Risk factors for survival in patients with von Hippel-Lindau disease

Wang, Jiangyi; Peng, Shuanghe; Li, Teng; Ning, Xianghui; Liu, Shengjie; Hong, Bo; Liu, Jiayuan; Wu, Pengjie; Zhou, Bowen; Zhou, Jingcheng; Qi, Nienie; Xiang, Ping; Zhang, Jiufeng; Ma, Kaifang; Cai, Lin; Gong, Kan

doi:10.1136/jmedgenet-2017-104995

Cited by 24 publications

(34 citation statements)

References 29 publications

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“…However, conditions such as hereditary von Hippel-Lindau (VHL) disease or sporadic somatic inactivation of the VHL gene have been found to have a very close genetic association with ccRCC (4). The VHL gene was mapped at chromosome 3p25.3 (7,8), and the protein encoded by this gene (pVHL) was subsequently shown to form a complex with elongin C, elongin B and cullin-2 (9), which possesses ubiquitin ligase E3 activity. Upon its formation, this complex specifically recognizes the α subunits of two transcription factors, the hypoxia-inducible factors (HIFs) 1A and 2A, and directs them for degradation along the ubiquitin-proteasome pathway (8).…”

Section: Introductionmentioning

confidence: 99%

Prognostic significance of VHL, HIF1A, HIF2A, VEGFA and p53 expression in patients with clear‑cell renal cell carcinoma treated with sunitinib as first‑line treatment

et al. 2019

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Clear cell renal cell carcinoma (ccRCC) is the most common subtype of renal cell cancer, characterized by the highest mortality rate among other RCC subtypes due to the occurrence of metastasis and drug resistance following surgery. The Von Hippel-Lindau tumor suppressor (VHL)-hypoxia-inducible factor 1 subunit α (HIF1A)/hypoxia-inducible factor 2α (HIF2A)-vascular endothelial growth factor A (VEGFA) protein axis is involved in the development and progression of ccRCC, whereas sunitinib, a tyrosine kinase inhibitor, blocks the binding of VEGFA to its receptor. The aim of the present study was to examine the possible association of the gene expression of VHL, HIF1A, HIF2A, VEGFA and tumor protein P53 ( P53 ) in cancer tissue with the outcome of ccRCC patients who were treated with sunitinib as first-line therapy following nephrec-tomy. A total of 36 ccRCC patients were enrolled, 11 of whom were administered sunitinib post-operatively. Tumor and control samples were collected, and mRNA and protein levels were assessed by reverse transcription-quantitative polymerase chain reaction and western blot analysis, respectively. High mRNA and protein expression levels of HIF2A and VEGFA were found to be associated with shorter overall survival (OS) and progression-free survival (PFS) rates, as well as with unfavorable risk factors of cancer recurrence and mortality. Resistance to sunitinib was also observed; the OS and PFS rates were shorter (median OS and PFS: 12 and 6 months, respectively, vs. undetermined). Sunitinib resistance was associated with high HIF2A and VEGFA protein levels (b=0.57 and b=0.69 for OS and PFS, respectively; P<0.001). Taken together, the findings of this study suggest that the protein levels of HIF2A and VEGFA in tumor tissue may serve as independent prognostic factors in ccRCC. ccRCC patients with increased intratumoral HIF2A and VEGFA protein levels, and unaltered VHL protein levels, are not likely to benefit from sunitinib treatment following nephrectomy; however, this hypothesis requires verification by large-scale replication studies.

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Section: Introductionmentioning

confidence: 99%

Prognostic significance of VHL, HIF1A, HIF2A, VEGFA and p53 expression in patients with clear‑cell renal cell carcinoma treated with sunitinib as first‑line treatment

et al. 2019

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“…Binderup et al (21) reported that the estimated mean life expectancy of a man with VHL is 67 years, whereas that for a woman with VHL is 60 years, which is higher than previously reported (49 years) (3). The results from our previous study demonstrated that the estimated median life expectancy is 62 years for Chinese patients with VHL disease (11). A deeper understanding of VHL syndrome, combined with the development of novel technology has therefore significantly improved the prognosis of affected patients.…”

Section: Discussionmentioning

confidence: 98%

“…It is therefore crucial to establish the optimal time point for surgery, in order to minimize the number of procedures, to preserve kidney integrity as long as possible and to improve patient quality of life. Medical advances and a deeper comprehension of VHL disease have allowed median survival time to increase from 49 to 62 years (3,11). A better understanding of the clinicopathological characteristics and prognosis of VHL-associated hereditary RCC may therefore aid clinicians in making more rational treatment decisions for patients with VHL.…”

