Genetic Screening for von Hippel-Lindau Gene Mutations in Non-syndromic Pheochromocytoma: Low Prevalence and False-positives or Misdiagnosis Indicate a Need for Caution

G. Eisenhofer; C. D. Vocke; A. Elkahloun; T.-T. Huynh; T. Prodanov; J.W. M. Lenders; H. J. Timmers; J. N. Benhammou; W. M. Linehan; K. Pacak

doi:10.1055/s-0032-1304662

Hormone and Metabolic Research, Table of Contents

Horm Metab Res 2012; 44(05): 343-348
DOI: 10.1055/s-0032-1304662

Humans, Clinical

Genetic Screening for von Hippel-Lindau Gene Mutations in Non-syndromic Pheochromocytoma: Low Prevalence and False-positives or Misdiagnosis Indicate a Need for Caution

G. Eisenhofer

¹Institute of Clinical Chemistry and Laboratory Medicine and Department of Medicine III, University of Dresden, Dresden, Germany

,

C. D. Vocke

²Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA

,

A. Elkahloun

³Genome Technology Branch, National Human Genome Research Institute, Bethesda, MD, USA

,

T.-T. Huynh

⁴Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development at the National Institutes of Health, Bethesda, MD, USA

,

T. Prodanov

⁴Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development at the National Institutes of Health, Bethesda, MD, USA

,

J.W. M. Lenders

⁵Department of Internal Medicine and Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands

,

H. J. Timmers

⁶Department of Endocrinology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands

,

J. N. Benhammou

²Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA

,

W. M. Linehan

²Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA

,

K. Pacak

⁴Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development at the National Institutes of Health, Bethesda, MD, USA

› Author Affiliations

Abstract

Genetic testing of tumor susceptibility genes is now recommended in most patients with pheochromocytoma or paraganglioma (PPGL), even in the absence of a syndromic presentation. Once a mutation is diagnosed there is rarely follow-up validation to assess the possibility of misdiagnosis. This study prospectively examined the prevalence of von Hippel-Lindau (VHL) gene mutations among 182 patients with non-syndromic PPGLs. Follow-up in positive cases included comparisons of biochemical and tumor gene expression data in 64 established VHL patients, with confirmatory genetic testing in cases with an atypical presentation. VHL mutations were detected by certified laboratory testing in 3 of the 182 patients with non-syndromic PPGLs. Two of the 3 had an unusual presentation of diffuse peritoneal metastases and substantial increases in plasma metanephrine, the metabolite of epinephrine. Tumor gene expression profiles in these 2 patients also differed markedly from those associated with established VHL syndrome. One patient was diagnosed with a partial deletion by Southern blot analysis and the other with a splice site mutation. Quantitative polymerase chain reaction, multiplex ligation-dependent probe amplification, and comparative genomic hybridization failed to confirm the partial deletion indicated by certified laboratory testing. Analysis of tumor DNA in the other patient with a splice site alteration indicated no loss of heterozygosity or second hit point mutation. In conclusion, VHL germline mutations represent a minor cause of non-syndromic PPGLs and misdiagnoses can occur. Caution should therefore be exercised in interpreting positive genetic test results as the cause of disease in patients with non-syndromic PPGLs.

Key words

pheochromocytoma - paraganglioma - von Hippel-Lindau syndrome - mutation testing - germline mutations - loss of heterozygosity

