Skip to main content

Thank you for visiting nature.com. 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.

Recurrent activating mutation in PRKACA in cortisol-producing adrenal tumors

Nature Genetics volume 46, pages 613–617 (2014)Cite this article

Subjects

A Corrigendum to this article was published on 26 June 2014

A Corrigendum to this article was published on 26 June 2014

This article has been updated

Abstract

Adrenal tumors autonomously producing cortisol cause Cushing's syndrome1,2,3,4. We performed exome sequencing of 25 tumor-normal pairs and identified 2 subgroups. Eight tumors (including three carcinomas) had many somatic copy number variants (CNVs) with frequent deletion of CDC42 and CDKN2A, amplification of 5q31.2 and protein-altering mutations in TP53 and RB1. Seventeen tumors (all adenomas) had no somatic CNVs or TP53 or RB1 mutations. Six of these had known gain-of-function mutations in CTNNB1 (β-catenin)5,6 or GNAS (Gαs)7,8. Six others had somatic mutations in PRKACA (protein kinase A (PKA) catalytic subunit) resulting in a p.Leu206Arg substitution. Further sequencing identified this mutation in 13 of 63 tumors (35% of adenomas with overt Cushing's syndrome). PRKACA, GNAS and CTNNB1 mutations were mutually exclusive. Leu206 directly interacts with the regulatory subunit of PKA, PRKAR1A9,10. Leu206Arg PRKACA loses PRKAR1A binding, increasing the phosphorylation of downstream targets. PKA activity induces cortisol production and cell proliferation11,12,13,14,15, providing a mechanism for tumor development. These findings define distinct mechanisms underlying adrenal cortisol-producing tumors.

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

Access options

Rent or buy this article

Get just this article for as long as you need it

$39.95

Learn more

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

Figure 1: Somatic mutations in cortisol-producing adrenal tumors.
Figure 2: PRKACA Leu206 interacts with PRKAR1A.
Figure 3: PRKACA L206R does not bind the regulatory subunit and results in increased phosphorylation of CREB and ATF1.

Accession codes

Primary accessions

Gene Expression Omnibus

Referenced accessions

NCBI Reference Sequence

Protein Data Bank

Change history

  • 05 June 2014

    In the version of this article initially published, the name of author John W. Kunstman was misspelled. The error has been corrected in the HTML and PDF versions of the article.

References

  1. Hatipoglu, B.A. Cushing's syndrome. J. Surg. Oncol. 106, 565–571 (2012).

    Article  CAS  PubMed  Google Scholar 

  2. Orth, D.N. Cushing's syndrome. N. Engl. J. Med. 332, 791–803 (1995).

    Article  CAS  PubMed  Google Scholar 

  3. Biller, B.M. et al. Treatment of adrenocorticotropin-dependent Cushing's syndrome: a consensus statement. J. Clin. Endocrinol. Metab. 93, 2454–2462 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Chiodini, I. Clinical review: diagnosis and treatment of subclinical hypercortisolism. J. Clin. Endocrinol. Metab. 96, 1223–1236 (2011).

    Article  CAS  PubMed  Google Scholar 

  5. El Wakil, A. & Lalli, E. The Wnt/β-catenin pathway in adrenocortical development and cancer. Mol. Cell. Endocrinol. 332, 32–37 (2011).

    Article  CAS  PubMed  Google Scholar 

  6. Tissier, F. et al. Mutations of β-catenin in adrenocortical tumors: activation of the Wnt signaling pathway is a frequent event in both benign and malignant adrenocortical tumors. Cancer Res. 65, 7622–7627 (2005).

    Article  CAS  PubMed  Google Scholar 

  7. Almeida, M.Q. & Stratakis, C.A. How does cAMP/protein kinase A signaling lead to tumors in the adrenal cortex and other tissues? Mol. Cell. Endocrinol. 336, 162–168 (2011).

