Co-occurrence of VHL and SDHA Pathogenic Variants: A Case Report

Tung, Moon Ley; Chandra, Bharatendu; Dillahunt, Kyle; Gosse, Matthew; Sato, Takamitsu; Sidhu, Alpa

doi:10.3389/fonc.2022.925582

Cited by 2 publications

(2 citation statements)

References 27 publications

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“…Some studies have also demonstrated that CHEK2 germline mutations could be detected in early-onset RCC or associated with renal cancer 30 36. Coincidentally, a recent case report showed that an earlier age of onset of pancreatic neuroendocrine tumour was observed in a patient with both VHL and SDHA germline mutations 37. These alterations could be genetic modifier factors that protect or aggravate the phenotype in patients with VHL disease, which needed further basic research to identify.…”

Section: Discussionmentioning

confidence: 99%

Genotype–phenotype correlations and clinical outcomes of patients with von Hippel-Lindau disease with large deletions

Zhang

Yang

et al. 2022

J Med Genet

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BackgroundApproximately 20%–40% of patients with von Hippel-Lindau (VHL) disease, an autosomal dominant hereditary disease, exhibit large deletions (LDs). Few studies have focused on this population. Hence, we aimed to elucidate the genotype–phenotype correlations and clinical outcomes in VHL patients with LDs.MethodsIn this retrospective study, we included 119 patients with VHL disease from 50 unrelated families in whom LDs were detected using traditional and next-generation sequencing methods. Other germline mutations were confirmed by Sanger sequencing. Genotype–phenotype correlations and survival were analysed in different groups using Kaplan-Meier and Cox regression. We also evaluated therapeutic response to tyrosine kinase inhibitor (TKI) therapy.ResultsThe overall penetrance of patients aged <60 was 95.2%. Two VHL patients with LDs also carried CHEK2 and FLCN germline mutations. An earlier age of onset of retinal haemangioblastoma was observed in the next generation. Patients with exon 2 deletion of VHL had an earlier onset age of renal cell carcinoma and pancreatic lesions. The risk of renal cell carcinoma was lower in VHL patients with LDs and a BRK1 deletion. The group with earlier age of onset received poorer prognosis. Four of eight (50%) patients showed partial response to TKI therapy.ConclusionThe number of generations and the status of exon 2 could affect age of onset of VHL-related manifestations. Onset age was an independent risk factor for overall survival. TKI therapy was effective in VHL patients with LDs. Our findings would further support clinical surveillance and decision-making processes.

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Section: Discussionmentioning

confidence: 99%

Genotype–phenotype correlations and clinical outcomes of patients with von Hippel-Lindau disease with large deletions

Zhang

Yang

et al. 2022

J Med Genet

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“…Mutations to each subunit or SDHAF2 have been linked to developing SHD-RCC, with SDHB being the most common [ 101 , 102 , 103 ]. Recently, a patient presenting with pancreatic neuroendocrine tumors was noted to have mutations to both SDHA and VHL , but it is unknown how potential RCC tumors would behave with this dual mutation burden [ 104 ]. Succinate dehydrogenase is unique in that it functions as both a key component of the Kreb’s/Tricarboxylic acid (TCA) cycle and the electron transport chain as Complex II, thus placing the tetramer at the center of cell metabolism [ 105 ].…”

Section: Succinate Dehydrogenase-deficient Renal Cell Carcinoma (Sdh-...mentioning

confidence: 99%

Tumorigenesis Mechanisms Found in Hereditary Renal Cell Carcinoma: A Review

Webster

Gopal

Ball

2022

Genes

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Renal cell carcinoma is a heterogenous cancer composed of an increasing number of unique subtypes each with their own cellular and tumor behavior. The study of hereditary renal cell carcinoma, which composes just 5% of all types of tumor cases, has allowed for the elucidation of subtype-specific tumorigenesis mechanisms that can also be applied to their sporadic counterparts. This review will focus on the major forms of hereditary renal cell carcinoma and the genetic alterations contributing to their tumorigenesis, including von Hippel Lindau syndrome, Hereditary Papillary Renal Cell Carcinoma, Succinate Dehydrogenase-Deficient Renal Cell Carcinoma, Hereditary Leiomyomatosis and Renal Cell Carcinoma, BRCA Associated Protein 1 Tumor Predisposition Syndrome, Tuberous Sclerosis, Birt–Hogg–Dubé Syndrome and Translocation RCC. The mechanisms for tumorigenesis described in this review are beginning to be exploited via the utilization of novel targets to treat renal cell carcinoma in a subtype-specific fashion.

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Co-occurrence of VHL and SDHA Pathogenic Variants: A Case Report

Cited by 2 publications

References 27 publications

Genotype–phenotype correlations and clinical outcomes of patients with von Hippel-Lindau disease with large deletions

Genotype–phenotype correlations and clinical outcomes of patients with von Hippel-Lindau disease with large deletions

Tumorigenesis Mechanisms Found in Hereditary Renal Cell Carcinoma: A Review

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