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Inhibin Alpha-Subunit (INHA) Expression in Adrenocortical Cancer Is Linked to Genetic and Epigenetic INHA Promoter Variation
by
de Herder, Wouter W.
, Uitterlinden, Andre G.
, de Jong, Frank H.
, Steenbergen, Jacobie
, Hofland, Johannes
, Verbiest, Michael M. P. J.
, Hofland, Leo J.
, Feelders, Richard A.
, de Krijger, Ronald R.
, Voorsluijs, Jacoba M.
in
Adrenal Cortex Neoplasms - genetics
/ Adrenal Cortex Neoplasms - metabolism
/ Adrenal glands
/ Adrenocortical Carcinoma - genetics
/ Adrenocortical Carcinoma - metabolism
/ Adult
/ Aged
/ Animal tissues
/ Base Sequence
/ Biology and life sciences
/ Biomarkers, Tumor - genetics
/ Child, Preschool
/ CpG islands
/ DNA methylation
/ DNA Methylation - genetics
/ Epigenesis, Genetic
/ Epigenetics
/ Female
/ Gene expression
/ Genetic analysis
/ Genetic diversity
/ Genetic Variation - genetics
/ Genotypes
/ Gonadectomy
/ Human performance
/ Humans
/ INHA gene
/ Inhibin
/ Inhibins - biosynthesis
/ Inhibins - blood
/ Inhibins - genetics
/ Male
/ Medicine and Health Sciences
/ Methylation
/ Middle Aged
/ Neuroendocrine tumors
/ Promoter Regions, Genetic - genetics
/ RNA, Messenger - genetics
/ Sequence Analysis, DNA
/ Tumor markers
/ Tumors
2014
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Inhibin Alpha-Subunit (INHA) Expression in Adrenocortical Cancer Is Linked to Genetic and Epigenetic INHA Promoter Variation
by
de Herder, Wouter W.
, Uitterlinden, Andre G.
, de Jong, Frank H.
, Steenbergen, Jacobie
, Hofland, Johannes
, Verbiest, Michael M. P. J.
, Hofland, Leo J.
, Feelders, Richard A.
, de Krijger, Ronald R.
, Voorsluijs, Jacoba M.
in
Adrenal Cortex Neoplasms - genetics
/ Adrenal Cortex Neoplasms - metabolism
/ Adrenal glands
/ Adrenocortical Carcinoma - genetics
/ Adrenocortical Carcinoma - metabolism
/ Adult
/ Aged
/ Animal tissues
/ Base Sequence
/ Biology and life sciences
/ Biomarkers, Tumor - genetics
/ Child, Preschool
/ CpG islands
/ DNA methylation
/ DNA Methylation - genetics
/ Epigenesis, Genetic
/ Epigenetics
/ Female
/ Gene expression
/ Genetic analysis
/ Genetic diversity
/ Genetic Variation - genetics
/ Genotypes
/ Gonadectomy
/ Human performance
/ Humans
/ INHA gene
/ Inhibin
/ Inhibins - biosynthesis
/ Inhibins - blood
/ Inhibins - genetics
/ Male
/ Medicine and Health Sciences
/ Methylation
/ Middle Aged
/ Neuroendocrine tumors
/ Promoter Regions, Genetic - genetics
/ RNA, Messenger - genetics
/ Sequence Analysis, DNA
/ Tumor markers
/ Tumors
2014
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Inhibin Alpha-Subunit (INHA) Expression in Adrenocortical Cancer Is Linked to Genetic and Epigenetic INHA Promoter Variation
by
de Herder, Wouter W.
, Uitterlinden, Andre G.
, de Jong, Frank H.
, Steenbergen, Jacobie
, Hofland, Johannes
, Verbiest, Michael M. P. J.
, Hofland, Leo J.
, Feelders, Richard A.
, de Krijger, Ronald R.
, Voorsluijs, Jacoba M.
in
Adrenal Cortex Neoplasms - genetics
/ Adrenal Cortex Neoplasms - metabolism
/ Adrenal glands
/ Adrenocortical Carcinoma - genetics
/ Adrenocortical Carcinoma - metabolism
/ Adult
/ Aged
/ Animal tissues
/ Base Sequence
/ Biology and life sciences
/ Biomarkers, Tumor - genetics
/ Child, Preschool
/ CpG islands
/ DNA methylation
/ DNA Methylation - genetics
/ Epigenesis, Genetic
/ Epigenetics
/ Female
/ Gene expression
/ Genetic analysis
/ Genetic diversity
/ Genetic Variation - genetics
/ Genotypes
/ Gonadectomy
/ Human performance
/ Humans
/ INHA gene
/ Inhibin
/ Inhibins - biosynthesis
/ Inhibins - blood
/ Inhibins - genetics
/ Male
/ Medicine and Health Sciences
/ Methylation
/ Middle Aged
/ Neuroendocrine tumors
/ Promoter Regions, Genetic - genetics
/ RNA, Messenger - genetics
/ Sequence Analysis, DNA
/ Tumor markers
/ Tumors
2014
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Inhibin Alpha-Subunit (INHA) Expression in Adrenocortical Cancer Is Linked to Genetic and Epigenetic INHA Promoter Variation
Journal Article
Inhibin Alpha-Subunit (INHA) Expression in Adrenocortical Cancer Is Linked to Genetic and Epigenetic INHA Promoter Variation
2014
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Overview
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.
Publisher
Public Library of Science,Public Library of Science (PLoS)
Subject
Adrenal Cortex Neoplasms - genetics
/ Adrenal Cortex Neoplasms - metabolism
/ Adrenocortical Carcinoma - genetics
/ Adrenocortical Carcinoma - metabolism
/ Adult
/ Aged
/ Biomarkers, Tumor - genetics
/ Female
/ Genetic Variation - genetics
/ Humans
/ Inhibin
/ Male
/ Medicine and Health Sciences
/ Promoter Regions, Genetic - genetics
/ Tumors
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