Sarah J Larkin1, Francesco Ferraù2, Niki Karavitaki2, Laura C Hernández-Ramírez2, Olaf Ansorge2, Ashley B Grossman2, Márta Korbonits2. 1. Nuffield Department of Clinical NeurosciencesDepartment of Neuropathology, Level 1 West Wing, John Radcliffe Hospital, Headley Way, Oxford OX3 9DU, UKDepartment of EndocrinologyBarts and London School of Medicine, Queen Mary University of London, London EC1A 6BQ, UKDepartment of EndocrinologyOxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Old Road, Headington, Oxford OX3 7LE, UK sarah.larkin@ndcn.ox.ac.uk. 2. Nuffield Department of Clinical NeurosciencesDepartment of Neuropathology, Level 1 West Wing, John Radcliffe Hospital, Headley Way, Oxford OX3 9DU, UKDepartment of EndocrinologyBarts and London School of Medicine, Queen Mary University of London, London EC1A 6BQ, UKDepartment of EndocrinologyOxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Old Road, Headington, Oxford OX3 7LE, UK.
Abstract
OBJECTIVE: The pathogenetic mechanisms of sporadic somatotroph adenomas are not well understood, but derangements of the cAMP pathway have been implicated. Recent studies have identified L206R mutations in the alpha catalytic subunit of protein kinase A (PRKACA) in cortisol-producing adrenocortical adenomas and amplification of the beta catalytic subunit of protein kinase A PRKACB in acromegaly associated with Carney complex. Given that both adrenocortical adenomas and somatotroph adenomas are known to be reliant on the cAMP signalling pathway, we sought to determine the relevance of the L206R mutation in both PRKACA and PRKACB for the pathogenesis of sporadic somatotroph adenomas. DESIGN: Somatotroph adenoma specimens, both frozen and formalin-fixed, from patients who underwent surgery for their acromegaly between 1995 and 2012, were used in the study. METHODS: The DNA sequence at codon 206 of PRKACA and PRKACB was determined by PCR amplification and sequencing. The results were compared with patient characteristics, the mutational status of the GNAS complex locus and the tumour granulation pattern. RESULTS: No mutations at codon 206 of PRKACA or PRKACB were found in a total of 92 specimens, comprising both WT and mutant GNAS cases, and densely, sparsely and mixed granulation patterns. CONCLUSIONS: It is unlikely that mutation at this locus is involved in the pathogenesis of sporadic somatotroph adenoma; however, gene amplification or mutations at other loci or in other components of the cAMP signalling pathway, while unlikely, cannot be ruled out.
OBJECTIVE: The pathogenetic mechanisms of sporadic somatotroph adenomas are not well understood, but derangements of the cAMP pathway have been implicated. Recent studies have identified L206R mutations in the alpha catalytic subunit of protein kinase A (PRKACA) in cortisol-producing adrenocortical adenomas and amplification of the beta catalytic subunit of protein kinase A PRKACB in acromegaly associated with Carney complex. Given that both adrenocortical adenomas and somatotroph adenomas are known to be reliant on the cAMP signalling pathway, we sought to determine the relevance of the L206R mutation in both PRKACA and PRKACB for the pathogenesis of sporadic somatotroph adenomas. DESIGN: Somatotroph adenoma specimens, both frozen and formalin-fixed, from patients who underwent surgery for their acromegaly between 1995 and 2012, were used in the study. METHODS: The DNA sequence at codon 206 of PRKACA and PRKACB was determined by PCR amplification and sequencing. The results were compared with patient characteristics, the mutational status of the GNAS complex locus and the tumour granulation pattern. RESULTS: No mutations at codon 206 of PRKACA or PRKACB were found in a total of 92 specimens, comprising both WT and mutant GNAS cases, and densely, sparsely and mixed granulation patterns. CONCLUSIONS: It is unlikely that mutation at this locus is involved in the pathogenesis of sporadic somatotroph adenoma; however, gene amplification or mutations at other loci or in other components of the cAMP signalling pathway, while unlikely, cannot be ruled out.
Authors: Kazutaka Nanba; Kei Omata; Scott A Tomlins; Thomas J Giordano; Gary D Hammer; William E Rainey; Tobias Else Journal: Eur J Endocrinol Date: 2016-05-10 Impact factor: 6.664
Authors: Maya B Lodish; Bo Yuan; Isaac Levy; Glenn D Braunstein; Charalampos Lyssikatos; Paraskevi Salpea; Eva Szarek; Alexander S Karageorgiadis; Elena Belyavskaya; Margarita Raygada; Fabio Rueda Faucz; Louise Izzat; Caroline Brain; James Gardner; Martha Quezado; J Aidan Carney; James R Lupski; Constantine A Stratakis Journal: Eur J Endocrinol Date: 2015-06 Impact factor: 6.664