Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Exome sequencing identifies MAX mutations as a cause of hereditary pheochromocytoma


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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Detection of MAX by immunohistochemistry with a MAX C-terminus–specific antibody.
Figure 2: Loss of heterozygosity (LOH) analysis of three tumors with MAX mutations.
Figure 3: Schematic representation of MAX mutations found in individuals with PCC.

Similar content being viewed by others

Accession codes


Gene Expression Omnibus


  1. Neumann, H.P. et al. Germ-line mutations in nonsyndromic pheochromocytoma. N. Engl. J. Med. 346, 1459–1466 (2002).

    Article  CAS  Google Scholar 

  2. Hao, H.X. et al. SDH5, a gene required for flavination of succinate dehydrogenase, is mutated in paraganglioma. Science 325, 1139–1142 (2009).

    Article  CAS  Google Scholar 

  3. Yao, L. et al. Spectrum and prevalence of FP/TMEM127 gene mutations in pheochromocytomas and paragangliomas. J. Am. Med. Assoc. 304, 2611–2619 (2010).

    Article  CAS  Google Scholar 

  4. Burnichon, N. et al. SDHA is a tumor suppressor gene causing paraganglioma. Hum. Mol. Genet. 19, 3011–3020 (2010).

    Article  CAS  Google Scholar 

  5. Hopewell, R. & Ziff, E.B. The nerve growth factor-responsive PC12 cell line does not express the Myc dimerization partner Max. Mol. Cell. Biol. 15, 3470–3478 (1995).

    Article  CAS  Google Scholar 

  6. Kohl, N.E. et al. Transposition and amplification of oncogene-related sequences in human neuroblastomas. Cell 35, 359–367 (1983).

    Article  CAS  Google Scholar 

  7. Mannelli, M. et al. Clinically guided genetic screening in a large cohort of Italian patients with pheochromocytomas and/or functional or nonfunctional paragangliomas. J. Clin. Endocrinol. Metab. 94, 1541–1547 (2009).

    Article  CAS  Google Scholar 

  8. Cascón, A. et al. Genetics of pheochromocytoma and paraganglioma in Spanish patients. J. Clin. Endocrinol. Metab. 94, 1701–1705 (2009).

    Article  Google Scholar 

  9. Favier, J. et al. The Warburg effect is genetically determined in inherited pheochromocytomas. PLoS ONE 4, e7094 (2009).

    Article  Google Scholar 

  10. Dahia, P.L. et al. A HIF1α regulatory loop links hypoxia and mitochondrial signals in pheochromocytomas. PLoS Genet. 1, 72–80 (2005).

    Article  CAS  Google Scholar 

  11. López-Jiménez, E. et al. Research resource: transcriptional profiling reveals different pseudohypoxic signatures in SDHB and VHL-related pheochromocytomas. Mol. Endocrinol. 24, 2382–2391 (2010).

    Article  Google Scholar 

  12. Atchley, W.R. & Fitch, W.M. Myc and Max: molecular evolution of a family of proto-oncogene products and their dimerization partner. Proc. Natl. Acad. Sci. USA 92, 10217–10221 (1995).

    Article  CAS  Google Scholar 

  13. Grandori, C., Cowley, S.M., James, L.P. & Eisenman, R.N. The Myc/Max/Mad network and the transcriptional control of cell behavior. Annu. Rev. Cell Dev. Biol. 16, 653–699 (2000).

    Article  CAS  Google Scholar 

  14. Bousset, K., Henriksson, M., Luscher-Firzlaff, J.M., Litchfield, D.W. & Luscher, B. Identification of casein kinase II phosphorylation sites in Max: effects on DNA-binding kinetics of Max homo- and Myc/Max heterodimers. Oncogene 8, 3211–3220 (1993).

    CAS  PubMed  Google Scholar 

  15. Prendergast, G.C., Hopewell, R., Gorham, B.J. & Ziff, E.B. Biphasic effect of Max on Myc cotransformation activity and dependence on amino- and carboxy-terminal Max functions. Genes Dev. 6, 2429–2439 (1992).

    Article  CAS  Google Scholar 

  16. Ribon, V., Leff, T. & Saltiel, A.R. c-Myc does not require max for transcriptional activity in PC-12 cells. Mol. Cell. Neurosci. 5, 277–282 (1994).

    Article  CAS  Google Scholar 

  17. Segouffin-Cariou, C. & Billaud, M. Transforming ability of MEN2A-RET requires activation of the phosphatidylinositol 3-kinase/AKT signaling pathway. J. Biol. Chem. 275, 3568–3576 (2000).

    Article  CAS  Google Scholar 

  18. Johannessen, C.M. et al. The NF1 tumor suppressor critically regulates TSC2 and mTOR. Proc. Natl. Acad. Sci. USA 102, 8573–8578 (2005).

