned. Further research has examined mutations in genes involved in chromosome remodelling (for example, PBRM1, BAP1 and SETD2), DNA methylation and DNA damage repair, all of which have been associated with clinical outcomes. Here, we provide a comprehensive overview of genomic evidence in the context of RCC and its potential predictive and prognostic value.
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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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Erdogan S, Ozcan A, Truong LD. Molecular Pathology of Kidney Tumors. KIDNEY CANCER 2020. [DOI: 10.1007/978-3-030-28333-9_18] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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Whiting D, Sriprasad S. Molecular biology and targeted therapy in metastatic renal cell carcinoma. JOURNAL OF CLINICAL UROLOGY 2020. [DOI: 10.1177/2051415819849322] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
The treatment of metastatic renal cell carcinoma is challenging as it has proven to be relatively resistant to conventional oncological treatments. An improved understanding of the molecular biology of renal cell carcinoma has led to the development of a number of targeted therapies in metastatic renal cell carcinoma. This includes vascular endothelial growth factor inhibitors, tyrosine kinase inhibitors, mammalian target of rapamycin inhibitors and most recently immune checkpoint inhibitors. This article will review the mechanisms of development and progression of renal cell carcinoma as well as the mechanisms of current approved treatments in metastatic disease.Level of evidence: Not applicable for this multicentre audit.
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Affiliation(s)
- D Whiting
- Department of Urology, Darent Valley Hospital, UK
| | - S Sriprasad
- Department of Urology, Darent Valley Hospital, UK
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Abstract
The discovery of the von Hippel-Lindau (VHL) gene marked a milestone in our understanding of clear cell renal cell carcinoma (ccRCC) pathogenesis. VHL inactivation is not only a defining feature of ccRCC, but also the initiating event. Herein, we discuss canonical and noncanonical pVHL functions, as well as breakthroughs shaping our understanding of ccRCC evolution and evolutionary subtypes. We conclude by presenting evolving strategies to therapeutically exploit effector mechanisms downstream of pVHL.
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Gupta A, Nath K, Bansal N, Kumar M. Role of metabolomics-derived biomarkers to identify renal cell carcinoma: a comprehensive perspective of the past ten years and advancements. Expert Rev Mol Diagn 2019; 20:5-18. [DOI: 10.1080/14737159.2020.1704259] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Affiliation(s)
- Ashish Gupta
- Centre of Biomedical Research, SGPGIMS Campus, Lucknow, India
| | - Kavindra Nath
- Department of Radiology, University of Pennsylvania, Pheladelphia, PA, USA
| | - Navneeta Bansal
- Department of Urology, King George’s Medical University, Lucknow, India
| | - Manoj Kumar
- Department of Urology, King George’s Medical University, Lucknow, India
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Magers MJ, Cheng L. Practical Molecular Testing in a Clinical Genitourinary Service. Arch Pathol Lab Med 2019; 144:277-289. [PMID: 31373513 DOI: 10.5858/arpa.2019-0134-ra] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
CONTEXT.— Molecular testing is increasingly playing a key role in the diagnosis, prognosis, and treatment of neoplasms of the genitourinary system. OBJECTIVE.— To provide a general overview of the clinically relevant molecular tests available for neoplasms of the genitourinary tract. DATA SOURCES.— Relevant medical literature indexed on PubMed. CONCLUSIONS.— Understanding of the molecular oncology of genitourinary neoplasms is rapidly advancing, and the pathologist must be aware of the practical implications of molecular testing. While many genomic abnormalities are not yet clinically relevant, there is an increasing library of ancillary tests that may guide diagnosis, prognosis, and/or treatment of many neoplasms. Recurrent genomic abnormalities have been identified in many types of renal cell carcinoma, and some types of renal cell carcinoma are specifically defined by the molecular abnormality. Two major routes of developing urothelial carcinoma have been molecularly described. Recurrent translocations involving ETS family genes are found in approximately half of prostate cancer cases. Testicular germ cell tumors typically harbor i(12p). Penile neoplasms are often high-risk human papillomavirus-driven cancers. Nonetheless, even as genitourinary neoplasms are increasingly better understood at the molecular level, further research with eventual clinical validation is needed for optimal diagnosis, prognosis, and treatment of aggressive malignancies in the genitourinary tract.