Full Text

References

References
1 Neumann HP, Bausch B, McWhinney SR, Bender BU, Gimm O, Franke G, Schipper J, Klisch J, Altehoefer C, Zerres K, Januszewicz A, Eng C, Smith WM, Munk R, Manz T, Glaesker S, Apel TW, Treier M, Reineke M, Walz MK, Hoang-Vu C, Brauckhoff M, Klein-Franke A, Klose P, Schmidt H, Maier-Woelfle M, Peczkowska M, Szmigielski C. Germ-line mutations in nonsyndromic pheochromocytoma. N Engl J Med 2002; 346: 1459-1466
2 Amar L, Bertherat J, Baudin E, Ajzenberg C, Bressac-de Paillerets B, Chabre O, Chamontin B, Delemer B, Giraud S, Murat A, Niccoli-Sire P, Richard S, Rohmer V, Sadoul JL, Strompf L, Schlumberger M, Bertagna X, Plouin PF, Jeunemaitre X, Gimenez-Roqueplo AP. Genetic testing in pheochromocytoma or functional paraganglioma. J Clin Oncol 2005; 23: 8812-8818
3 Cascon A, Pita G, Burnichon N, Landa I, Lopez-Jimenez E, Montero-Conde C, Leskela S, Leandro-Garcia LJ, Leton R, Rodriguez-Antona C, Diaz JA, Lopez-Vidriero E, Gonzalez-Neira A, Velasco A, Matias-Guiu X, Gimenez-Roqueplo AP, Robledo M. Genetics of pheochromocytoma and paraganglioma in Spanish patients. J Clin Endocrinol Metab 2009; 94: 1701-1705
4 Bayley JP, Kunst HP, Cascon A, Sampietro ML, Gaal J, Korpershoek E, Hinojar-Gutierrez A, Timmers HJ, Hoefsloot LH, Hermsen MA, Suarez C, Hussain AK, Vriends AH, Hes FJ, Jansen JC, Tops CM, Corssmit EP, de Knijff P, Lenders JW, Cremers CW, Devilee P, Dinjens WN, de Krijger RR, Robledo M. SDHAF2 mutations in familial and sporadic paraganglioma and phaeochromocytoma. Lancet Oncol 2010; 11: 366-372
5 Qin Y, Yao L, King EE, Buddavarapu K, Lenci RE, Chocron ES, Lechleiter JD, Sass M, Aronin N, Schiavi F, Boaretto F, Opocher G, Toledo RA, Toledo SP, Stiles C, Aguiar RC, Dahia PL. Germline mutations in TMEM127 confer susceptibility to pheochromocytoma. Nat Genet 2010; 42: 229-233
6 Comino-Méndez I, Gracia-Aznárez FJ, Schiavi F, Landa I, Leandro-García LJ, Letón R, Honrado E, Ramos-Medina R, Caronia D, Pita G, Gómez-Graña A, de Cubas AA, Inglada-Pérez L, Maliszewska A, Taschin E, Bobisse S, Pica G, Loli P, Hernández-Lavado R, Díaz JA, Gómez-Morales M, González-Neira A, Roncador G, Rodríguez-Antona C, Benítez J, Mannelli M, Opocher G, Robledo M, Cascón A. Exome sequencing identifies MAX mutations as a cause of hereditary pheochromocytoma. Nat Genet 2011; 43: 663-667
7 Pacak K, Eisenhofer G, Ahlman H, Bornstein SR, Gimenez-Roqueplo AP, Grossman AB, Kimura N, Mannelli M, McNicol AM, Tischler AS. Pheochromocytoma: recommendations for clinical practice from the First International Symposium. Nat Clin Pract Endocrinol Metab 2007; 3: 92-102
8 Hattori K, Teranishi J, Stolle C, Yoshida M, Kondo K, Kishida T, Kanno H, Baba M, Kubota Y, Yao M. Detection of germline deletions using real-time quantitative polymerase chain reaction in Japanese patients with von Hippel-Lindau disease. Cancer Sci 2006; 97: 400-405
9 Eisenhofer G, Pacak K, Huynh TT, Qin N, Bratslavsky G, Linehan WM, Mannelli M, Friberg P, Grebe SK, Timmers HJ, Bornstein SR, Lenders JW. Catecholamine metabolomic and secretory phenotypes in phaeochromocytoma. Endocr Relat Cancer 2011; 18: 97-111
10 Eisenhofer G, Lenders JW, Timmers H, Mannelli M, Grebe SK, Hofbauer LC, Bornstein SR, Tiebel O, Adams K, Bratslavsky G, Linehan WM, Pacak K. Measurements of plasma methoxytyramine, normetanephrine, and metanephrine as discriminators of different hereditary forms of pheochromocytoma. Clin Chem 2011; 57: 411-420
11 Benhammou JN, Vocke CD, Santani A, Schmidt LS, Baba M, Seyama K, Wu X, Korolevich S, Nathanson KL, Stolle CA, Linehan WM. Identification of intragenic deletions and duplication in the FLCN gene in Birt-Hogg-Dube syndrome. Genes Chromosomes Cancer 2011; 50: 466-477
12 Brauch H, Hoeppner W, Jahnig H, Wohl T, Engelhardt D, Spelsberg F, Ritter MM. Sporadic pheochromocytomas are rarely associated with germline mutations in the vhl tumor suppressor gene or the ret protooncogene. J Clin Endocrinol Metab 1997; 82: 4101-4104