    Article  CAS  PubMed  Google Scholar 

  8. Fragoso, M.C. et al. Cushing's syndrome secondary to adrenocorticotropin-independent macronodular adrenocortical hyperplasia due to activating mutations of GNAS1 gene. J. Clin. Endocrinol. Metab. 88, 2147–2151 (2003).

    Article  CAS  PubMed  Google Scholar 

  9. Kim, C., Xuong, N.H. & Taylor, S.S. Crystal structure of a complex between the catalytic and regulatory (RIα) subunits of PKA. Science 307, 690–696 (2005).

    Article  CAS  PubMed  Google Scholar 

  10. Ubersax, J.A. & Ferrell, J.E. Jr. Mechanisms of specificity in protein phosphorylation. Nat. Rev. Mol. Cell Biol. 8, 530–541 (2007).

    Article  CAS  PubMed  Google Scholar 

  11. Bertherat, J. et al. Molecular and functional analysis of PRKAR1A and its locus (17q22-24) in sporadic adrenocortical tumors: 17q losses, somatic mutations, and protein kinase A expression and activity. Cancer Res. 63, 5308–5319 (2003).

    CAS  PubMed  Google Scholar 

  12. Casey, M. et al. Mutations in the protein kinase A R1α regulatory subunit cause familial cardiac myxomas and Carney complex. J. Clin. Invest. 106, R31–R38 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Cazabat, L., Ragazzon, B., Groussin, L. & Bertherat, J. PRKAR1A mutations in primary pigmented nodular adrenocortical disease. Pituitary 9, 211–219 (2006).

    Article  CAS  PubMed  Google Scholar 

  14. Cho-Chung, Y.S., Pepe, S., Clair, T., Budillon, A. & Nesterova, M. cAMP-dependent protein kinase: role in normal and malignant growth. Crit. Rev. Oncol. Hematol. 21, 33–61 (1995).

    Article  CAS  PubMed  Google Scholar 

  15. Kirschner, L.S. et al. Genetic heterogeneity and spectrum of mutations of the PRKAR1A gene in patients with the Carney complex. Hum. Mol. Genet. 9, 3037–3046 (2000).

    Article  CAS  PubMed  Google Scholar 

  16. Saffran, M. Mechanisms of adrenocortical control. Br. Med. Bull. 18, 122–126 (1962).

    Article  CAS  PubMed  Google Scholar 

  17. Stocco, D.M. & Clark, B.J. Regulation of the acute production of steroids in steroidogenic cells. Endocr. Rev. 17, 221–244 (1996).

    CAS  PubMed  Google Scholar 

  18. Gillies, G.E., Linton, E.A. & Lowry, P.J. Corticotropin releasing activity of the new CRF is potentiated several times by vasopressin. Nature 299, 355–357 (1982).

    Article  CAS  PubMed  Google Scholar 

  19. Rivier, C. & Vale, W. Modulation of stress-induced ACTH release by corticotropin-releasing factor, catecholamines and vasopressin. Nature 305, 325–327 (1983).

    Article  CAS  PubMed  Google Scholar 

  20. Ramachandran, J., Tsubokawa, M. & Gohil, K. Corticotropin receptors. Ann. NY Acad. Sci. 512, 415–425 (1987).

    Article  CAS  PubMed  Google Scholar 

  21. Simpson, E.R. & Waterman, M.R. Regulation of the synthesis of steroidogenic enzymes in adrenal cortical cells by ACTH. Annu. Rev. Physiol. 50, 427–440 (1988).

    Article  CAS  PubMed  Google Scholar 

  22. Roger, P.P., Reuse, S., Maenhaut, C. & Dumont, J.E. Multiple facets of the modulation of growth by cAMP. Vitam. Horm. 51, 59–191 (1995).

    Article  CAS  PubMed  Google Scholar 

  23. Rosenberg, D. et al. Role of the PKA-regulated transcription factor CREB in development and tumorigenesis of endocrine tissues. Ann. NY Acad. Sci. 968, 65–74 (2002).

    Article  CAS  PubMed  Google Scholar 

  24. Newell-Price, J., Trainer, P., Besser, M. & Grossman, A. The diagnosis and differential diagnosis of Cushing's syndrome and pseudo-Cushing's states. Endocr. Rev. 19, 647–672 (1998).

