Should genetic testing be performed in each patient with sporadic pheochromocytoma at presentation?

Pigny, Pascal; Cardot-Bauters, Catherine; Cao, Christine Do; Vantyghem, Marie-Christine; Carnaille, B.; Pattou, François; Caron, Philippe; Wémeau, Jean-Louis; Porchet, Nicole

doi:10.1530/eje-08-0574

Cited by 26 publications

(24 citation statements)

References 12 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The U.S.-based costs of clinical mutation testing of each gene were obtained by averaging costs posted by GeneDx 25 and supplied by the Clinical Diagnostic Laboratories of the University of Pittsburgh and Children's Hospital of Philadelphia. The costs are similar in the European countries and Australia.…”

Section: Translational Relevancementioning

confidence: 99%

Clinical Predictors and Algorithm for the Genetic Diagnosis of Pheochromocytoma Patients

Erlic

Rybicki

Pęczkowska³

et al. 2009

Clinical Cancer Research

157

133

View full text Add to dashboard Cite

Purpose: Six pheochromocytoma susceptibility genes causing distinct syndromes have been identified; approximately one of three of all pheochromocytoma patients carry a predisposing germline mutation. When four major genes (VHL, RET, SDHB, SDHD) are analyzed in a clinical laboratory, costs are ∼$3,400 per patient. The aim of the study is to systematically obtain a robust algorithm to identify who should be genetically tested, and to determine the order in which genes should be tested. Experimental Design: DNA from 989 apparently nonsyndromic patients were scanned for germline mutations in the genes VHL, RET, SDHB, SDHC, and SDHD. Clinical parameters were analyzed as potential predictors for finding mutations by multiple logistic regression, validated by bootstrapping. Cost reduction was calculated between prioritized gene testing compared with that for all genes. Results: Of 989 apparently nonsyndromic pheochromocytoma cases, 187 (19%) harbored germline mutations. Predictors for presence of mutation are age <45 years, multiple pheochromocytoma, extra-adrenal location, and previous head and neck paraganglioma. If we used the presence of any one predictor as indicative of proceeding with gene testing, then 342 (34.6%) patients would be excluded, and only 8 carriers (4.3%) would be missed. We were also able to statistically model the priority of genes to be tested given certain clinical features. E.g., for patients with prior head and neck paraganglioma, the priority would be SDHD>SDHB>RET>VHL. Using the clinical predictor algorithm to prioritize gene testing and order, a 44.7% cost reduction in diagnostic process can be achieved. Conclusions: Clinical parameters can predict for mutation carriers and help prioritize gene testing to reduce costs in nonsyndromic pheochromocytoma presentations. (Clin Cancer Res 2009;15(20):6378-85)

show abstract

Section: Translational Relevancementioning

confidence: 99%

Clinical Predictors and Algorithm for the Genetic Diagnosis of Pheochromocytoma Patients

Erlic

Rybicki

Pęczkowska³

et al. 2009

Clinical Cancer Research

157

133

View full text Add to dashboard Cite

show abstract

“…while the majority of patients undergoing SDHB mutation analysis have missense and nonsense mutations, some mutation negative patients have been reported to carry either large partial or total deletions of the SDHB gene [10][11][12][13][14][15][16][17][18]. to investigate this possibility, we carried out MLPA and identified a heterozygous SDHB gene deletion encompassing sequences corresponding to the promoter region, exon 1 and exon 2 ( Fig.…”

Section: Sdhb Mutation Analysismentioning

confidence: 99%

“…Given that only a small number of SDHB deletion cases have been described [10][11][12][13][14][15][16][17][18], it is difficult to meaningfully compare the phenotypes and penegest to us that these tests capable of detecting such large deletions, such as MLPA, should be made routine. Conceivably, MLPA could be used to screen for large deletions in all three SDHx genes in a single test.…”

Section: Mlpa Analysis [22]mentioning

confidence: 99%

“…Since large deletions are rare and are undetectable using this method, neither the frequency nor the clinical manifestation associated with large SDHB deletions is well known. recently, in addition to these mutations, the use of methods such as multiplex ligation-dependent probe amplification (MLPA) and quantitative multiplex PCR of short fluorescent fragments (QmPSF) have resulted in increased reports of large SDHB deletions [10][11][12][13][14][15][16][17][18].…”

mentioning

confidence: 99%

See 1 more Smart Citation

A Large Deletion in the Succinate Dehydrogenase B Gene (SDHB) in a Japanese Patient with Abdominal Paraganglioma and Concomitant Metastasis

