Abstract
Adrenocortical carcinoma (ACC) is a rare, but highly malignant tumor of unknown origin. Inhibin α-subunit (Inha) knockout mice develop ACCs following gonadectomy. In man, INHA expression varies widely within ACC tissues and its circulating peptide inhibin pro-αC 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-αC 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-αC levels. In conclusion, aberrant methylation and common genetic variation in the INHA promoter occur in human ACCs and are associated with decreased INHA expression.
Highlights
Adrenocortical carcinoma (ACC) is a rare malignancy with a poor survival rate [1,2]
The present analysis showed absence of Inhibin Alpha-Subunit (INHA) expression in 3 ACC whereas the other ACCs demonstrated a wide range of expression from 0.080 to 220 arbitrary units (A.U.)
The inhibin a-subunit has been implicated in adrenocortical tumorigenesis since it was observed that gonadectomized Inhibin a-subunit (Inha) 2/2 mice developed adrenocortical carcinomas with almost complete penetrance [11]
Summary
Adrenocortical carcinoma (ACC) is a rare malignancy with a poor survival rate [1,2]. The occurrence of ACC has a female preponderance and a bimodal distribution with an increased incidence in children and in adults over 60 years [3]. Familial ACC occurs in the context of genetic syndromes, such as Beckwith-Wiedemann syndrome [4] and Li-Fraumeni syndrome [5]. Mutations in genes underlying these disorders have been linked to sporadic ACC formation, especially in the case of TP53 [6]. The most frequent alteration found in ACC is overexpression of the maternally imprinted IGF-II locus [7]. Mutations in the Wnt/b-catenin pathway have been shown to occur during adrenocortical tumor progression [8]. Genetic causes and the role of chromosomal aberrations in adrenocortical tumorigenesis remain largely unknown
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