    CAS  PubMed  Google Scholar 

  25. Almeida, M.Q. & Stratakis, C.A. Carney complex and other conditions associated with micronodular adrenal hyperplasias. Best Pract. Res. Clin. Endocrinol. Metab. 24, 907–914 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Horvath, A. et al. A genome-wide scan identifies mutations in the gene encoding phosphodiesterase 11A4 (PDE11A) in individuals with adrenocortical hyperplasia. Nat. Genet. 38, 794–800 (2006).

    Article  CAS  PubMed  Google Scholar 

  27. Horvath, A. et al. Adrenal hyperplasia and adenomas are associated with inhibition of phosphodiesterase 11A in carriers of PDE11A sequence variants that are frequent in the population. Cancer Res. 66, 11571–11575 (2006).

    Article  CAS  PubMed  Google Scholar 

  28. Nieman, L.K. et al. The diagnosis of Cushing's syndrome: an Endocrine Society Clinical Practice Guideline. J. Clin. Endocrinol. Metab. 93, 1526–1540 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Mermel, C.H. et al. GISTIC2.0 facilitates sensitive and confident localization of the targets of focal somatic copy-number alteration in human cancers. Genome Biol. 12, R41 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Tömböl, Z. et al. Integrative molecular bioinformatics study of human adrenocortical tumors: microRNA, tissue-specific target prediction, and pathway analysis. Endocr. Relat. Cancer 16, 895–906 (2009).

    Article  CAS  PubMed  Google Scholar 

  31. Bonnet, S. et al. Wnt/β-catenin pathway activation in adrenocortical adenomas is frequently due to somatic CTNNB1-activating mutations, which are associated with larger and nonsecreting tumors: a study in cortisol-secreting and -nonsecreting tumors. J. Clin. Endocrinol. Metab. 96, E419–E426 (2011).

    Article  CAS  PubMed  Google Scholar 

  32. Zhu, J. et al. The UCSC Cancer Genomics Browser. Nat. Methods 6, 239–240 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Cancer Genome Atlas Network. Comprehensive molecular characterization of human colon and rectal cancer. Nature 487, 330–337 (2012).

  34. Cancer Genome Atlas Network. Comprehensive molecular portraits of human breast tumours. Nature 490, 61–70 (2012).

  35. Cancer Genome Atlas Research Network. Comprehensive genomic characterization of squamous cell lung cancers. Nature 489, 519–525 (2012).

  36. Hsiao, H.P. et al. Clinical and genetic heterogeneity, overlap with other tumor syndromes, and atypical glucocorticoid hormone secretion in adrenocorticotropin-independent macronodular adrenal hyperplasia compared with other adrenocortical tumors. J. Clin. Endocrinol. Metab. 94, 2930–2937 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Songyang, Z. et al. Use of an oriented peptide library to determine the optimal substrates of protein kinases. Curr. Biol. 4, 973–982 (1994).

    Article  CAS  PubMed  Google Scholar 

  38. Taylor, S.S. et al. Dynamics of signaling by PKA. Biochim. Biophys. Acta 1754, 25–37 (2005).

    Article  CAS  PubMed  Google Scholar 

  39. Zheng, J. et al. 2.2 A refined crystal structure of the catalytic subunit of cAMP-dependent protein kinase complexed with MnATP and a peptide inhibitor. Acta Crystallogr. D Biol. Crystallogr. 49, 362–365 (1993).

    Article  CAS  PubMed  Google Scholar 

  40. de Joussineau, C. et al. The cAMP pathway and the control of adrenocortical development and growth. Mol. Cell. Endocrinol. 351, 28–36 (2012).

    Article  CAS  PubMed  Google Scholar 

  41. Lania, A.G., Mantovani, G. & Spada, A. Mechanisms of disease: mutations of G proteins and G-protein-coupled receptors in endocrine diseases. Nat. Clin. Pract. Endocrinol. Metab. 2, 681–693 (2006).

