Abstract

Hereditary pheochromocytoma (PCC) is often caused by germline mutations in one of nine susceptibility genes described to date1,2,3,4, but there are familial cases without mutations in these known genes. We sequenced the exomes of three unrelated individuals with hereditary PCC (cases) and identified mutations in MAX, the MYC associated factor X gene. Absence of MAX protein in the tumors and loss of heterozygosity caused by uniparental disomy supported the involvement of MAX alterations in the disease. A follow-up study of a selected series of 59 cases with PCC identified five additional MAX mutations and suggested an association with malignant outcome and preferential paternal transmission of MAX mutations. The involvement of the MYC-MAX-MXD1 network in the development and progression of neural crest cell tumors is further supported by the lack of functional MAX in rat PCC (PC12) cells5 and by the amplification of MYCN in neuroblastoma6 and suggests that loss of MAX function is correlated with metastatic potential.

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Acknowledgements

This work was supported in part by the Fondo de Investigaciones Sanitarias (projects PS09/00942 and P1080883 to A.C. and M.R., respectively), Mutua Madrileña (project AP2775/2008 to M.R.), FP7-Grant (ENS@T-CANCER; HEALTH-F2-2010-259735) and Innovation project INTRA-706-2 ISCIII CIBER-ER (Center for Biomedical Research on Rare Diseases). I.C.-M. holds a shuttle CIBER-ER fellowship.

Author information

Author notes

    • Iñaki Comino-Méndez
    • , Francisco J Gracia-Aznárez
    •  & Francesca Schiavi

    These authors contributed equally to this work.

Affiliations

  1. Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.

    • Iñaki Comino-Méndez
    • , Iñigo Landa
    • , Luis J Leandro-García
    • , Rocío Letón
    • , Álvaro Gómez-Graña
    • , Aguirre A de Cubas
    • , Lucía Inglada-Pérez
    • , Agnieszka Maliszewska
    • , Cristina Rodríguez-Antona
    • , Mercedes Robledo
    •  & Alberto Cascón
  2. Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain.

    • Iñaki Comino-Méndez
    • , Francisco J Gracia-Aznárez
    • , Lucía Inglada-Pérez
    • , Cristina Rodríguez-Antona
    • , Javier Benítez
    • , Mercedes Robledo
    •  & Alberto Cascón
  3. Human Genetics Group, Spanish National Cancer Research Centre, Madrid, Spain.

    • Francisco J Gracia-Aznárez
    •  & Javier Benítez
  4. Familial Cancer Clinic, Veneto Institute of Oncology, Padova, Italy.

    • Francesca Schiavi
    • , Elisa Taschin
    • , Sara Bobisse
    •  & Giuseppe Opocher
  5. Anatomical Pathology Service, Hospital de León, León, Spain.

    • Emiliano Honrado
  6. Monoclonal Antibodies Unit, Biotechnology Programme, Spanish National Cancer Research Centre, Madrid, Spain.

    • Rocío Ramos-Medina
    •  & Giovanna Roncador
  7. Human Genotyping Unit-CeGen, Human Cancer Genetics Programme, Spanish National Cancer Centre, Madrid, Spain.

    • Daniela Caronia
    • , Guillermo Pita
    •  & Anna González-Neira
  8. Endocrinology and Metabolic Diseases, University of Foggia, Foggia, Italy.

    • Giuseppe Pica
  9. Department of Endocrinology, Ospedale Niguarda Ca' Granda, Milan, Italy.

    • Paola Loli
  10. Endocrinology Section, Hospital Infanta Cristina, Badajoz, Spain.

    • Rafael Hernández-Lavado
  11. Department of Endocrinology, Hospital Universitario Clínico San Carlos, Madrid, Spain.

    • José A Díaz
  12. Department of Pathology, University Hospital, University of Granada, Granada, Spain.

    • Mercedes Gómez-Morales
  13. Department of Clinical Pathophysiology, University of Florence and Istituto Toscano Tumori, Florence, Italy.

    • Massimo Mannelli
  14. Department of Medical and Surgical Sciences, University of Padova, Padova, Italy.

    • Giuseppe Opocher

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Contributions

A.C., M.R., F.S. and G.O. conceived the project. G. Pica, P.L., R.H.-L., J.A.D., M.G.-M. and M.M. collected tumor samples. F.J.G.-A., I.C.-M. and A.C. performed next-generation sequencing analysis and filtering. I.C.-M., F.J.G.-A., F.S., I.L., L.J.L.-G., R.L., R.R.-M., D.C., A.G.-G., A.A.d.C., L.I.-P., E.T., S.B., A.M., A.G.-N. and G.R. performed additional experiments. A.C., I.C.-M., E.H. and G. Pita performed additional data analysis. A.C., I.C.-M., F.J.G.-A., M.R., C.R.-A. and J.B. wrote the manuscript. All authors approved the final draft.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Mercedes Robledo or Alberto Cascón.

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https://doi.org/10.1038/ng.861

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