Mutations in the RET proto-oncogene and the von Hippel-Lindau disease tumour suppressor gene in sporadic and syndromic phaeochromocytomas.

Eng, Charis; Crossey, Paul A.; Mulligan, Lois M.; Healey, Catherine S.; Houghton, Carol; Prowse, Amanda; Chew, Shern L.; Dahia, Patricia L.M.; O’Riordan, J. L. H.; Toledo, S. P. A.

doi:10.1136/jmg.32.12.934

Cited by 152 publications

(82 citation statements)

References 29 publications

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“…Somatic VHL mutations are commonly involved in the tumorigenesis of hemangioblastomas, accounting for up to 50% of sporadic retinal and CNS hemangioblastomas [Maher et al, 1990a;Neumann et al, 1989;Oberstrass et al, 1996;Richard et al, 1998]. Interestingly, sporadic pheochromocytoma are rarely (3%) due to somatic VHL mutations [Bar et al, 1997;Eng et al, 1995;Glasker et al, 2001;Neumann et al, 1993;Sprenger et al, 2001]. However, up to 25% of seemingly sporadic pheochromocytomas actually have a germline VHL, NF-1, c-RET, or SDH mutations.…”

Section: Sporadic Diseasesmentioning

confidence: 99%

Genetic analysis of von Hippel-Lindau disease

et al. 2010

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Mutations in the von Hippel-Lindau (VHL) gene are responsible for VHL disease, congenital polycythemia, and are found in many sporadic tumor types as well. Reports of VHL mutations are dispersed throughout original articles and databases that have not been recently updated. We compiled a comprehensive mutation table of 1,548 germline and somatic VHL mutations, derived from this protein of only 213 amino acids. We describe detailed phenotype and gene mutation information for 945 VHL families, including 30 previously unpublished kindreds from The Netherlands (six novel mutations). These data represent the most extensive catalog of germline VHL mutations to date. We also review VHL disease, known and theorized pathogenesis of common VHL manifestations, and genotype-phenotype correlations. Analysis of all VHL families, excluding germline mutations resulting in congenital polycythemias, describes the spectrum of mutation types: 52% missense, 13% frameshift, 11% nonsense, 6% in-frame deletions/insertions, 11% large/complete deletions, and 7% splice mutations. This easy-to-use compilation of VHL mutations is intended to facilitate research and function as a necessary adjunct for physicians when providing patient information. Hum Mutat 31:521-537,

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Section: Sporadic Diseasesmentioning

confidence: 99%

Genetic analysis of von Hippel-Lindau disease

et al. 2010

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“…[5][6][7][8] Moreover, the biological behavior of PCC has been analyzed in various immunohistochemical studies. [9][10][11][12] Unlike the mitotic count, which was found to be useless for predicting the malignant behavior of PCC, 13 the expression of Ki-67 is of prognostic significance.…”

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confidence: 99%

CGH and CD 44/MIB-1 immunohistochemistry are helpful to distinguish metastasized from nonmetastasized sporadic pheochromocytomas

August¹,

August²,

Schroeder³

et al. 2004

Modern Pathology

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The natural course of pheochromocytomas (PCC) cannot be predicted for certain on the basis of primary histology, their malignant character can only be confirmed by the occurrence of metastases during follow-up. Based on the recently proposed PASS score for evaluation we examined 37 adrenal (36 sporadic and one familial) and six sporadic extra-adrenal paragangliomas (all designated as pheochromocytomas) with a 'malignant histology' to find additional predictive factors. Drawing upon the follow-up (18 months to 12 years, mean 5.8 years) metastasized (n ¼ 20) and nonmetastasized (n ¼ 23) courses could be distinguished. Metastasized PCC revealed significantly (P ¼ 0.03) more copy number changes on comparative genomic hybridization (CGH) (mean 8.3) than nonmetastasized tumors (mean: 4.3). The most frequent chromosomal alterations were losses on 1p (75.6%) and 3q (44%). Both were detected with identical frequency in metastasized and nonmetastasized PCC. A gain on 17q (P ¼ 0.025) was significantly predominant in malignant courses and suggests similarities in the genetic origin and progression of PCC and neuroblastomas. The proliferative activity (MIB-1 score) of metastasized PCC (n ¼ 20) was found to be significantly higher in metastasized tumors (mean 12.8% vs mean 3.5%). In contrast, the semiquantitatively scored membrane-bound staining of CD 44-S was stronger in tumors without metastases (mean 2.1 vs mean: 0.25) during the follow-up period (Po0.01). Although the results correspond to the established weight differences the tumor weight does not appear to be an independent prognostic factor. Our study suggests that CD 44-S and MIB-1 immunostaining as well as the CGH results might complement the PASS score in predicting a metastasized course of PCC. Regardless of tumor weight, tumors with a 'malignant histology' are highly prone to metastasize when more than 5% of MIB1-positive nuclei are present or CD44-S immunostaining is negative, or both. PCC with 10 or more copy number changes on CGH must be referred to as malignant tumors. The safe distinction between benign and malignant pheochromocytomas (PCC) is an unresolved dilemma beleaguering diagnostic pathology to the present day. In most cases the decision is therefore based on the occurrence of metastases as the only proof of malignancy. Recently, Thompson 1 proposed an adrenal gland scoring scale (PASS) capable of determining malignancy solely on the grounds of conventional histological criteria. Within the framework of this scoring scale, less prognostic importance is attributed to vascular and capsular invasion (with a score of 1 point each) than to growth pattern, necroses and characteristics of proliferative behavior (high cellularity, cellular monotony, more than three mitoses/10 HPF and the occurrence of atypical mitoses). These characteristics each have a score of two points).In recent reports on adrenal and extra-adrenal PCC a number of chromosomal aberrations were discussed with a view to their possible involvement