    Article  CAS  PubMed  Google Scholar 

  42. Meoli, E. et al. Protein kinase A effects of an expressed PRKAR1A mutation associated with aggressive tumors. Cancer Res. 68, 3133–3141 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Choi, M. et al. K+ channel mutations in adrenal aldosterone-producing adenomas and hereditary hypertension. Science 331, 768–772 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Scholl, U.I. et al. Somatic and germline CACNA1D calcium channel mutations in aldosterone-producing adenomas and primary aldosteronism. Nat. Genet. 45, 1050–1054 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Scholl, U.I. et al. Hypertension with or without adrenal hyperplasia due to different inherited mutations in the potassium channel KCNJ5. Proc. Natl. Acad. Sci. USA 109, 2533–2538 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  46. Almeida, M.Q. et al. Mouse Prkar1a haploinsufficiency leads to an increase in tumors in the Trp53+/− or Rb1+/− backgrounds and chemically induced skin papillomas by dysregulation of the cell cycle and Wnt signaling. Hum. Mol. Genet. 19, 1387–1398 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Gaujoux, S. et al. Wnt/β-catenin and 3′,5′-cyclic adenosine 5′-monophosphate/protein kinase A signaling pathways alterations and somatic β-catenin gene mutations in the progression of adrenocortical tumors. J. Clin. Endocrinol. Metab. 93, 4135–4140 (2008).

    Article  CAS  PubMed  Google Scholar 

  48. Hino, S., Tanji, C., Nakayama, K.I. & Kikuchi, A. Phosphorylation of β-catenin by cyclic AMP–dependent protein kinase stabilizes β-catenin through inhibition of its ubiquitination. Mol. Cell. Biol. 25, 9063–9072 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Taurin, S., Sandbo, N., Qin, Y., Browning, D. & Dulin, N.O. Phosphorylation of β-catenin by cyclic AMP–dependent protein kinase. J. Biol. Chem. 281, 9971–9976 (2006).

    Article  CAS  PubMed  Google Scholar 

  50. Schinner, S. et al. Adipocyte-derived products induce the transcription of the StAR promoter and stimulate aldosterone and cortisol secretion from adrenocortical cells through the Wnt-signaling pathway. Int. J. Obes. (Lond.) 31, 864–870 (2007).

    Article  CAS  Google Scholar 

  51. Cancer Genome Atlas Research Network. Integrated genomic characterization of endometrial carcinoma. Nature 497, 67–73 (2013).

  52. Cleary, S.P. et al. Identification of driver genes in hepatocellular carcinoma by exome sequencing. Hepatology 58, 1693–1702 (2013).

    Article  CAS  PubMed  Google Scholar 

  53. Beuschlein, F. et al. Constitutive activation of PKA catalytic subunit in adrenal Cushing's syndrome. N. Engl. J. Med. 370, 1019–1028 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Zenkert, S. et al. Steroidogenic acute regulatory protein mRNA expression in adrenal tumours. Eur. J. Endocrinol. 142, 294–299 (2000).

    Article  CAS  PubMed  Google Scholar 

  55. Brauckhoff, M. et al. Peritoneal carcinosis in apparently benign cortisol producing adrenal adenoma ≥ 5 cm in diameter: the need of regular postoperative surveillance. Exp. Clin. Endocrinol. Diabetes 120, 472–476 (2012).

    Article  CAS  PubMed  Google Scholar 

  56. Almeida, M.Q. et al. Integrated genomic analysis of nodular tissue in macronodular adrenocortical hyperplasia: progression of tumorigenesis in a disorder associated with multiple benign lesions. J. Clin. Endocrinol. Metab. 96, E728–E738 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Heaton, J.H. et al. Progression to adrenocortical tumorigenesis in mice and humans through insulin-like growth factor 2 and β-catenin. Am. J. Pathol. 181, 1017–1033 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Ronchi, C.L. et al. Single nucleotide polymorphism array profiling of adrenocortical tumors—evidence for an adenoma carcinoma sequence? PLoS ONE 8, e73959 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Dhanasekaran, N., Heasley, L.E. & Johnson, G.L. G protein–coupled receptor systems involved in cell growth and oncogenesis. Endocr. Rev. 16, 259–270 (1995).

