Abstract
Pheochromocytoma (PCC) and Paraganglioma are rare tumours originating from neuroendocrine cells. Up to 60 % of cases have either germline or somatic mutation in one of eleven described susceptibility loci, SDHA, SDHB, SDHC, SDHD, SDHAF2, VHL, EPAS1, RET, NF1, TMEM127 and MYC associated factor-X (MAX). Recently, germline mutations in MAX were found to confer susceptibility to PCC and paraganglioma (PGL). A subsequent multicentre study found about 1 % of PCCs and PGLs to have germline or somatic mutations in MAX. However, there has been no study investigating the frequency of MAX mutations in a Scandinavian cohort. We analysed tumour specimens from 63 patients with PCC and PGL treated at Uppsala University hospital, Sweden, for re-sequencing of MAX using automated Sanger sequencing. Our results show that 0 % (0/63) of tumours had mutations in MAX. Allele frequencies of known single nucleotide polymorphisms rs4902359, rs45440292, rs1957948 and rs1957949 corresponded to those available in the Single Nucleotide Polymorphism Database. We conclude that MAX mutations remain unusual events and targeted genetic screening should be considered after more common genetic events have been excluded.
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References
Manger WM (2006) An overview of pheochromocytoma: history, current concepts, vagaries, and diagnostic challenges. Ann N Y Acad Sci 1073:1–20
Kimura N, Watanabe T, Noshiro T, Shizawa S, Miura Y (2005) Histological grading of adrenal and extra-adrenal pheochromocytomas and relationship to prognosis: a clinicopathological analysis of 116 adrenal pheochromocytomas and 30 extra-adrenal sympathetic paragangliomas including 38 malignant tumors. Endocr Pathol 16(1):23–32
Burnichon N, Vescovo L, Amar L, Libe R, de Reynies A, Venisse A, Jouanno E, Laurendeau I, Parfait B, Bertherat J, Plouin PF, Jeunemaitre X, Favier J, Gimenez-Roqueplo AP (2011) Integrative genomic analysis reveals somatic mutations in pheochromocytoma and paraganglioma. Hum Mol Genet 20(20):3974–3985. doi:10.1093/hmg/ddr324
Burnichon N, Cascon A, Schiavi F, Paes Morales N, Comino-Mendez I, Abermil N, Inglada-Perez L, de Cubas AA, Amar L, Barontini MB, Bernaldo de Quiros S, Bertherat J, Bignon YJ, Blok MJ, Bobisse S, Borrego S, Castellano M, Chanson P, Chiara MD, Corssmit EP, Giacche M, de Krijger RR, Ercolino T, Girerd X, Gomez-Garcia EB, Gomez-Grana A, Guilhem I, Hes F, Honrado E, Korpershoek E, Lenders JW, Leton R, Mensenkamp AR, Merlo A, Mori L, Murat A, Pierre P, Plouin PF, Prodanov T, Quesada-Charneco M, Qin N, Rapizzi E, Raymond V, Reisch N, Roncador G, Ruiz-Ferrer M, Schillo F, Stegmann AP, Suarez C, Taschin E, Timmers HJ, Tops C, Urioste M, Beuschlein F, Pacak K, Mannelli M, Dahia PL, Opocher G, Eisenhofer G, Gimenez-Roqueplo AP, Robledo M (2012) MAX mutations cause hereditary and sporadic pheochromocytoma and paraganglioma. Clin Cancer Res 27:27
Burnichon N, Buffet A, Parfait B, Letouze E, Laurendeau I, Loriot C, Pasmant E, Abermil N, Valeyrie-Allanore L, Bertherat J, Amar L, Vidaud D, Favier J, Gimenez-Roqueplo AP (2012) Somatic NF1 inactivation is a frequent event in sporadic pheochromocytoma. Hum Mol Genet 6:6
Welander J, Larsson C, Backdahl M, Hareni N, Sivler T, Brauckhoff M, Soderkvist P, Gimm O (2012) Integrative genomics reveals frequent somatic NF1 mutations in sporadic pheochromocytomas. Hum Mol Genet 24:24
Burnichon N, Briere JJ, Libe R, Vescovo L, Riviere J, Tissier F, Jouanno E, Jeunemaitre X, Benit P, Tzagoloff A, Rustin P, Bertherat J, Favier J, Gimenez-Roqueplo AP (2010) SDHA is a tumor suppressor gene causing paraganglioma. Hum Mol Genet 19(15):3011–3020. doi:10.1093/hmg/ddq206
Astuti D, Latif F, Dallol A, Dahia PL, Douglas F, George E, Skoldberg F, Husebye ES, Eng C, Maher ER (2001) Gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma. Am J Hum Genet 69(1):49-54. Epub 2001 Jun 2012
Niemann S, Muller U (2000) Mutations in SDHC cause autosomal dominant paraganglioma, type 3. Nat Genet 26(3):268–270
Baysal BE, Ferrell RE, Willett-Brozick JE, Lawrence EC, Myssiorek D, Bosch A, van der Mey A, Taschner PE, Rubinstein WS, Myers EN, Richard CW III, Cornelisse CJ, Devilee P, Devlin B (2000) Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma. Science 287(5454):848–851
Hao HX, Khalimonchuk O, Schraders M, Dephoure N, Bayley JP, Kunst H, Devilee P, Cremers CW, Schiffman JD, Bentz BG, Gygi SP, Winge DR, Kremer H, Rutter J (2009) SDH5, a gene required for flavination of succinate dehydrogenase, is mutated in paraganglioma. Science 325(5944):1139–1142. Epub 2009 Jul 1123
Latif F, Tory K, Gnarra J, Yao M, Duh FM, Orcutt ML, Stackhouse T, Kuzmin I, Modi W, Geil L et al (1993) Identification of the von Hippel-Lindau disease tumor suppressor gene. Science 260(5112):1317–1320
Zhuang Z, Yang C, Lorenzo F, Merino M, Fojo T, Kebebew E, Popovic V, Stratakis CA, Prchal JT, Pacak K (2012) Somatic HIF2A gain-of-function mutations in paraganglioma with polycythemia. N Engl J Med 367(10), 922-930
Mulligan LM, Kwok JB, Healey CS, Elsdon MJ, Eng C, Gardner E, Love DR, Mole SE, Moore JK, Papi L et al (1993) Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A. Nature 363(6428):458–460
Wallace MR, Marchuk DA, Andersen LB, Letcher R, Odeh HM, Saulino AM, Fountain JW, Brereton A, Nicholson J, Mitchell AL et al (1990) Type 1 neurofibromatosis gene: identification of a large transcript disrupted in three NF1 patients. Science 249(4965):181–186
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 (2010) Germline mutations in TMEM127 confer susceptibility to pheochromocytoma. Nat Genet 42(3):229–233. Epub 2010 Feb 2014
Comino-Mendez I, Gracia-Aznarez FJ, Schiavi F, Landa I, Leandro-Garcia LJ, Leton R, Honrado E, Ramos-Medina R, Caronia D, Pita G, Gomez-Grana A, de Cubas AA, Inglada-Perez L, Maliszewska A, Taschin E, Bobisse S, Pica G, Loli P, Hernandez-Lavado R, Diaz JA, Gomez-Morales M, Gonzalez-Neira A, Roncador G, Rodriguez-Antona C, Benitez J, Mannelli M, Opocher G, Robledo M, Cascon A (2011) Exome sequencing identifies MAX mutations as a cause of hereditary pheochromocytoma. Nat Genet 43(7):663–667. doi:10.1038/ng.861
Nair SK, Burley SK (2003) X-ray structures of Myc-Max and Mad-Max recognizing DNA. Molecular bases of regulation by proto-oncogenic transcription factors. Cell 112(2):193–205
Cascon A, Robledo M (2012) MAX and MYC: a heritable breakup. Cancer Res 72(13):3119–3124. Epub 2012 Jun 3115
Nesbit CE, Tersak JM, Prochownik EV (1999) MYC oncogenes and human neoplastic disease. Oncogene 18(19):3004–3016
Piccini V, Rapizzi E, Bacca A, Di Trapani G, Pulli R, Giache V, Zampetti B, Lucci-Cordisco E, Canu L, Corsini E, Faggiano A, Deiana L, Carrara D, Tantardini V, Mariotti S, Ambrosio MR, Zatelli MC, Parenti G, Colao A, Pratesi C, Bernini G, Ercolino T, Mannelli M (2012) Head and neck paragangliomas: genetic spectrum and clinical variability in 79 consecutive patients. Endocr Relat Cancer 12:12
Peczkowska M, Kowalska A, Sygut J, Waligorski D, Malinoc A, Janaszek-Sitkowska H, Prejbisz A, Januszewicz A, Neumann HP (2013) Testing new susceptibility genes in the cohort of apparently sporadic pheochromocytoma/paraganglioma patients with clinical characteristics of hereditary syndromes. Clin Endocrinol 1(10):12218
Eisenhofer G, Walther MM, Huynh TT, Li ST, Bornstein SR, Vortmeyer A, Mannelli M, Goldstein DS, Linehan WM, Lenders JW, Pacak K (2001) Pheochromocytomas in von Hippel-Lindau syndrome and multiple endocrine neoplasia type 2 display distinct biochemical and clinical phenotypes. J Clin Endocrinol Metab 86(5):1999–2008
Muth A, Abel F, Jansson S, Nilsson O, Ahlman H, Wangberg B (2012) Prevalence of germline mutations in patients with pheochromocytoma or abdominal paraganglioma and sporadic presentation: a population-based study in Western sweden. World J Surg 36(6):1389–1394
Akerstrom T, Crona J, Delgado Verdugo A, Starker LF, Cupisti K, Willenberg HS, Knoefel WT, Saeger W, Feller A, Ip J, Soon P, Anlauf M, Alesina PF, Schmid KW, Decaussin M, Levillain P, Wangberg B, Peix JL, Robinson B, Zedenius J, Backdahl M, Caramuta S, Iwen KA, Botling J, Stalberg P, Kraimps JL, Dralle H, Hellman P, Sidhu S, Westin G, Lehnert H, Walz MK, Akerstrom G, Carling T, Choi M, Lifton RP, Bjorklund P (2012) Comprehensive re-sequencing of adrenal aldosterone producing lesions reveal three somatic mutations near the KCNJ5 potassium channel selectivity filter. PLoS One 7(7):e41926. Epub 42012 Jul 41927
Crona J, Delgado Verdugo A, Granberg D, Welin S, Stalberg P, Hellman P, Bjorklund P (2013) Next generation sequencing in genetic screening of pheochromocytoma and paraganglioma. Endocr Connect. doi:10.1530/ec-13-0009
Acknowledgments
We thank professor Gunnar Westin for generously sharing research facilities and Mrs. Birgitta Bondesson for excellent technical assistance. Supported by grants from Swedish Cancer Society, Swedish Society for Medical Research, Selander Foundation, and Lions Cancer Foundation Uppsala. PB is a Swedish Cancer Society Investigator.
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The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research.
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Crona, J., Maharjan, R., Delgado Verdugo, A. et al. MAX mutations status in Swedish patients with pheochromocytoma and paraganglioma tumours. Familial Cancer 13, 121–125 (2014). https://doi.org/10.1007/s10689-013-9666-3
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DOI: https://doi.org/10.1007/s10689-013-9666-3