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“…Germline mutations in SDHD (11q23) and SDHB (1p36.1), encoding subunits of the mitochondrial complex II (reviewed in Benn et al, 2002) have also been associated with familial phaeochromocytoma (Astuti et al,200la,b). However, the molecular pathogenesis of sporadic disease remains largely unknown, although somatic mutations have been identified in VHL (2%), RET (10%) and SDHD (6% ) (Eng et al, 1995;Hofstra et al, 1996;Gimm et al, 2000), yet none in SDHB (Astuti et al, 2001b) in these tumours. Loss of heterozygosity (LOH) studies have suggested that chromosome lp may be the site of at least two and possibly three tumour suppressor genes with a region at 1p36 being involved not only in phaeochromocytomas (Benn et al, 2000), but also in other endocrine and neural crest-derived tumours such as neuroblastoma (Williamson et al, 1997;Caron et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

Novel succinate dehydrogenase subunit B (SDHB) mutations in familial phaeochromocytomas and paragangliomas, but an absence of somatic SDHB mutations in sporadic phaeochromocytomas

et al. 2003

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Phaeochromocytomas arising in adrenal or extra-adrenal sites and paragangliomas of the head and neck, in particular of the carotid bodies, occur sporadically and also in a familial setting. In addition to mutations in RET and VHL in familial disease, germline mutations in SDHD and SDHB genes that encode subunits of mitochondrial complex II have also been associated with the development of familial phaeochromocytomas. To further investigate the role of SDHD and SDHB in the development of these tumours we determined the occurrence of germline SDHD and SDHB mutations in four patients with a family history of phaeochromocytoma with associated head and neck paraganglioma, one patient with a family history of phaeochromocytoma only and two patients with apparently sporadic extra-adrenal phaeochromocytoma, one of whom had early onset disease. Secondly, we investigated whether somatic SDHB mutations correlated with loss of heterozygosity at 1p36 in a subgroup of 11 sporadic and three MEN 2-associated RET-mutation-positive phaeochromocytomas. Novel SDHB mutations were identified in the probands from four families and two apparently sporadic cases (six of seven probands studied), including two missense mutations, a single nonsense and frameshift mutation, as well as two splice site mutations, one of which was shown to have partial penetrance resulting in 'leaky' splicing. Further, five intronic polymorphisms in SDHB were found. No SDHD mutations were identified. In addition, no somatic SDHB mutations were found in the remaining allele of the 11 sporadic adrenal phaeochromocytomas with allelic loss at 1p36 or the three MEN 2-associated RET-mutation-positive phaeochromocytomas. Therefore, we conclude that SDHB has a major role in the pathogenesis of familial phaeochromocytomas, but the possible role of SDHB in sporadic tumours showing allelic loss at 1p36 has yet to be ascertained.

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Mutations in the RET proto-oncogene and the von Hippel-Lindau disease tumour suppressor gene in sporadic and syndromic phaeochromocytomas.

Cited by 152 publications

References 29 publications

Genetic analysis of von Hippel-Lindau disease

Genetic analysis of von Hippel-Lindau disease

CGH and CD 44/MIB-1 immunohistochemistry are helpful to distinguish metastasized from nonmetastasized sporadic pheochromocytomas

Novel succinate dehydrogenase subunit B (SDHB) mutations in familial phaeochromocytomas and paragangliomas, but an absence of somatic SDHB mutations in sporadic phaeochromocytomas

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