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Abstract：
Pheochromocytoma (PCC) and abdominal paraganglioma (aPGL) (together abbreviated PPGL) frequently present with an underlying genetic event in a PPGL driver gene, and additional susceptibility genes are anticipated. Here, we re-analyzed whole-exome sequencing data for PCC patients and identified two patients with rare missense variants in the calcium voltage-gated channel subunit 1H gene (CACNA1H). CACNA1H variants were also found in the clinical setting in PCC patients using targeted sequencing and from analysis of The Cancer Genome Atlas database. In total, CACNA1H variants were found in six PCC cases. Three of these were constitutional, and two are known to have functional consequences on hormone production and gene expression in primary aldosteronism and aldosterone-producing adrenocortical adenoma. In general, PPGL exhibited reduced CACNA1H mRNA expression as compared to normal adrenal. Immunohistochemistry showed strong CACNA1H (CaV3.2) staining in adrenal medulla while PPGL typically had weak or negative staining. Reduced CACNA1H gene expression was especially pronounced in PCC compared to aPGL and in PPGL with cluster 2 kinase signaling phenotype. Furthermore, CACNA1H levels correlated with HIF1A and HIF2A. Moreover, TCGA data revealed a correlation between CACNA1H methylation density and gene expression. Expression of rCacna1h in PC12 cells induced differential protein expression profiles, determined by mass spectrometry, as well as a shift in the membrane potential where maximum calcium currents were observed, as determined by electrophysiology. The findings suggest the involvement of CACNA1H/CaV3.2 in pheochromocytoma development and establish a potential link between the etiology of adrenomedullary and adrenocortical tumor development.
摘要：
嗜铬细胞瘤（PCC）和腹部副神经节瘤（aPGL）（一起缩写为PPGL）经常出现在PPGL驱动基因中的潜在遗传事件，和其他易感基因预计。在这里，我们重新分析了PCC患者的全外显子组测序数据，并确定了两名在钙电压门控通道亚基1H基因（CACNA1H）中具有罕见错义变异的患者。CACNA1H变体也在PCC患者的临床环境中使用靶向测序和从癌症基因组图谱数据库的分析中发现。总的来说,在6例PCC病例中发现了CACNA1H变体。其中三个是结构性的，两个已知对原发性醛固酮增多症和产生醛固酮的肾上腺皮质腺瘤的激素产生和基因表达具有功能性影响。总的来说,与正常肾上腺相比,PPGL表现出降低的CACNA1HmRNA表达。免疫组织化学显示肾上腺髓质中的强CACNA1H(CaV3.2)染色,而PPGL通常具有弱染色或阴性染色。与aPGL相比,降低的CACNA1H基因表达在PCC中和在具有簇2激酶信号传导表型的PPGL中尤其显著。此外，CACNA1H水平与HIF1A和HIF2A相关。此外，TCGA数据显示CACNA1H甲基化密度与基因表达之间存在相关性。rCacna1h在PC12细胞中的表达诱导了通过质谱确定的差异蛋白质表达谱以及通过电生理学确定的观察到最大钙电流的膜电位的变化。研究结果表明，CACNA1H/CaV3.2参与嗜铬细胞瘤的发展，并在肾上腺髓质的病因和肾上腺皮质肿瘤的发展之间建立了潜在的联系。
