Larkin Sarah J, Ferraù Francesco, Karavitaki Niki, Hernández-Ramírez Laura C, Ansorge Olaf, Grossman Ashley B, Korbonits Márta
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
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.
Eur J Endocrinol. 2014 Dec;171(6):705-10. doi: 10.1530/EJE-14-0545. Epub 2014 Sep 15.
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.
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.
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.
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.
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.
散发性生长激素腺瘤的发病机制尚未完全明确，但cAMP信号通路紊乱与之相关。近期研究已在产生皮质醇的肾上腺皮质腺瘤中发现蛋白激酶A（PRKACA）的α催化亚基存在L206R突变，以及在与卡尼综合征相关的肢端肥大症中发现蛋白激酶A PRKACB的β催化亚基扩增。鉴于肾上腺皮质腺瘤和生长激素腺瘤均依赖cAMP信号通路，我们试图确定PRKACA和PRKACB中的L206R突变与散发性生长激素腺瘤发病机制的相关性。
本研究使用了1995年至2012年间因肢端肥大症接受手术患者的冷冻及福尔马林固定的生长激素腺瘤标本。
通过PCR扩增和测序确定PRKACA和PRKACB第206密码子的DNA序列。将结果与患者特征、GNAS复合位点的突变状态及肿瘤颗粒模式进行比较。
在总共92个标本中，包括野生型和突变型GNAS病例以及致密、稀疏和混合颗粒模式的标本，均未发现PRKACA或PRKACB第206密码子的突变。
该位点的突变不太可能参与散发性生长激素腺瘤的发病机制；然而，基因扩增或其他位点或cAMP信号通路其他组分的突变虽可能性不大，但不能排除。