    Article  CAS  Google Scholar 

  19. Qin, Y. et al. Germline mutations in TMEM127 confer susceptibility to pheochromocytoma. Nat. Genet. 42, 229–233 (2010).

    Article  CAS  Google Scholar 

  20. Zhu, J., Blenis, J. & Yuan, J. Activation of PI3K/Akt and MAPK pathways regulates Myc-mediated transcription by phosphorylating and promoting the degradation of Mad1. Proc. Natl. Acad. Sci. USA 105, 6584–6589 (2008).

    Article  CAS  Google Scholar 

  21. Jimenez, R.H. et al. Regulation of gene expression in hepatic cells by the mammalian Target of Rapamycin (mTOR). PLoS ONE 5, e9084 (2010).

    Article  Google Scholar 

  22. Vaqué, J.P. et al. c-Myc inhibits Ras-mediated differentiation of pheochromocytoma cells by blocking c-Jun up-regulation. Mol. Cancer Res. 6, 325–339 (2008).

    Article  Google Scholar 

  23. Nair, S.K. & Burley, S.K. X-ray structures of Myc-Max and Mad-Max recognizing DNA. Molecular bases of regulation by proto-oncogenic transcription factors. Cell 112, 193–205 (2003).

    Article  CAS  Google Scholar 

  24. Dang, C.V., McGuire, M., Buckmire, M. & Lee, W.M. Involvement of the 'leucine zipper' region in the oligomerization and transforming activity of human c-myc protein. Nature 337, 664–666 (1989).

    Article  CAS  Google Scholar 

  25. Teh, M.T. et al. Genomewide single nucleotide polymorphism microarray mapping in basal cell carcinomas unveils uniparental disomy as a key somatic event. Cancer Res. 65, 8597–8603 (2005).

    Article  CAS  Google Scholar 

  26. Murthy, S.K., DiFrancesco, L.M., Ogilvie, R.T. & Demetrick, D.J. Loss of heterozygosity associated with uniparental disomy in breast carcinoma. Mod. Pathol. 15, 1241–1250 (2002).

    Article  Google Scholar 

  27. Tiu, R.V. et al. New lesions detected by single nucleotide polymorphism array-based chromosomal analysis have important clinical impact in acute myeloid leukemia. J. Clin. Oncol. 27, 5219–5226 (2009).

    Article  Google Scholar 

  28. Kurosawa, K. et al. Paternal UPD14 is responsible for a distinctive malformation complex. Am. J. Med. Genet. 110, 268–272 (2002).

    Article  Google Scholar 

  29. Wilson, M. et al. The clinical phenotype of mosaicism for genome-wide paternal uniparental disomy: two new reports. Am. J. Med. Genet. A. 146A, 137–148 (2008).

    Article  CAS  Google Scholar 

  30. Baysal, B.E. et al. Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma. Science 287, 848–851 (2000).

    Article  CAS  Google Scholar 

  31. Sambrook, J., Maniatis, T. & Fritsch, E.F. Molecular Cloning: A Laboratory Manual, 3 v. (Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, 1989).

  32. Li, H. et al. The Sequence Alignment/Map format and SAMtools. Bioinformatics 25, 2078–2079 (2009).

    Article  Google Scholar 

  33. Wang, K., Li, M. & Hakonarson, H. ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res. 38, e164 (2010).

    Article  Google Scholar 

  34. Simon-Sanchez, J. et al. Genome-wide SNP assay reveals structural genomic variation, extended homozygosity and cell-line induced alterations in normal individuals. Hum. Mol. Genet. 16, 1–14 (2007).

    Article  CAS  Google Scholar 

  35. Cascón, A. et al. Gross SDHB deletions in patients with paraganglioma detected by multiplex PCR: a possible hot spot? Genes Chromosom. Cancer 45, 213–219 (2006).

    Article  Google Scholar 

  36. Astuti, D. et al. Epigenetic alteration at the DLK1–GTL2 imprinted domain in human neoplasia: analysis of neuroblastoma, phaeochromocytoma and Wilms' tumour. Br. J. Cancer 92, 1574–1580 (2005).

    Article  CAS  Google Scholar 

  37. Landa, I. et al. Allelic variant at -79 (C>T) in CDKN1B (p27Kip1) confers an increased risk of thyroid cancer and alters mRNA levels. Endocr. Relat. Cancer 17, 317–328 (2010).

    Article  CAS  Google Scholar 

Download references


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

Authors and Affiliations



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.

Corresponding authors

Correspondence to Mercedes Robledo or Alberto Cascón.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–4 and Supplementary Tables 1–3. (PDF 315 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Comino-Méndez, I., Gracia-Aznárez, F., Schiavi, F. et al. Exome sequencing identifies MAX mutations as a cause of hereditary pheochromocytoma. Nat Genet 43, 663–667 (2011).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

This article is cited by


Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer