Microinsertions in PRKACA cause activation of the protein kinase A pathway in cardiac myxoma.

Cardiac myxoma is the most common cardiac tumour. Most lesions occur sporadically, but occasional lesions develop in patients with Carney complex, a syndrome characterized by cardiac myxoma, spotty pigmentation, and endocrine overactivity. Two-thirds of patients with Carney complex harbour germline mutations in PRKAR1A, which encodes the type I regulatory subunit of protein kinase A (PKA). Most studies have not found a mutation in PRKAR1A in sporadic cardiac myxoma cases. Recent studies identified frequent mutations in PRKACA, which encodes the catalytic subunit of PKA, in cortisol-secreting adrenocortical adenoma cases. To determine whether the PRKACA mutation is involved in the tumourigenesis of cardiac myxoma, we performed Sanger sequencing of 41 specimens of sporadic cardiac myxoma to test for the presence of mutations in the coding regions and intron-exon boundaries of PRKACA. Mutations were identified in four cases (9.7%). In contrast to the point mutations identified in adrenocortical adenoma, all mutations were in-frame microinsertions of 18-33 bp clustered in exons 7 and 8. The mutated PRKACA proteins lost their ability to bind to PRKAR1A, and thereby lead to constitutive activation of the PKA pathway. Together with previous reports of PRKAR1A mutations in syndromic cardiac myxoma, our study demonstrates the importance of the PKA pathway in the tumourigenesis of cardiac myxoma. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

NKX6-1 Is a Novel Immunohistochemical Marker for Pancreatic and Duodenal Neuroendocrine Tumors.

NKX6-1 is a homeobox transcription factor participating in the development and regulation of endocrine function of pancreatic islets. This study evaluated the potential use of NKX6-1 as a diagnostic marker for well-differentiated neuroendocrine tumors (WDNETs). In total, 178 primary and 26 metastatic WDNETs of different origins were analyzed through immunohistochemistry for NKX6-1, TTF-1, CDX2, ISL1, and polyclonal PAX8. NKX6-1 was expressed in 36 of the 44 (82%) primary pancreatic WDNETs, 12 of the 18 (67%) primary duodenal WDNETs, and rarely in pulmonary, gastric, and appendiceal WDNETs. The specificity of using NKX6-1 as a marker for pancreatic and duodenal WDNETs is 93%. Of the 26 metastatic WDNETs, NKX6-1 was expressed only in the tumors of pancreatic origin (sensitivity: 63%, specificity: 100%). The combinatorial use of NKX6-1, CDX2, TTF-1, and ISL1 distinguished WDNETs of different origins with high specificity. Our results indicated that the inclusion of NKX6-1 in an immunohistochemical panel will be beneficial for identifying the primary sites of WDNETs.