    Article  CAS  PubMed  Google Scholar 

  60. Lau, S.K. & Weiss, L.M. The Weiss system for evaluating adrenocortical neoplasms: 25 years later. Hum. Pathol. 40, 757–768 (2009).

    Article  PubMed  Google Scholar 

  61. Duregon, E. et al. Oncocytic adrenocortical tumors: diagnostic algorithm and mitochondrial DNA profile in 27 cases. Am. J. Surg. Pathol. 35, 1882–1893 (2011).

    Article  PubMed  Google Scholar 

  62. Lawrence, M.S. et al. Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature 499, 214–218 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Farrell, C.M. et al. Current status and new features of the Consensus Coding Sequence database. Nucleic Acids Res. 42, D865–D872 (2014).

    Article  CAS  PubMed  Google Scholar 

  64. Kim, D. et al. TopHat2: accurate alignment of transcriptomes in the presence of insertions, deletions and gene fusions. Genome Biol. 14, R36 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Trapnell, C. et al. Differential analysis of gene regulation at transcript resolution with RNA-seq. Nat. Biotechnol. 31, 46–53 (2013).

    Article  CAS  PubMed  Google Scholar 

  66. Shibata, S., Zhang, J., Puthumana, J., Stone, K.L. & Lifton, R.P. Kelch-like 3 and Cullin 3 regulate electrolyte homeostasis via ubiquitination and degradation of WNK4. Proc. Natl. Acad. Sci. USA 110, 7838–7843 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported in part by the US National Institutes of Health (NIH) Centers for Mendelian Genomics (5U54HG006504). G.G. is supported by the Agency for Science, Technology and Research of Singapore. T.C. is a Damon Runyon Clinical Investigator supported in part by the Damon Runyon Cancer Research Foundation. R.P.L. is an investigator of the Howard Hughes Medical Institute.

Author information

Authors and Affiliations

  1. Department of Genetics, Yale University School of Medicine, New Haven, Connecticut, USA

    Gerald Goh, Ute I Scholl, Murim Choi, Carol Nelson-Williams & Richard P Lifton

  2. Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut, USA

    Gerald Goh, Ute I Scholl, Murim Choi, Carol Nelson-Williams & Richard P Lifton

  3. Division of Nephrology, University Hospital Düsseldorf, Düsseldorf, Germany

    Ute I Scholl

  4. Department of Surgery, Yale Endocrine Neoplasia Laboratory, Yale University School of Medicine, New Haven, Connecticut, USA

    James M Healy, John W Kunstman, Reju Korah & Tobias Carling

  5. Yale Center for Mendelian Genomics, New Haven, Connecticut, USA

    Murim Choi & Richard P Lifton

  6. Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, USA

    Manju L Prasad

  7. Department of Pathology, University Hospital Düsseldorf, Düsseldorf, Germany

    Anna-Carinna Suttorp

  8. Institute of Pathology, University of Bonn, Bonn, Germany

    Dimo Dietrich

  9. Division of Endocrinology and Diabetology, University Hospital Düsseldorf, Düsseldorf, Germany

    Matthias Haase & Holger S Willenberg

  10. Department of Surgical Sciences, Uppsala University, Uppsala, Sweden

    Peter Stålberg, Per Hellman, Göran Åkerström & Peyman Björklund

  11. Yale Cancer Center, Yale University School of Medicine, New Haven, Connecticut, USA

    Tobias Carling

Authors
  1. Gerald Goh
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ute I Scholl
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. James M Healy
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Murim Choi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Manju L Prasad
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Carol Nelson-Williams
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. John W Kunstman
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Reju Korah
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Anna-Carinna Suttorp
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Dimo Dietrich
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Matthias Haase
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Holger S Willenberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Peter Stålberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Per Hellman
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Göran Åkerström
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Peyman Björklund
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Tobias Carling
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Richard P Lifton
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