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Affiliation(s)
- Martin J Magers
- From the Departments of Pathology and Laboratory Medicine (Drs Magers and Cheng) and Urology (Dr Cheng), Indiana University School of Medicine, Indianapolis, Indiana
| | - Liang Cheng
- From the Departments of Pathology and Laboratory Medicine (Drs Magers and Cheng) and Urology (Dr Cheng), Indiana University School of Medicine, Indianapolis, Indiana
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46
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Guo X, Gao L, Hong X, Guo D, Di W, Wang X, Xu Z, Xing B. Whole-exome sequencing and immunohistochemistry findings in von Hippel-Lindau disease. Mol Genet Genomic Med 2019; 7:e880. [PMID: 31317677 PMCID: PMC6732316 DOI: 10.1002/mgg3.880] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2019] [Revised: 05/07/2019] [Accepted: 07/08/2019] [Indexed: 12/21/2022] Open
Abstract
Background von Hippel–Lindau (VHL) disease has a hereditary, autosomal dominant pattern, and multiple tumors can develop in multiple organs of a single patient. However, the exact mechanisms of tumorigenesis are unclear, and further studies are needed to clarify whether the same signaling pathways are involved in different VHL‐related tumors. Methods Whole‐exome sequencing (WES) of tumor and paired peripheral blood samples were performed for a VHL disease pedigree. A bioinformatics analysis was conducted to identify candidate somatic single‐nucleotide variants (SNVs) present in all tumor tissues. Sanger sequencing was then used to validate the SNVs identified using WES. Immunohistochemistry was performed to analyze components of the mTOR pathway, which was abnormally activated in tumor tissues. Results Two hemangioblastomas and two renal cell carcinomas were sequenced. The bioinformatics analysis revealed a VHL somatic variant in all tumors; no other SNV was detected. Immunohistochemistry showed the abnormal expression of the phospho‐S6 ribosomal protein in the hemangioblastomas, but not in the renal clear cell carcinomas. Conclusion Except for a SNV in the VHL gene, no other somatic SNVs were detected using WES. The phospho‐S6 ribosomal protein in the mTOR pathway is a potential target in VHL‐related cerebellum hemangioblastomas.
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Affiliation(s)
- Xiaopeng Guo
- Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, P.R. China
| | - Lu Gao
- Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, P.R. China
| | - Xiafei Hong
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, P.R. China
| | - Dan Guo
- Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Corelabs, Beijing, P.R. China.,Clinical Bio-bank, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, P.R. China
| | - Wenyu Di
- Department of Pathology, Xinxiang Medical University First Affiliated Hospital, Weihui, P.R. China
| | - Xiaoman Wang
- State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, P.R. China
| | - Zhiqin Xu
- Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, P.R. China
| | - Bing Xing
- Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, P.R. China
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Chang YW, Singh KP. Arsenic-Induced Neoplastic Transformation Involves Epithelial-Mesenchymal Transition and Activation of the β-Catenin/c-Myc Pathway in Human Kidney Epithelial Cells. Chem Res Toxicol 2019; 32:1299-1309. [PMID: 31120745 DOI: 10.1021/acs.chemrestox.9b00089] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Arsenic contamination is a serious environmental and public health issue worldwide including the United States. Accumulating evidence suggests that kidney is one of the target organs for arsenic-induced carcinogenesis. However, the mechanism of arsenic-induced renal carcinogenesis is not well understood. Therefore, the objective of this study was to evaluate the carcinogenicity of chronic exposure to an environmentally relevant concentration of arsenic on kidney epithelial cells and identify the molecular mechanism underlying this process. HK-2 kidney epithelial cells were treated with arsenic for acute, long-term, and chronic durations, and cellular responses to arsenic exposure at these time points were evaluated by the changes in growth, morphology, and expression of genes. The results revealed a significant growth increase after long-term and chronic exposure to arsenic in HK-2 cells. The morphological changes of EMT and stem cell sphere formation were also observed in long-term arsenic exposed cells. The anchorage-independent growth assay for colony formation and cell maintenance in cancer stem cell medium further confirmed neoplastic transformation and the induced cancer stem cell properties of arsenic-exposed cells. Additionally, the expression of marker genes confirmed the increased growth, EMT, and stemness during arsenic-induced carcinogenesis. Moreover, the increase expression of β-catenin and c-Myc further suggested the role of these signaling molecules during carcinogenesis in HK-2 cells. In summary, results of this study suggest that chronic exposure to arsenic even at a relatively lower concentration can induce neoplastic transformation through acquisitions of EMT, stemness, and MET phenotypes, which might be related to the β-catenin/c-Myc signaling pathway.
