Exome sequencing identifies MAX mutations as a cause of hereditary pheochromocytoma

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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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.

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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.

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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.

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Correspondence to Mercedes Robledo or Alberto Cascón.

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The authors declare no competing financial interests.

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

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

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