Section: Introductionmentioning

confidence: 99%

Distinctive clinicopathological features of Von�Hippel‑Lindau‑associated hereditary renal cell carcinoma: A single‑institution study

et al. 2019

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Von Hippel-Lindau (VHL) disease is a genetic syndrome that involves the development of tumors in numerous organs. The kidney is one of the most frequently affected organs, and patients with VHL and renal tumors require repeated nephrectomy. The present study aimed to further determine the clinicopathological characteristics of patients with VHL-associated renal cell carcinoma (RCC), which may allow more rational clinical treatment decisions. This study included 27 patients with VHL who underwent radical or partial nephrectomy at the Peking University First Hospital between January 2010 and April 2018. The clinicopathological characteristics and prognosis of the patients were retrospectively reviewed. The expression of RCC-associated molecular markers was evaluated by immunohistochemistry. The mean size of the renal tumors was 4.3±2.0 cm (range 1.3–9.5 cm). The pathological type in 26 cases (96.3%) was clear cell RCC (CCRCC), whereas only one patient was diagnosed with CCRCC and clear cell papillary RCC. Renal cysts with a clear cell lining were observed, and RCC cell clusters were scattered in renal cyst cavities. Among the 27 patients, 21 (77.8%) were diagnosed with stage IA/T1N0M0, according to Tumor-Node-Metastasis staging, and 16 (59.3%) had grade 1 tumors. The mean postoperative follow-up duration was 39.0±24.0 months (range, 1.7–96.5 months). No metastasis or VHL-associated mortality was observed. VHL-associated RCC is a relatively low-risk disease, and a tumor size of 4 cm was determined as a threshold for nephron-sparing surgery. In addition, to prevent tumor cell dispersion, renal cysts should be carefully treated. A comprehensive understanding of the clinicopathological characteristics and underlying mechanisms of RCC associated with VHL syndrome may improve patient prognosis.

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“…In addition, two asymptomatic VHL gene carriers (F2-III1, 5 years of age, p.N78S; F3-IV2, 21 years of age, p.R167Q) were identified via gene testing. Early diagnosis and genetic counseling, regular cancer screening and surveillance are therefore helpful for disease management and for the improvement of prognosis ( 40 ).…”

Section: Discussionmentioning

confidence: 99%

Clinical diagnosis, treatment and screening of the VHL gene in three von Hippel‑Lindau disease pedigrees

et al. 2020

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The present study aimed to investigate the clinical characteristics of von Hippel-Lindau (VHL) disease and the clinical significance of VHL gene detection. The clinical materials of patients with VHL disease were collected from 3 different families between May 1985 and October 2017. A systematic pedigree study and VHL gene detection at the germline level were performed together with a literature review. Of the 22 patients from 3 VHL pedigrees, 10 exhibited VHL gene mutations (3 genotypes) at the germline level. The genotypes of pedigree were VHL-p.R161Q (c.482G>A), VHL-p.N78S (c.233A>G), and VHL-p.R167Q (c.500G>A). During the follow-up period, the symptoms were stable in 10 patients, including 2 cases of central nervous system hemangioblastomas (CNS-HB), 3 cases of bilateral multiple renal cell carcinoma (RCC) and 5 cases of adrenal pheochromocytoma without local recurrence or distant metastasis. Patients with p.R161Q and p.N78S were not associated with CNS-HB, which was different from the clinical phenotype of previously reported families. RCC were Fuhrman II grade, which was consistent with the previous study. The results of the present study indicated that the standardization of early diagnosis and the improvement of long-term efficacy may be achieved by combining clinical screening and VHL gene detection.

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Risk factors for survival in patients with von Hippel-Lindau disease

Abstract: This largest VHL survival analysis indicates that onset age, family history, mutation type and first presenting symptom have an effect on the survival of patients with VHL disease, which is helpful to genetic counselling and clinical decision-making.

Cited by 24 publications

References 29 publications

Prognostic significance of VHL, HIF1A, HIF2A, VEGFA and p53 expression in patients with clear‑cell renal cell carcinoma treated with sunitinib as first‑line treatment

Prognostic significance of VHL, HIF1A, HIF2A, VEGFA and p53 expression in patients with clear‑cell renal cell carcinoma treated with sunitinib as first‑line treatment

Distinctive clinicopathological features of Von�Hippel‑Lindau‑associated hereditary renal cell carcinoma: A single‑institution study

Clinical diagnosis, treatment and screening of the VHL gene in three von Hippel‑Lindau disease pedigrees

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