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Affiliation(s)
- Yu-Wei Chang
- Department of Environmental Toxicology, The Institute of Environmental and Human Health (TIEHH) , Texas Tech University , Lubbock , Texas , United States
| | - Kamaleshwar P Singh
- Department of Environmental Toxicology, The Institute of Environmental and Human Health (TIEHH) , Texas Tech University , Lubbock , Texas , United States
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Alessandrino F, Shinagare AB, Bossé D, Choueiri TK, Krajewski KM. Radiogenomics in renal cell carcinoma. Abdom Radiol (NY) 2019; 44:1990-1998. [PMID: 29713740 DOI: 10.1007/s00261-018-1624-y] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Radiogenomics, a field of radiology investigating the association between the imaging features of a disease and its gene expression pattern, has expanded considerably in the last few years. Recent advances in whole-genome sequencing of clear cell renal cell carcinoma (ccRCC) and the identification of mutations with prognostic significance have led to increased interest in the relationship between imaging and genomic data. ccRCC is particularly suitable for radiogenomic analysis as the relative paucity of mutated genes allows for more straightforward genomic-imaging associations. The ultimate aim of radiogenomics of ccRCC is to retrieve additional data for accurate diagnosis, prognostic stratification, and optimization of therapy. In this review article, we will present the state-of-the-art of radiogenomics of ccRCC, and after briefly reviewing updates in genomics, we will discuss imaging-genomic associations for diagnosis and staging, prognosis, and for assessment of optimal therapy in ccRCC.
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Affiliation(s)
- Francesco Alessandrino
- Department of Imaging, Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Avenue, Boston, MA, 02215, USA.
- Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA, 02115, USA.
| | - Atul B Shinagare
- Department of Imaging, Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Avenue, Boston, MA, 02215, USA
- Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA, 02115, USA
| | - Dominick Bossé
- Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Dana 1230, Boston, MA, 02215, USA
| | - Toni K Choueiri
- Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Dana 1230, Boston, MA, 02215, USA
| | - Katherine M Krajewski
- Department of Imaging, Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Avenue, Boston, MA, 02215, USA
- Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA, 02115, USA
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Siebenthall KT, Miller CP, Vierstra JD, Mathieu J, Tretiakova M, Reynolds A, Sandstrom R, Rynes E, Haugen E, Johnson A, Nelson J, Bates D, Diegel M, Dunn D, Frerker M, Buckley M, Kaul R, Zheng Y, Himmelfarb J, Ruohola-Baker H, Akilesh S. Integrated epigenomic profiling reveals endogenous retrovirus reactivation in renal cell carcinoma. EBioMedicine 2019; 41:427-442. [PMID: 30827930 PMCID: PMC6441874 DOI: 10.1016/j.ebiom.2019.01.063] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2018] [Revised: 01/30/2019] [Accepted: 01/31/2019] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Transcriptional dysregulation drives cancer formation but the underlying mechanisms are still poorly understood. Renal cell carcinoma (RCC) is the most common malignant kidney tumor which canonically activates the hypoxia-inducible transcription factor (HIF) pathway. Despite intensive study, novel therapeutic strategies to target RCC have been difficult to develop. Since the RCC epigenome is relatively understudied, we sought to elucidate key mechanisms underpinning the tumor phenotype and its clinical behavior. METHODS We performed genome-wide chromatin accessibility (DNase-seq) and transcriptome profiling (RNA-seq) on paired tumor/normal samples from 3 patients undergoing nephrectomy for removal of RCC. We incorporated publicly available data on HIF binding (ChIP-seq) in a RCC cell line. We performed integrated analyses of these high-resolution, genome-scale datasets together with larger transcriptomic data available through The Cancer Genome Atlas (TCGA). FINDINGS Though HIF transcription factors play a cardinal role in RCC oncogenesis, we found that numerous transcription factors with a RCC-selective expression pattern also demonstrated evidence of HIF binding near their gene body. Examination of chromatin accessibility profiles revealed that some of these transcription factors influenced the tumor's regulatory landscape, notably the stem cell transcription factor POU5F1 (OCT4). Elevated POU5F1 transcript levels were correlated with advanced tumor stage and poorer overall survival in RCC patients. Unexpectedly, we discovered a HIF-pathway-responsive promoter embedded within a endogenous retroviral long terminal repeat (LTR) element at the transcriptional start site of the PSOR1C3 long non-coding RNA gene upstream of POU5F1. RNA transcripts are induced from this promoter and read through PSOR1C3 into POU5F1 producing a novel POU5F1 transcript isoform. Rather than being unique to the POU5F1 locus, we found that HIF binds to several other transcriptionally active LTR elements genome-wide correlating with broad gene expression changes in RCC. INTERPRETATION Integrated transcriptomic and epigenomic analysis of matched tumor and normal tissues from even a small number of primary patient samples revealed remarkably convergent shared regulatory landscapes. Several transcription factors appear to act downstream of HIF including the potent stem cell transcription factor POU5F1. Dysregulated expression of POU5F1 is part of a larger pattern of gene expression changes in RCC that may be induced by HIF-dependent reactivation of dormant promoters embedded within endogenous retroviral LTRs.
