Somatic point mutation of the wild-type allele detected in tumors of patients with VHL germline deletion

Vortmeyer, Alexander O.; Huang, Shun; Pack, Svetlana D.; Koch, Christian A.; Lubensky, Irina A.; Oldfield, Edward H.; Zhuang, Zhengping

doi:10.1038/sj.onc.1205121

Cited by 40 publications

(22 citation statements)

References 8 publications

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“…A similar discrepancy in the frequency of LOH between patients with a germline gene deletion and a germline intragenic mutation has been observed in tumors of patients with the von Hippel-Lindau (VHL) syndrome and in patients with retinoblastoma. In VHL patients with a germline deletion of VHL, no LOH was observed in eight tumors analyzed (0/8 tumors, 95% CI, 0-31%) (Vortmeyer et al, 2002;Wait et al, 2004), while this is a frequent event in tumors without a germline deletion (81/132 tumors ¼ 61%, 95% CI, 52-70%) (Crossey et al, 1994;Zeiger et al, 1995;Prowse et al, 1997;Bender et al, 2000;Glasker et al, 2001;Vortmeyer et al, 2002). Also, no LOH was observed for RB1 in 12 retinoblastoma patients with a germline deletion of RB1 (0/12 tumors, 95% CI, 0-22%), whereas 69% of the tumors from individuals without a germline deletion had LOH (101/146 tumors, 95% CI, 61-77%) (Hagstrom and Dryja, 1999).…”

Section: Discussionmentioning

confidence: 90%

Somatic loss of wild type NF1 allele in neurofibromas: Comparison of NF1 microdeletion and non‐microdeletion patients

Raedt

Maertens

Chmara

et al. 2006

Genes Chromosomes & Cancer

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Neurofibromatosis type I (NF1) is an autosomal dominant familial tumor syndrome characterized by the presence of multiple benign neurofibromas. In 95% of NF1 individuals, a mutation is found in the NF1 gene, and in 5% of the patients, the germline mutation consists of a microdeletion that includes the NF1 gene and several flanking genes. We studied the frequency of loss of heterozygosity (LOH) in the NF1 region as a mechanism of somatic NF1 inactivation in neurofibromas from NF1 patients with and without a microdeletion. There was a statistically significant difference between these two patient groups in the proportion of neurofibromas with LOH. None of the 40 neurofibromas from six different NF1 microdeletion patients showed LOH, whereas LOH was observed in 6/28 neurofibromas from five patients with an intragenic NF1 mutation (P = 0.0034, Fisher's exact). LOH of the NF1 microdeletion region in NF1 microdeletion patients would de facto lead to a nullizygous state of the genes located in the deletion region and might be lethal. The mechanisms leading to LOH were further analyzed in six neurofibromas. In two out of six neurofibromas, a chromosomal microdeletion was found; in three, a mitotic recombination was responsible for the observed LOH; and in one, a chromosome loss with reduplication was present. These data show an important difference in the mechanisms of second hit formation in the 2 NF1 patient groups. We conclude that NF1 is a familial tumor syndrome in which the type of germline mutation influences the type of second hit in the tumors.

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Section: Discussionmentioning

confidence: 90%

Somatic loss of wild type NF1 allele in neurofibromas: Comparison of NF1 microdeletion and non‐microdeletion patients

Raedt

Maertens

Chmara

et al. 2006

Genes Chromosomes & Cancer

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“…For the tumor to develop, a second hit must occur [Knudson, 1971] that inactivates the wild-type VHL allele. In the majority of tumors, this second hit consists of a large VHL deletion or a VHL point mutation [Vortmeyer et al, 2002;Wait et al, 2004;Wong et al, 2007].…”

