Differences in genetic and epigenetic alterations between von Hippel–Lindau disease–related and sporadic hemangioblastomas of the central nervous system

Takayanagi, Shunsaku; Mukasa, Akitake; Tanaka, Shota; Nomura, Masashi; Omata, Mayu; Yanagisawa, Shunsuke; Yamamoto, Shozo; Ichimura, Koichi; Nakatomi, Hirofumi; Ueki, Keisuke; Aburatani, Hiroyuki; Saito, Nobuhito

doi:10.1093/neuonc/nox034

Cited by 29 publications

(20 citation statements)

References 36 publications

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“…In total, in 85% of sporadic ELSTs (11/13), VHL alterations were detected by next‐generation sequencing compared to 38% by direct sequencing. A higher detection rate of VHL alterations in VHL‐disease‐related tumours by targeted deep sequencing compared to direct sequencing has also been demonstrated for haemangioblastomas [40, 41]. The lower detection rate of VHL alterations by direct sequencing might be explained by the higher detection limits of classical sequencing approaches together with the low tumour cell content in some cases, reflected in the low mutant allele frequencies (mean 20%, ranging from 2% in #2 to 43% in #4) observed in our series of sporadic ELSTs.…”

Section: Discussionsupporting

confidence: 50%

Molecular characterisation of sporadic endolymphatic sac tumours and comparison to von Hippel–Lindau disease‐related tumours

Schweizer

Thierfelder

Thomas

et al. 2021

Neuropathology Appl Neurobio

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Aims Although inactivation of the von Hippel–Lindau gene (VHL) on chromosome 3p25 is considered to be the major cause of hereditary endolymphatic sac tumours (ELSTs), the genetic background of sporadic ELST is largely unknown. The aim of this study was to determine the prevalence of VHL mutations in sporadic ELSTs and compare their characteristics to VHL‐disease‐related tumours. Methods Genetic and epigenetic alterations were compared between 11 sporadic and 11 VHL‐disease‐related ELSTs by targeted sequencing and DNA methylation analysis. Results VHL mutations and small deletions detected by targeted deep sequencing were identified in 9/11 sporadic ELSTs (82%). No other cancer‐related genetic pathway was altered except for TERT promoter mutations in two sporadic ELST and one VHL‐disease‐related ELST (15%). Loss of heterozygosity of chromosome 3 was found in 6/10 (60%) VHL‐disease‐related and 10/11 (91%) sporadic ELSTs resulting in biallelic VHL inactivation in 8/10 (73%) sporadic ELSTs. DNA methylation profiling did not reveal differences between sporadic and VHL‐disease‐related ELSTs but reliably distinguished ELST from morphological mimics of the cerebellopontine angle. VHL patients were significantly younger at disease onset compared to sporadic ELSTs (29 vs. 52 years, p < 0.0001, Fisher's exact test). VHL‐disease status was not associated with an increased risk of recurrence, but the presence of clear cells was found to be associated with shorter progression‐free survival (p = 0.0002, log‐rank test). Conclusion Biallelic inactivation of VHL is the main mechanism underlying ELSTs, but unknown mechanisms beyond VHL may rarely be involved in the pathogenesis of sporadic ELSTs.

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Section: Discussionsupporting

confidence: 50%

Molecular characterisation of sporadic endolymphatic sac tumours and comparison to von Hippel–Lindau disease‐related tumours

Schweizer

Thierfelder

Thomas

et al. 2021

Neuropathology Appl Neurobio

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“…Netw. 2013, Dahia 2017, Guo et al 2011, Pena-Llopis et al 2012, Sato et al 2013, Takayanagi et al 2017). An interesting exception is paraganglioma, where analysis of biallelic VHL mutations, even when detected in seemingly sporadic tumors, often indicates that the first hit was present in the germ line (Dahia 2017.…”

Section: Introductionmentioning

confidence: 99%

The von Hippel–Lindau Tumor Suppressor Protein

Kaelin

2018

Annu. Rev. Cancer Biol.

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The von Hippel-Lindau (VHL) gene is a two-hit tumor suppressor gene and is linked to the development of the most common form of kidney cancer, clear cell renal carcinoma; blood vessel tumors of the retina, cerebellum, and spinal cord called hemangioblastomas; and tumors of the sympathoadrenal nervous system called paragangliomas. The VHL gene product, pVHL, is the substrate recognition subunit of a cullin-dependent ubiquitin ligase that targets the α subunits of hypoxia-inducible factor (HIF) for destruction when oxygen is plentiful. Mounting evidence implicates HIF2 in the pathogenesis of pVHL-defective tumors and has provided a conceptual foundation for the development of drugs to treat them that inhibit HIF2-responsive gene products such as VEGF and, more recently, HIF2 itself. pVHL has additional, noncanonical functions that are cancer relevant, including roles related to the primary cilium, chromosome stability, extracellular matrix formation, and survival signaling.

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“…An unresolved issue is the mechanism how the exon 2 skipping mechanism causes the Type 2A disease phenotype which typically involves missense mutations. Clinically, the PHEO tumors in patients carrying c.414A > G mutation lost the other WT allele [17,18], demonstrating LOH as described in classic VHL disease [25]. Therefore, it is conceivable that this hypomorphic mutation in the backdrop of LOH creates a residual amount of pVHL activity that makes cells in the adrenal glands and CNS, but not kidney, susceptible to tumorigenesis.…”

Section: Discussionmentioning

confidence: 98%

Case report: a synonymous VHL mutation (c.414A > G, p.Pro138Pro) causes pathogenic familial hemangioblastoma through dysregulated splicing

et al. 2020

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Background: von Hippel-Lindau (VHL) disease is a familial neoplasia syndrome that results from the germline mutation of VHL. Pathogenic VHL mutations include deletion, frameshift, nonsense and missense mutations. Synonymous mutations are expected to be phenotypically silent and their role in VHL disease remains poorly understood. Case presentation: We report a Caucasian male with a family history of pheochromocytoma and the synonymous VHL mutation c.414A > G (p.Pro138Pro). At 47-years, MRI revealed pheochromocytoma in the left adrenal gland and hemangioblastomas in the spine and brain. Pheochromocytoma was treated by adrenalectomy. Radiotherapy, followed by craniotomy and resection were needed to reduce hemangioblastomas to residual lesions. Two of three of the proband's children inherited the mutation and both presented with retinal hemangioblastomas without pheochromocytoma at age 7: one twin needed four laser treatments. Primary skin fibroblasts carrying the heterozygous mutation or wild type VHL were established from the family. Mutant fibroblasts downregulated fulllength VHL mRNA and protein, and upregulated the short VHL mRNA isoform (a result of exon 2 skipping in splicing) at the mRNA level but not at the protein level. Conclusions: Our study shows that the synonymous VHL mutation c.414A > G can within 7 years induce pediatric retinal hemangioblastoma in absence of pheochromocytoma. This highlights the need to include splicing-altering synonymous mutations into the screening for VHL disease. This is also the first report on detecting and validating a synonymous VHL mutation using patient-derived fibroblasts. The mutation c.414A > G translates to p.Pro138Pro, yet it is not functionally silent, because it causes aberrant splicing by skipping exon 2. The reduced but not completely abolished pVHL protein in a loss-of-heterozygosity genetic backdrop may underlie the etiology of VHL disease.

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Differences in genetic and epigenetic alterations between von Hippel–Lindau disease–related and sporadic hemangioblastomas of the central nervous system

Abstract: Although biallelic inactivation of VHL is a dominant mechanistic cause of the pathogenesis of HB, other unknown mechanisms may also be involved, and such mechanisms may be different between VHL-related and sporadic HB.

Cited by 29 publications

References 36 publications

Molecular characterisation of sporadic endolymphatic sac tumours and comparison to von Hippel–Lindau disease‐related tumours

Molecular characterisation of sporadic endolymphatic sac tumours and comparison to von Hippel–Lindau disease‐related tumours

The von Hippel–Lindau Tumor Suppressor Protein

Case report: a synonymous VHL mutation (c.414A > G, p.Pro138Pro) causes pathogenic familial hemangioblastoma through dysregulated splicing

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