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Affiliation(s)
- Kyle T Siebenthall
- Altius Institute for Biomedical Sciences, Seattle, WA 98121, United States
| | - Chris P Miller
- Department of Pathology, University of Washington, Seattle, WA 98195, United States
| | - Jeff D Vierstra
- Altius Institute for Biomedical Sciences, Seattle, WA 98121, United States
| | - Julie Mathieu
- Institute for Stem Cell and Regenerative Medicine, Seattle, WA 98109, United States; Department of Comparative Medicine, University of Washington, Seattle, WA 98195, United States
| | - Maria Tretiakova
- Department of Pathology, University of Washington, Seattle, WA 98195, United States
| | - Alex Reynolds
- Altius Institute for Biomedical Sciences, Seattle, WA 98121, United States
| | - Richard Sandstrom
- Altius Institute for Biomedical Sciences, Seattle, WA 98121, United States
| | - Eric Rynes
- Altius Institute for Biomedical Sciences, Seattle, WA 98121, United States
| | - Eric Haugen
- Altius Institute for Biomedical Sciences, Seattle, WA 98121, United States
| | - Audra Johnson
- Altius Institute for Biomedical Sciences, Seattle, WA 98121, United States
| | - Jemma Nelson
- Altius Institute for Biomedical Sciences, Seattle, WA 98121, United States
| | - Daniel Bates
- Altius Institute for Biomedical Sciences, Seattle, WA 98121, United States
| | - Morgan Diegel
- Altius Institute for Biomedical Sciences, Seattle, WA 98121, United States
| | - Douglass Dunn
- Altius Institute for Biomedical Sciences, Seattle, WA 98121, United States
| | - Mark Frerker
- Altius Institute for Biomedical Sciences, Seattle, WA 98121, United States
| | - Michael Buckley
- Altius Institute for Biomedical Sciences, Seattle, WA 98121, United States
| | - Rajinder Kaul
- Altius Institute for Biomedical Sciences, Seattle, WA 98121, United States
| | - Ying Zheng
- Department of Bioengineering, University of Washington, Seattle, WA 98195, United States; Kidney Research Institute, Seattle, WA 98104, United States
| | - Jonathan Himmelfarb
- Division of Nephrology, Department of Medicine, University of Washington, Seattle, WA 98195, United States; Kidney Research Institute, Seattle, WA 98104, United States
| | - Hannele Ruohola-Baker
- Department of Biochemistry, University of Washington, Seattle, WA 98195, United States; Institute for Stem Cell and Regenerative Medicine, Seattle, WA 98109, United States
| | - Shreeram Akilesh
- Department of Pathology, University of Washington, Seattle, WA 98195, United States; Kidney Research Institute, Seattle, WA 98104, United States.
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Venkatesh P, Takkar B. Proposed Classification System for Retinal Capillary Angiomatosis. Ophthalmic Res 2018; 61:115-119. [DOI: 10.1159/000494498] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2018] [Accepted: 10/13/2018] [Indexed: 11/19/2022]
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