et al. 2010

View full text Add to dashboard Cite

The nuclear genes encoding two mitochondrial complex II subunit proteins, succinate dehydrogenase D (SDHD) and SDHB, have been reported to be associated with the development of familial pheochromocytoma and paraganglioma (hereditary pheochromocytoma/paraganglioma syndrome: HPPS) [1,2]. Growing evidence suggests that point mutations in SDHB are highly associated with abdominal paraganglioma and the following distant metastasis (malignant paraganglioma) [3][4][5][6][7][8]. Indeed, it has been found that SDHB mutations are present in 40% to 50% of malignant pheochromocytoma/paraganglioma patients which far exceeds the incidence of mutations of other genes in these malignant tumors. By contrast, among all patients with malignant pheochromocytoma/paraganglioma, the frequency of SDHB mutations is re- . Growing evidence suggests that the mutation of SDHB is highly associated with abdominal paraganglioma and the following distant metastasis (malignant paraganglioma). In the present study, we used multiplex ligation dependent probe amplification (MLPA) analysis to identify a large heterozygous SDHB gene deletion encompassing sequences corresponding to the promoter region, in addition to exon 1 and exon 2, in a malignant paraganglioma patient in whom previously characterized SDHB mutations were undetectable. This is the first Japanese case report of malignant paraganglioma, with a large SDHB deletion. our present findings strongly support the notion that large deletions in the SDHB gene should be considered in patients lacking characterized SDHB mutations.Key words: malignant pheochromocytoma, SDHB, MLPA, HPPS (hereditary pheochromocytoma/paraganglioma syndrome), Paraganglioma ported to be around one third, suggesting that SDHB mutations in these malignant tumors may not be as rare as expected [9]. It should be noted, however, that these findings are based on mutations including point mutations as well as small deletions, which are detectable by direct sequencing method [3][4][5][6][7][8][9]. Since large deletions are rare and are undetectable using this method, neither the frequency nor the clinical manifestation associated with large SDHB deletions is well known. recently, in addition to these mutations, the use of methods such as multiplex ligation-dependent probe amplification (MLPA) and quantitative multiplex PCR of short fluorescent fragments (QmPSF) have resulted in increased reports of large SDHB deletions [10][11][12][13][14][15][16][17][18].Here we report a large heterozygous SDHB gene deletion encompassing sequences corresponding to the promoter region, in addition to exon 1 and exon 2, in a malignant paraganglioma patient in whom previously characterized SDHB mutations were undetectable. This is the first Japanese case report of malignant

show abstract

“…While over 200 missense and nonsense mutations are listed in the SDH mutation database (Bayley et al 2005; http://chromium.liacs.nl/lovd_sdh/), only 10 distinct large deletions of the SDH genes have been described (Baysal et al 2004, McWhinney et al 2004, Cascon et al 2006, Amar et al 2007, Fish et al 2007, Pasini et al 2008, Pigny et al 2009). We wished to assess the nature and frequency of deletions of the SDH genes in the Dutch paraganglioma population.…”

Section: Introductionmentioning

confidence: 99%

Molecular characterization of novel germline deletions affecting SDHD and SDHC in pheochromocytoma and paraganglioma patients

Bayley

Weiss

Grimbergen

et al. 2009

Endocrine-Related Cancer

View full text Add to dashboard Cite

A major cause of paraganglioma and pheochromocytoma is germline mutation of the tumor suppressor genes SDHB, SDHC, and SDHD, encoding subunits of succinate dehydrogenase (SDH). While many SDH missense/nonsense mutations have been identified, few large deletions have been described. We performed multiplex ligation-dependent probe amplification deletion analysis in 126 point mutation-negative patients, and here we describe four novel deletions of SDHD and SDHC. Long-range PCR was used for the fine mapping of deletions. One patient had a 10 kb AluSg-AluSx-mediated deletion including SDHD exons 1 and 2, the entire TIMM8B gene, and deletion of exons of C11orf57. A second patient had a deletion of SDHD exons 1 and 2 and exon 1 of the TIMM8B gene. A third patient showed a deletion of exon 2 of SDHD, together with a 235 bp MIRb-Tensin gene insertion. In a fourth patient, a deletion of exons 5 and 6 of the SDHC gene was found, only the second SDHC deletion currently known. The deletions of the TIMM8B and C11orf57 genes are the first to be described, but do not appear to result in an additional phenotype in these patients. Four of the eight breakpoints occurred in Alu sequences and all three SDHD deletions showed an intron 2 breakpoint. This study underlines the fact that clinically relevant deletions may encompass neighboring genes, with the potential to modify phenotype. Gene deletions of SDHD and SDHC represent a substantial proportion of all mutations, and must be considered in paraganglioma patients shown to be negative for mutations by sequencing.

show abstract

Should genetic testing be performed in each patient with sporadic pheochromocytoma at presentation?

Cited by 26 publications

References 12 publications

Clinical Predictors and Algorithm for the Genetic Diagnosis of Pheochromocytoma Patients

Clinical Predictors and Algorithm for the Genetic Diagnosis of Pheochromocytoma Patients

A Large Deletion in the Succinate Dehydrogenase B Gene (SDHB) in a Japanese Patient with Abdominal Paraganglioma and Concomitant Metastasis

Molecular characterization of novel germline deletions affecting SDHD and SDHC in pheochromocytoma and paraganglioma patients

Contact Info

Product

Resources

About