13 Pigny P, Cardot-Bauters C, Do Cao C, Vantyghem MC, Carnaille B, Pattou F, Caron P, Wemeau JL, Porchet N. Should genetic testing be performed in each patient with sporadic pheochromocytoma at presentation?. Eur J Endocrinol 2009; 160: 227-231
14 Eisenhofer G, Walther MM, Huynh TT, Li ST, Bornstein SR, Vortmeyer A, Mannelli M, Goldstein DS, Linehan WM, Lenders JW, Pacak K. Pheochromocytomas in von Hippel-Lindau syndrome and multiple endocrine neoplasia type 2 display distinct biochemical and clinical phenotypes. J Clin Endocrinol Metab 2001; 86: 1999-2008
15 Dahia PL, Ross KN, Wright ME, Hayashida CY, Santagata S, Barontini M, Kung AL, Sanso G, Powers JF, Tischler AS, Hodin R, Heitritter S, Moore F, Dluhy R, Sosa JA, Ocal IT, Benn DE, Marsh DJ, Robinson BG, Schneider K, Garber J, Arum SM, Korbonits M, Grossman A, Pigny P, Toledo SP, Nose V, Li C, Stiles CD. A HIF1alpha regulatory loop links hypoxia and mitochondrial signals in pheochromocytomas. PLoS Genet 2005; 1: 72-80
16 Eisenhofer G, Huynh TT, Pacak K, Brouwers FM, Walther MM, Linehan WM, Munson PJ, Mannelli M, Goldstein DS, Elkahloun AG. Distinct gene expression profiles in norepinephrine- and epinephrine-producing hereditary and sporadic pheochromocytomas: activation of hypoxia-driven angiogenic pathways in von Hippel-Lindau syndrome. Endocr Rel Cancer 2004; 11: 897-911
17 Zbar B, Kishida T, Chen F, Schmidt L, Maher ER, Richards FM, Crossey PA, Webster AR, Affara NA, Ferguson-Smith MA, Brauch H, Glavac D, Neumann HPH, Tisherman S, Mulvihill JJ, Gross DJ, Shuin T, Whaley J, Seizinger B, Kley N, Olschwang S, Boisson C, Richard S, Lips CHM, Linehan WM, Lerman M. Germline mutations in the Von Hippel-Lindau disease (VHL) gene in families from North America, Europe, and Japan. Hum Mutat 1996; 8: 348-357
18 Young AC, Craven RA, Cohen D, Taylor C, Booth C, Harnden P, Cairns DA, Astuti D, Gregory W, Maher ER, Knowles MA, Joyce A, Selby PJ, Banks RE. Analysis of VHL gene alterations and their relationship to clinical parameters in sporadic conventional renal cell carcinoma. Clin Cancer Res 2009; 15: 7582-7592
19 Ercolino T, Becherini L, Valeri A, Maiello M, Gagliano MS, Parenti G, Ramazzotti M, Piscitelli E, Simi L, Pinzani P, Nesi G, DeglInnocenti D, Console N, Bergamini C, Mannelli M. Uncommon clinical presentations of pheochromocytoma and paraganglioma in two different patients affected by two distinct novel VHL germline mutations. Clin Endocrinol (Oxf) 2008; 68: 762-768
20 Solano AR, Dourisboure RJ, Weitzel J, Podesta EJ. A cautionary note: false homozygosity for BRCA2 6174delT mutation resulting from a single nucleotide polymorphism masking the wt allele. Eur J Hum Genet 2002; 10: 395-397
21 Ramus SJ, Harrington PA, Pye C, Peock S, Cook MR, Cox MJ, Jacobs IJ, DiCioccio RA, Whittemore AS, Piver MS, Embrace Easton DF, Ponder BA, Pharoah PD, Gayther SA. Screening for the BRCA1-ins6kbEx13 mutation: potential for misdiagnosis. Mutation in brief #964. Online. Hum Mutat 2007; 28: 525-526
22 Choi JH, Velayati A, Stubblefield BK, Orr-Urtreger A, Gan-Or Z, Tayebi N, Sidransky E. False-positive results using a Gaucher diagnostic kit – RecTL and N370S. Mol Genet Metab 2010; 100: 100-102
23 Miolo G, Crovatto M, Manno M, Pivetta B, Tessitori G, Picci L. Heterozygous variant at nucleotide position 875+11A>T in exon 6A cystic fibrosis transmembrane conductance regulator gene induces 852del22 mutation false-positivity by line probe assay. Fertil Steril 2011; 95 (1121) e1121-e1124
24 Cascon A, Lopez-Jimenez E, Landa I, Leskela S, Leandro-Garcia LJ, Maliszewska A, Leton R, de la Vega L, Garcia-Barcina MJ, Sanabria C, Alvarez-Escola C, Rodriguez-Antona C, Robledo M. Rationalization of genetic testing in patients with apparently sporadic pheochromocytoma/paraganglioma. Horm Metab Res 2009; 41: 672-675
25 Eisenhofer G, Timmers H, Lenders JW, Bornstein SR, Tiebel O, Mannelli M, King KS, Vocke C, Linehan WM, Bratslavsky G, Pacak K. Age at diagnosis of pheochromocytoma differs according to catecholamine phenotype and tumor location. J Clin Endocrinol Metab 2011; 96: 375-384