Inhibin Alpha-Subunit (INHA) Expression in Adrenocortical Cancer Is Linked to Genetic and Epigenetic INHA Promoter Variation
Inhibin Alpha-Subunit (INHA) Expression in Adrenocortical Cancer Is Linked to Genetic and Epigenetic INHA Promoter Variation
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DOI：
10.1371/journal.pone.0104944
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发表时间：
2014-08-11
期刊：
影响因子：
3.7
通讯作者：
de Jong, Frank H.
中科院分区：
文献类型：
--
作者：
Hofland, Johannes;Steenbergen, Jacobie;de Jong, Frank H.
肾上腺皮质癌是一种罕见的，但高度恶性肿瘤的起源不明。抑制素α亚基（Inha）敲除小鼠在性腺切除术后发生ACC。在人类中，INHA的表达在ACC组织内变化很大，其循环肽cannabin pro-alpha C已被描述为ACC的一种新的肿瘤标志物。我们研究了人类ACC中INHA基因的遗传和表观遗传变化是否会导致INHA表达的丢失或变化。为此，在人肾上腺皮质组织中进行INHA序列、启动子甲基化和mRNA表达的分析。还测量了ACC患者的血清白蛋白前α C水平。在37个独特的ACC中的INHA遗传分析揭示了10个新的杂合罕见变异。在受影响的3个编码碱基中，一个变体是同义变体，两个是错义变体：S72 F和S184 F。在ACC样本中观察到rs 11893842 - 124 bp的次要等位基因频率较低（24%），并与INHA mRNA水平降低相关：AA为4.7 +/- 1.9任意单位，而AG/GG基因型为26 +/- 11（P = 0.034）。与正常肾上腺（18.4 +/-0.6%，P = 0.0052）相比，5个ACC（47.7 +/- 3.9%）中4个近端INHA启动子CpG的甲基化异常增加，而研究的其他14个ACC显示启动子甲基化减少（9.8 +/-1.1%，P = 0.020）。CpG甲基化与ACC中的INHA mRNA水平呈负相关（r =-0.701，p = 0.0036），但与血清白蛋白前α C水平无关。总之，INHA启动子的异常甲基化和常见遗传变异发生在人类ACC中，并与INHA表达降低相关。
Adrenocortical carcinoma (ACC) is a rare, but highly malignant tumor of unknown origin. Inhibin alpha-subunit (Inha) knockout mice develop ACCs following gonadectomy. In man, INHA expression varies widely within ACC tissues and its circulating peptide inhibin pro-alpha C has been described as a novel tumor marker for ACC. We investigated whether genetic and epigenetic changes of the INHA gene in human ACC cause loss or variation of INHA expression. To this end, analyses of INHA sequence, promoter methylation and mRNA expression were performed in human adrenocortical tissues. Serum inhibin pro-alpha C levels were also measured in ACC patients. INHA genetic analysis in 37 unique ACCs revealed 10 novel, heterozygous rare variants. Of the 3 coding bases affected, one variant was synonymous and two were missense variants: S72F and S184F. The minor allele of rs11893842 at -124 bp was observed at a low frequency (24%) in ACC samples and was associated with decreased INHA mRNA levels: 4.7 +/- 1.9 arbitrary units for AA, compared to 26 +/- 11 for AG/GG genotypes (P = 0.034). The methylation of four proximal INHA promoter CpGs was aberrantly increased in five ACCs (47.7 +/- 3.9%), compared to normal adrenals (18.4 +/- 0.6%, P = 0.0052), whereas the other 14 ACCs studied showed diminished promoter methylation (9.8 +/- 1.1%, P = 0.020). CpG methylation was inversely correlated to INHA mRNA levels in ACCs (r = -0.701, p = 0.0036), but not associated with serum inhibin pro-alpha C levels. In conclusion, aberrant methylation and common genetic variation in the INHA promoter occur in human ACCs and are associated with decreased INHA expression.