Comprehensive Re-Sequencing of Adrenal Aldosterone Producing Lesions Reveal Three Somatic Mutations near the KCNJ5 Potassium Channel Selectivity Filter

BackgroundAldosterone producing lesions are a common cause of hypertension, but genetic alterations for tumorigenesis have been unclear. Recently, either of two recurrent somatic missense mutations (G151R or L168R) was found in the potassium channel KCNJ5 gene in aldosterone producing adenomas. These mutations alter the channel selectivity filter and result in Na+ conductance and cell depolarization, stimulating aldosterone production and cell proliferation. Because a similar mutation occurs in a Mendelian form of primary aldosteronism, these mutations appear to be sufficient for cell proliferation and aldosterone production. The prevalence and spectrum of KCNJ5 mutations in different entities of adrenocortical lesions remain to be defined. Materials and MethodsThe coding region and flanking intronic segments of KCNJ5 were subjected to Sanger DNA sequencing in 351 aldosterone producing lesions, from patients with primary aldosteronism and 130 other adrenocortical lesions. The specimens had been collected from 10 different worldwide referral centers. ResultsG151R or L168R somatic mutations were identified in 47% of aldosterone producing adenomas, each with similar frequency. A previously unreported somatic mutation near the selectivity filter, E145Q, was observed twice. Somatic G151R or L168R mutations were also found in 40% of aldosterone producing adenomas associated with marked hyperplasia, but not in specimens with merely unilateral hyperplasia. Mutations were absent in 130 non-aldosterone secreting lesions. KCNJ5 mutations were overrepresented in aldosterone producing adenomas from female compared to male patients (63 vs. 24%). Males with KCNJ5 mutations were significantly younger than those without (45 vs. 54, respectively; pKCNJ5 mutations were larger than those without (27.1 mm vs. 17.1 mm; p DiscussionEither of two somatic KCNJ5 mutations are highly prevalent and specific for aldosterone producing lesions. These findings provide new insight into the pathogenesis of primary aldosteronism.背景 醛固酮生成性病变是高血压的常见病因，但其肿瘤发生的遗传学改变尚未明确。近期研究在醛固酮生成性腺瘤的钾离子通道KCNJ5基因中，发现两种复发性体细胞错义突变：G151R与L168R。此类突变可改变该通道的选择性滤过结构，引发钠离子电导增强与细胞去极化，进而刺激醛固酮生成与细胞增殖。由于原发性醛固酮增多症的孟德尔遗传亚型中也存在类似突变，提示上述突变足以驱动细胞增殖与醛固酮生成。不过，KCNJ5突变在不同肾上腺皮质病变类型中的患病率与突变谱仍有待明确。 材料与方法 本研究对来自全球10家不同转诊中心的351例原发性醛固酮增多症患者的醛固酮生成性病变标本，以及130例其他肾上腺皮质病变标本，针对KCNJ5基因的编码区及其侧翼内含子片段开展桑格DNA（Sanger DNA）测序。 结果 47%的醛固酮生成性腺瘤中检测到G151R或L168R体细胞突变，二者检出频率相近。此外还观察到1例此前未被报道的、位于选择性滤过结构附近的体细胞突变E145Q。在伴明显增生的醛固酮生成性腺瘤中，40%的标本检出G151R或L168R体细胞突变，但仅单侧增生的标本未检出此类突变。130例非醛固酮分泌性病变标本中均未发现KCNJ5突变。相较于男性患者，女性患者的醛固酮生成性腺瘤KCNJ5突变检出率更高（63% vs. 24%）。携带KCNJ5突变的男性患者年龄显著低于未携带突变者（分别为45岁与54岁；P），且突变阳性腺瘤的直径显著大于未突变者（27.1 mm vs. 17.1 mm；P）。 讨论 两种体细胞KCNJ5突变均具有较高的患病率，且与醛固酮生成性病变高度特异性相关。本研究结果为原发性醛固酮增多症的发病机制提供了新的见解。