U.I.S., J.M.H., M.L.P., J.W.K., R.K., A.-C.S., D.D., M.H., H.S.W., P.S., P.H., P.B., G.Å. and T.C. ascertained and recruited subjects and obtained samples and medical records. U.I.S., R.K., P.B. and C.N.-W. prepared DNA and RNA samples and maintained sample archives. G.G. performed and analyzed targeted DNA and RNA sequencing. G.G., M.C. and R.P.L. analyzed exome sequencing and RNA sequencing results. G.G. generated constructs and performed immunoprecipitation and protein blot analysis. G.G. and J.M.H. performed immunohistochemistry. G.G. and M.L.P. reviewed histology and immunohistochemistry. G.G., U.I.S. and R.P.L. wrote the manuscript.

Corresponding author

Correspondence to Richard P Lifton.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Integrated supplementary information

Supplementary Figure 1 Overview of copy number variants in CNV-positive tumors.

Frequency of gains (red) and losses (blue) plotted across genome.

Supplementary Figure 2 Significant, focal CNVs in tumors.

Left, deletions in blue. Right, amplifications in red. The green line signifies the threshold for significance, q = 0.25.

Supplementary Figure 3 RNA-seq of a PRKACA-mutant tumor.

Both wild-type (A) and mutant (C) alleles are detected in the tumor, as shown in the position highlighted.

Supplementary Figure 4 Increased levels of phosphorylated CREB in PRKACA-mutant tumors.

Representative images of PRKACA-mutant tumor and wild-type tumor (no mutation in PRKACA, CTNNB1 or GNAS) stained for CREB phosphorylated at Ser133. Intense nuclear-specific staining is observed in the majority of the nuclei in the mutant tumor (a) but not in the wild-type tumor (b). Scale bars represent 60 μm.

Supplementary Figure 5 Histology of PRKACA-mutant tumors.

All tumors reviewed with PRKACA mutations (n = 6) were well-defined, solitary adrenal cortical nodules with well-differentiated morphology. The majority of these tumors had low-grade nuclei (5/6), and none of the tumors showed fibrosis, necrosis, mitosis and hemorrhage, consistent with benign adenomas. (a) 2.6-cm cortisol-secreting adrenal cortical adenoma showing a bright yellow and brown cut surface that corresponds to its cellular composition as shown in b. The ruler is in centimeters and millimeters. (b) The tumor comprises lipid-rich clear cells (filled arrow) and oncocytic cells (open arrow) with granular eosinophilic cytoplasm. The scale bar represents 60 μm.

Supplementary Figure 6 Model for cortisol-producing adrenal tumor formation due to gain-of-function mutation in PRKACA.

(a) In quiescent adrenal fasciculata cells, protein kinase A exists as an inactive tetramer, with the catalytic subunits bound to a dimer of regulatory subunits. (b) ACTH binds to its receptor, melanocortin receptor 2, which stimulates adenylyl cyclase via Gas, leading to an increase in intracellular cAMP levels. cAMP binds to the regulatory subunits, causing the release of the catalytic subunits and downstream signaling, which leads to cell proliferation and cortisol production. (c) The mutant catalytic subunits are not bound by the regulatory subunit and are thus constitutively active in the absence of external stimuli. The resulting uncontrolled cell proliferation and cortisol production lead to the formation of a cortisol-producing adrenal tumor. MC2, melanocortin receptor 2; AC, adenylyl cyclase; R, regulatory subunit; C, catalytic subunit.

Supplementary information

Supplementary Text and Figures

Supplementary Tables 1–7 and Supplementary Figures 1–6 (PDF 5510 kb)

Rights and permissions

Reprints and Permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Goh, G., Scholl, U., Healy, J. et al. Recurrent activating mutation in PRKACA in cortisol-producing adrenal tumors. Nat Genet 46, 613–617 (2014). https://doi.org/10.1038/ng.2956

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng.2956

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing