Characteristic genomic imbalances in pediatric pheochromocytoma

Hering, Antje; Guratowska, Monika; Bucsky, Peter; Claussen, Uwe; Decker, Jochen; Ernst, Germana; Hoeppner, Wolfgang; Michel, Susanne; Neumann, Hartmut P. H.; Parlowsky, Thomas; Lončarević, Ivan F.

doi:10.1002/gcc.20323

Cited by 13 publications

(17 citation statements)

References 34 publications

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“…In agreement with other studies [4,[19][20][21][22], we found unbalanced chromosomal aberrations in PCCs, using CGH. This suggests that chromosomal changes might be an important tumorigenic event.…”

Section: Discussionsupporting

confidence: 94%

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Molecular Cytogenetic Characterization in Four Pediatric Pheochromocytomas and Paragangliomas

Vícha

Holzerová

Křepelová

et al. 2011

Pathol. Oncol. Res.

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Pheochromocytomas (PCCs) are rare tumors among children and adolescents and therefore are not genetically well characterized. The most frequently observed chromosomal changes in PCC are losses of 1p, 3q and/or 3p, 6q, 17p, 11q, 22q, and gains of 9q and 17q. Aberrations involving chromosome 11 are more common in malignant tumors. Unfortunately information about gene aberrations in childhood PCC's is limited. We used comparative genomic hybridization (CGH) and array comparative genomic hybridization (aCGH) to screen for copy number changes in four children suffering from pheochromocytoma or paraganglioma. Patients were diagnosed at the age 13 or 14 years. Bilateral pheochromocytoma was associated with von Hippel-Lindau syndrome (VHL). Multiple paraganglioma was associated with a germline mutation in SDHB. We found very good concordance between the results of CGH and aCGH techniques. Losses were observed more frequently than gains. All cases had a loss of chromosome 11 or 11p. Other aberrations were loss of chromosome 3 and 11 in sporadic pheochromocytoma, and loss of 3p and 11p in pheochromocytoma, which carried the VHL mutation. The deletion of chromosome 1p and other changes were observed in paragangliomas. We conclude that both array CGH and CGH analysis identified similar chromosomal regions involved in tumorigenesis of pheochromocytoma and paragangliomas, but we found 3 discrepancies between the methods. We didn't find any, of the proposed, molecular markers of malignancy in our benign cases and therefore we speculate that molecular cytogenetic examination may be helpful in separating benign and malignant forms in the future.

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Section: Discussionsupporting

confidence: 94%

“…progenetix.net/progenetix/;14.9. 2009) showed high concordance of the aberration pattern [19][20][21].…”

Section: Resultsmentioning

confidence: 89%

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Molecular Cytogenetic Characterization in Four Pediatric Pheochromocytomas and Paragangliomas

Vícha

Holzerová

Křepelová

et al. 2011

Pathol. Oncol. Res.

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“…This pattern of loss has been previously mentioned in PCC from VHL patients, but has so far not been related to a subgroup of sporadic PCC (Lui et al 2002, Hering et al 2006. In order to exclude that this subgroup represented occult VHL disease, we performed mutation analysis of the entire VHL coding region, in which we could not detect germline mutations.…”

Section: Discussionmentioning

confidence: 73%

“…VHL-related PCC, however, show distinct genetic aberrations consisting of loss of chromosomes 3 and 11 (Lui et al 2002, Hering et al 2006.…”

Section: Introductionmentioning

confidence: 99%

Array-comparative genomic hybridization in sporadic benign pheochromocytomas

Nederveen¹,

Korpershoek²,

deLeeuw³

et al. 2009

Endocrine-Related Cancer

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Pheochromocytomas (PCC) are catecholamine-producing tumors arising from the adrenal medulla that occur either sporadically or in the context of hereditary cancer syndromes, such as multiple endocrine neoplasia type 2 (MEN2), von Hippel-Lindau disease (VHL), neurofibromatosis type 1, and the PCC-paraganglioma syndrome. Conventional comparative genomic hybridization studies have shown loss of 1p and 3q in the majority of sporadic and MEN2-related PCC, and 3p and 11p loss in VHL-related PCC. The development of a submegabase tiling resolution array enabled us to perform a genome-wide high-resolution analysis of 36 sporadic benign PCC. The results show that there are two distinct patterns of abnormalities in these sporadic PCC, one consisting of loss of 1p with or without concomitant 3q loss in 20/36 cases (56%), the other characterized by loss of 3p with or without concomitant 11p loss in 11/36 (31%). In addition, we found loss of chromosome 22q at high frequency (35%), as well as the novel finding of high frequency chromosome 21q loss (21%). We conclude that there appear to be two subgroups of benign sporadic PCC, one of which has a pattern of chromosomal abnormalities that is comparable with PCC from patients with MEN2 and the other that is comparable with the PCC that arise in patients with VHL disease. In addition, genes on 21q and 22q might play a more important role in PCC pathogenesis than had been assumed thus far.

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Bilateral Pheochromocytomas, Hemihyperplasia, and Subtle Somatic Mosaicism: The Importance of Detecting Low‐Level Uniparental Disomy

Kalish

Conlin

Mostoufi‐Moab

et al. 2013

American J of Med Genetics Pt A

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We report on a patient with early onset pediatric bilateral pheochromocytomas caused by mosaic chromosome 11p15 paternal uniparental isodisomy (UPD). Hemihyperplasia of the arm was diagnosed in a 4-month-old female and clinical methylation testing for 11p15 in the blood was normal, with a reported detection threshold for mosaicism of 20%. She was subsequently diagnosed at 18 months with bilateral pheochromocytomas. Single-nucleotide polymorphism (SNP) array analysis of pheochromocytoma tissue demonstrated mosaic deletions of 8p12pter, 21q21.1qter, 22q11.23qter; commonly seen in pheochromocytomas. In addition, mosaic 11p15.3pter homozygosity was noted. Molecular testing for other causes of pheochromocytomas was normal, suggesting that 11p15 homozygosity was the primary event. Subsequent SNP array analysis of skin fibroblasts from the hyperplastic side demonstrated 5% mosaic paternal UPD for 11p15. We have subsequently used SNP array analysis to identify four patients with subtle hemihyperplasia with low-level mosaic UPD that was not detected by methylation analysis. Given the increased sensitivity of SNP array analysis to detect UPD along with the increased incidence of tumorigenesis in these UPD patients, we suggest that it has high utility in the clinical work-up of hemihyperplasia. The present case also suggests that 11p15 paternal UPD may be an under-detected mechanism of sporadic pheochromocytoma in the pediatric population. Furthermore, a review of the literature suggests that patients with 11p15 paternal UPD may present after 8 years of age with pheochromocytoma and raises the possibility that ultrasound screening could be considered beyond 8 years of age in this subset of hemihyperplasia and Beckwith–Wiedemann syndrome patients.

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Characteristic genomic imbalances in pediatric pheochromocytoma

Cited by 13 publications

References 34 publications

Molecular Cytogenetic Characterization in Four Pediatric Pheochromocytomas and Paragangliomas

Molecular Cytogenetic Characterization in Four Pediatric Pheochromocytomas and Paragangliomas

Array-comparative genomic hybridization in sporadic benign pheochromocytomas

Bilateral Pheochromocytomas, Hemihyperplasia, and Subtle Somatic Mosaicism: The Importance of Detecting Low‐Level Uniparental Disomy

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