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Comparative Study
. 2012 Apr;97(4):E687-93.
doi: 10.1210/jc.2011-3000. Epub 2012 Jan 18.

Activation of cyclic AMP signaling leads to different pathway alterations in lesions of the adrenal cortex caused by germline PRKAR1A defects versus those due to somatic GNAS mutations

Madson Q Almeida  1 , Monalisa F Azevedo, Paraskevi Xekouki, Eirini I Bimpaki, Anelia Horvath, Michael T Collins, Lefkothea P Karaviti, George S Jeha, Nisan Bhattacharyya, Chris Cheadle, Tonya Watkins, Isabelle Bourdeau, Maria Nesterova, Constantine A Stratakis
Affiliations
Comparative Study

Activation of cyclic AMP signaling leads to different pathway alterations in lesions of the adrenal cortex caused by germline PRKAR1A defects versus those due to somatic GNAS mutations

Madson Q Almeida et al. J Clin Endocrinol Metab. 2012 Apr.

Abstract

Context: The overwhelming majority of benign lesions of the adrenal cortex leading to Cushing syndrome are linked to one or another abnormality of the cAMP or protein kinase pathway. PRKAR1A-inactivating mutations are responsible for primary pigmented nodular adrenocortical disease, whereas somatic GNAS activating mutations cause macronodular disease in the context of McCune-Albright syndrome, ACTH-independent macronodular hyperplasia, and, rarely, cortisol-producing adenomas.

Objective and design: The whole-genome expression profile (WGEP) of normal (pooled) adrenals, PRKAR1A- (3) and GNAS-mutant (3) was studied. Quantitative RT-PCR and Western blot were used to validate WGEP findings.

Results: MAPK and p53 signaling pathways were highly overexpressed in all lesions against normal tissue. GNAS-mutant tissues were significantly enriched for extracellular matrix receptor interaction and focal adhesion pathways when compared with PRKAR1A-mutant (fold enrichment 3.5, P < 0.0001 and 2.1, P < 0.002, respectively). NFKB, NFKBIA, and TNFRSF1A were higher in GNAS-mutant tumors (P < 0.05). Genes related to the Wnt signaling pathway (CCND1, CTNNB1, LEF1, LRP5, WISP1, and WNT3) were overexpressed in PRKAR1A-mutant lesions.

Conclusion: WGEP analysis revealed that not all cAMP activation is the same: adrenal lesions harboring PRKAR1A or GNAS mutations share the downstream activation of certain oncogenic signals (such as MAPK and some cell cycle genes) but differ substantially in their effects on others.

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Figures

Fig. 1.
Fig. 1.
A, Functional analysis of whole-genome transcriptome profiling of PPNAD and adrenal masses harboring the GNAS mutation. The array functional analysis was performed using DAVID Bioinformatics Resources 2008, National Institute of Allergy and Infectious Diseases, National Institutes of Health (http://david.abcc.ncifcrf.gov/home.jsp). B, Expression of NFKB1, RAB13, EPAC2 and BMP4 in the GNAS mutant lesions compared with PPNAD by quantitative PCR. C, NFKB1, IKBa, and RAB13 proteins by Western blot. D, NFKB1 and IKBa staining was stronger in AIMAH/MMAD with the R201H GNAS mutation than in a PRKAR1A-mutant PPNAD. IMAH, ACTH-independent macronodular adrenocortical hyperplasia; GAPDH, glyceraldehyde-3-phosphate dehydrogenase.
Fig. 2.
Fig. 2.
A, Basal and cAMP-stimulated PKA activity in PRKAR1A- and GNAS-mutant lesions. B, A qRT-PCR array including 84 genes involved in Wnt signaling demonstrated that key oncogenes were overexpressed in PRKAR1A- vs. GNAS-mutant lesions. C and D, β-Catenin staining was strong in both PRKAR1A- and GNAS-mutant lesions, but interestingly only in nodules in the former.
See this image and copyright information in PMC

References

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