802 SOMATIC MUTATIONS OF KCNJ5 ARE COMMON IN ALDOSTERONE-PRODUCING ADENOMAS OF THE ADRENAL, AND DISTINGUISH A PHENOTYPE OF YOUNGER WOMEN WITH ZF-LIKE LARGE ADENOMAS FROM OLDER MEN WITH ZG-LIKE SMALL ADENOMAS

Abstract

Background: Among aldosterone-producing adenomas (APAs), heterogeneity of phenotype is well recognized. Choi's finding of KCNJ5 mutations in 8/22 APAs [1], offered a possible explanation for heterogeneity and hence prompted the question whether there are genotype:phenotype correlations. Method: The K+-selectivity region of KCNJ5 was sequenced in 46 APAs. Each was blindly histologically graded. A microarray comparison of ZF- vs ZG-like APAs suggested putative ZG genes, whose expression was compared between ZG and ZF cells from normal adrenal using laser capture microdissection (LCM). Confirmed ZG genes were compared between mutant and wild-type APA. Immunohistochemistry for KCNJ5 was undertaken in adrenals with and without the mutation. Result: 20/46 APAs (43%(95%CI[29,58]%)) had KCNJ5 somatic mutations. Mutant APAs were larger, 2.27 vs 0.78cm3, (p = 0.001). Regression analysis distinguished: [i] younger women, with mainly mutant, larger APAs, from [ii] older men with mainly wild-type smaller APAs (Figure). APAs with KCNJ5 mutation had histological appearance of ZF cells, in particular the classical feature of higher cytoplasm to nucleus ratio. Genes confirmed as ZG-selective on LCM were less abundant in mutant APAs while the ZF-gene CYP17A1 was higher (0.51 vs 0.15, P = 0.011). KCNJ5 staining was observed in all APAs regardless of genotype.Conclusion: The mutant and wild-type phenotypes differ by age, gender, size, gene expression profile and histology, and may arise respectively from ZF and ZG. Small ZG-like APAs may elude diagnosis at a young age and progress to cause resistant hypertension. Reference Choi M et al. K+-channel mutations in adrenal aldosterone-producing adenomas and hereditary hypertension. Science 2011;331:768-772.