Comprehensive characterization of a Canadian cohort of von Hippel‐Lindau disease patients

Salama, Yasser; Albanyan, Saleh; Szybowska, Marta; Bullivant, Garrett; Gallinger, Bailey; Giles, Rachel H.; Asa, Sylvia; Badduke, Chansonette; Chiorean, Andreea; Druker, Harriet; Ezzat, Shereen; Hannah‐Shmouni, Fady; Hernandez, Karen; Inglese, Cara; Jani, Payal; Kaur, Yuvreet; Krema, Hatem; Krimus, Lior; Laperrière, Normand; Lichner, Zsuzanna; Mete, Özgür; Sit, Marisa; Zadeh, Gelareh; Jewett, Michael A.S.; Malkin, David; Stockley, Tracy L.; Wasserman, Jonathan D.; Xu, Wei; Schachter, Nathan F.; Kim, Raymond H.

doi:10.1111/cge.13613

Cited by 18 publications

(34 citation statements)

References 28 publications

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“…VHL syndrome, an autosomal dominant syndrome caused by germline mutations in the VHL tumor suppressor gene on chromosome 3 (3p25-26), is also closely associated with PanNETs. Up to 17% of patients with VHL syndrome develop PanNETs, [47][48][49][50]. The VHL gene encodes a protein involved in the regulation of a transcription factor called hypoxia-inducible factor (HIF) molecules (HIF-2A, GLUT1, and carbonic anhydrase IX): its mutations lead to HIF activation and expression of HIF targets involved in many cellular processes, including angiogenesis and cell metabolism [51].…”

Section: Genetic Alterations Of Hereditary Conditionsmentioning

confidence: 99%

Molecular Pathology of Well-Differentiated Gastro-entero-pancreatic Neuroendocrine Tumors

et al. 2021

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Well differentiated neuroendocrine tumors (NETs) arising in the gastrointestinal and pancreaticobiliary system are the most common neuroendocrine neoplasms. Studies of the molecular basis of these lesions have identified genetic mutations that predispose to familial endocrine neoplasia syndromes and occur both as germline events and in sporadic tumors. The mutations often involve epigenetic regulators rather than the oncogenes and tumor suppressors that are affected in other malignancies. Somatic copy number alterations and miRNAs have also been implicated in the development and progression of some of these tumors. The molecular profiles differ by location, but many are shared by tumors in other sites, including those outside the gastroenteropancreatic system. The approach to therapy relies on both the neuroendocrine nature of these tumors and the identification of specific alterations that can serve as targets for precision oncologic approaches.

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Section: Genetic Alterations Of Hereditary Conditionsmentioning

confidence: 99%

Molecular Pathology of Well-Differentiated Gastro-entero-pancreatic Neuroendocrine Tumors

et al. 2021

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“…On the basis of predecessors, we classified patients with missense mutations (M group) by mutation locations into three subgroups, whose missense mutations were located in the HIFbinding region (residues 65-117, MH subgroup), Elongin C binding region (residues 158-184, ME subgroup), and others region (MO subgroup), respectively (Ong et al, 2007;Lee et al, 2016;Liu et al, 2018;Salama et al, 2019). It's a remarkable fact that the number of MO group was far less than the other two groups in our cohort.…”

Section: Comparison Of Age-related Tumor Risk Among Subgroupmentioning

confidence: 99%

The Genotype-Phenotype Association of Von Hipple Lindau Disease Based on Mutation Locations: A Retrospective Study of 577 Cases in a Chinese Population

Qiu

Zhang

et al. 2020

Front. Genet.

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PurposeVon Hippel-Lindau (VHL) disease is a hereditary kidney cancer syndrome, with which patients are more likely to get affected by renal cell carcinoma (RCC), pancreatic cyst or tumor (PCT), central nervous system hemangioblastoma (CHB), retinal angiomas (RA), and pheochromocytoma (PHEO). Mutations of VHL gene located in 3p25 may impair the function of the VHL protein and lead to the disease. It’s unclear why obvious phenotype varieties exist among VHL patients. Here we aimed to ascertain whether the mutation types and locations affect the phenotype.MethodsWe enrolled 577 Chinese VHL patients from 211 families and divided them into three groups and six subgroups according to their mutation types and locations. Cox survival analysis and Kaplan-Meier analysis were used to compare intergroup age-related tumor risks.ResultsPatients with nonsense or frameshift mutations that were located before residues 117 of VHL protein (NoF1 subgroup) hold lower age-related risks of VHL associated tumors (HR = 0.638, 95%CI 0.461–0.883, p = 0.007), CHB (HR = 0.596, 95%CI 0.409–0.868, p = 0.007) or PCT (HR = 0.595, 95%CI 0.368–0.961, p = 0.034) than patients whose mutations were located after residues 117 (NoF2 subgroup). Patients in NoF1 subgroup still had lower age-related risks of CHB (HR = 0.652, 95%CI 0.476–0.893, p = 0.008) and PCT (HR = 0.605, 95%CI 0.398–0.918, p = 0.018) compared with those in combined NoF2 subgroup and other truncating mutation patients. NoF1 subgroup correspondingly had a longer estimated median lifespan (64 vs. 55 year, p = 0.037) than NoF2 subgroup. Among patients with missense mutations of VHL, only a small minority (23 of 286 missense mutations carriers) carried mutations involving neither HIF-α binding region nor elongin C binding region, who were grouped in MO subgroup. MO subgroup seemed to have a higher age-related risk of PHEO. In the whole cohort (n = 577), PHEO was an independent protective factor for CHB (p = 0.001) and survival (p = 0.005). RA and CHB failed to predict the age-related risk of each other.ConclusionThe mutation types and locations of VHL gene are associated with phenotypes. Genetic counselors could predict phenotypes more accurately based on more detailed genotype-phenotype correlations. Further genotype-phenotype studies should focus on the prediction of tumor recurrence, progression, and metastasis. The deep molecular mechanism of genotype-phenotype correlation is worth further exploring.

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“…Hemangioblastomas are vascular tumors that often occur in the central nervous system (CNS), especially the cerebellum. Most cases are sporadic, and about 20-38% of patients also have Von-Hippel-Lindau (VHL) disease, which is an autosomal dominant genetic condition with an incidence of 1/27,300-1/45,000 [1][2][3]. The VHL gene located on chromosome 3p25-26 and is an important tumor suppressor gene that contains 3 exons [4,5].…”

Section: Introductionmentioning

confidence: 99%

CT and MRI Characteristic Findings of Sporadic Renal Hemangioblastoma: Two Case Reports and Review of the Literature

Liu

et al. 2020

Preprint

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BackgroundHemangioblastoma in the kidney is rare. Although a few renal hemangioblastoma cases have been reported, the content of these articles mainly focused on clinical and pathological research, with minimal descriptions of radiologic findings. Moreover, there are no descriptions of magnetic resonance imaging with enhancement for this condition. We herein report two cases of renal hemangioblastoma with computed tomography and magnetic resonance imaging findings.Case presentationTwo patients presented to our institution due to dull pain of the left abdomen, and a mass in the left kidney was found by ultrasound examination in each case. They had no special family history. Physical examination revealed no obvious tenderness or percussion pain in the renal region and ureteral walking area, and there was no obvious mass. Routine blood and urine tests were normal, and serum tumor markers were negative. No obvious lesions were found on imaging of other body parts. Similar radiologic findings were observed in both cases and mimicked those of cavernous hemangiomas of the liver, including peripheral nodular enhancement in the corticomedullary phase, progressive centripetal enhancement in the nephrographic and delayed phases, and occasional complete “filling in” in the delayed phase. Given the suspicion for renal cell carcinoma, both patients underwent partial nephrectomy. The pathological results showed renal hemangioblastoma.ConclusionsRenal hemangioblastoma is a rare benign tumor that is easily misdiagnosed as clear cell carcinoma. Characteristic computed tomography and magnetic resonance imaging manifestations may improve preoperative diagnostic accuracy to avoid surgery or indicate nephron-sparing surgery.

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Comprehensive characterization of a Canadian cohort of von Hippel‐Lindau disease patients

Cited by 18 publications

References 28 publications

Molecular Pathology of Well-Differentiated Gastro-entero-pancreatic Neuroendocrine Tumors

Molecular Pathology of Well-Differentiated Gastro-entero-pancreatic Neuroendocrine Tumors

The Genotype-Phenotype Association of Von Hipple Lindau Disease Based on Mutation Locations: A Retrospective Study of 577 Cases in a Chinese Population

CT and MRI Characteristic Findings of Sporadic Renal Hemangioblastoma: Two Case Reports and Review of the Literature

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