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, 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

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)E687-E693
JournalJournal of Clinical Endocrinology and Metabolism
Volume97
Issue number4
DOIs
StatePublished - Apr 1 2012

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Endocrinology
  • Clinical Biochemistry
  • Biochemistry, medical

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    Almeida, M. Q., Azevedo, M. F., Xekouki, P., Bimpaki, E. I., Horvath, A., Collins, M. T., Karaviti, L. P., Jeha, G. S., Bhattacharyya, N., Cheadle, C., Watkins, T., Bourdeau, I., Nesterova, M., & Stratakis, C. A. (2012). 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. Journal of Clinical Endocrinology and Metabolism, 97(4), E687-E693. https://doi.org/10.1210/jc.2011-3000