Section: Official Journal Wwwhgvsorgmentioning

confidence: 99%

Alu-Alurecombination underlies the vast majority of largeVHLgermline deletions: Molecular characterization and genotype-phenotype correlations in VHL patients

et al. 2009

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Von Hippel-Lindau disease (VHL) is an autosomal dominant cancer syndrome. Affected individuals are predisposed to multiple tumors, primarily of the central nervous system (CNS), eyes, adrenals, and kidneys. The VHL tumor suppressor gene on chromosome 3p26-25 is partially or completely deleted in 20 to 30% of families with VHL. We identified deletions ranging from 0.5 kb to 250 kb affecting part of or the entire VHL and flanking genes in 54 families. In 33 of the index patients, the breakpoints were precisely characterized by DNA sequencing. Of the 66 breakpoints, 90% were located in Alu elements, revealing Alu-mediated recombination as the major mechanism for large germline deletions of the VHL gene, which lies in a region of high Alu density. Interestingly, an AluYa5 element in VHL intron 2, the evolutionarily youngest Alu element and the only such element in the entire region, was found to be the most recombinogenic, involved in 7 out of the 33 deletions. In comparison to VHL patients in general, the 54 index cases and their affected relatives showed a higher occurrence of renal cell carcinomas (RCC) and of CNS hemangioblastomas. We not only noted the association of RCC with retention of the HSPC300 gene, but also observed a significant correlation between retention of HSPC300 and the development of retinal angiomas (AR). This study reveals that germline VHL deletions provide a particularly rich source for the study of Alu-mediated unequal crossover events, and provides evidence for a protective role of the loss of the actin-regulator gene HSPC300 for the development of both RCC and AR.

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“…In addition, approximately 20% of VHL patients exhibit germline deletion of an entire copy or of at least a substantial part of the VHL gene [Friedrich, 2001]. According to the genotype, one might expect that patients carrying a germline gross deletion would develop a ccRCC, but interestingly a lower prevalence of ccRCC has been described in patients with complete germline deletions of VHL, suggesting that this genotype may be associated with a mild clinical presentation (low risk of ccRCC) [Cybulski et al, 2002;Maranchie et al, 2004;Vortmeyer et al, 2002;Wait et al, 2004].…”

Section: Introductionmentioning

confidence: 95%

Loss of the actin regulator HSPC300 results in clear cell renal cell carcinoma protection in Von Hippel-Lindau patients

et al. 2007

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Clear cell renal cell carcinoma (ccRCC) is the most common malignant neoplasm of the kidney. The majority of hereditary and sporadic ccRCC cases are associated with germline and somatic mutations in the Von Hippel-Lindau gene (VHL), respectively. Gross deletions at the VHL locus can result either in ccRCC or in a mild clinical phenotype, with the absence of ccRCC development. Our goal in this study was to identify the molecular basis responsible for these differences in the clinical behavior in order to predict patients' phenotype. Using multiplex ligation-dependent amplification (MLPA), we identified and characterized gross VHL deletions in Spanish VHL families. A candidate gene related to this clinical association, HSPC300, was identified and depleted by RNA interference. It was possible to narrow the susceptibility region related to the mild clinical phenotype down to approximately 14 kb that included HSPC300 (C3orf10), a regulator of actin dynamics and cytoskeleton organization. Whereas 9 out of 10 families with ccRCC retained HSPC300 in the germline, loss of the HSPC300 locus was associated with mild clinical presentation of the disease in 6 out of 8 families. In fact, genetic depletion of HSPC300 resulted in cytoskeleton abnormalities and cytokinesis arrest in several tumor cell lines including ccRCC cells, suggesting that tumor cell proliferation was compromised in the absence of HSPC300. These clinical and functional data indicate a relevant function of HSPC300 in tumor cell progression, and suggest future therapeutic strategies based upon the inhibition of HSPC300 in renal cell carcinoma and possibly on other cancers.

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Somatic point mutation of the wild-type allele detected in tumors of patients with VHL germline deletion

Cited by 40 publications

References 8 publications

Somatic loss of wild type NF1 allele in neurofibromas: Comparison of NF1 microdeletion and non‐microdeletion patients

Somatic loss of wild type NF1 allele in neurofibromas: Comparison of NF1 microdeletion and non‐microdeletion patients

Alu-Alurecombination underlies the vast majority of largeVHLgermline deletions: Molecular characterization and genotype-phenotype correlations in VHL patients

Loss of the actin regulator HSPC300 results in clear cell renal cell carcinoma protection in Von Hippel-Lindau patients

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