title: Inhibin alpha-subunit (INHA) expression in adrenocortical cancer is linked to genetic and epigenetic INHA promoter variation.
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.
authors.affiliation: Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Johannes
authors.initials: J
authors.lastname: Hofland
authors.affiliation: Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Jacobie
authors.initials: J
authors.lastname: Steenbergen
authors.affiliation: Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Jacoba M
authors.initials: JM
authors.lastname: Voorsluijs
authors.affiliation: Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Michael M P J
authors.initials: MM
authors.lastname: Verbiest
authors.affiliation: Department of Pathology, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Ronald R
authors.initials: RR
authors.lastname: de Krijger
authors.affiliation: Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Leo J
authors.initials: LJ
authors.lastname: Hofland
authors.affiliation: Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Wouter W
authors.initials: WW
authors.lastname: de Herder
authors.affiliation: Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Andre G
authors.initials: AG
authors.lastname: Uitterlinden
authors.affiliation: Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Feelders
authors.affiliation: Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Frank H
authors.initials: FH
authors.lastname: de Jong
mesh_terms: D000306:Adrenal Cortex Neoplasms / Q000235:genetics* / Q000378:metabolism; D018268:Adrenocortical Carcinoma / Q000235:genetics* / Q000378:metabolism; D000328:Adult; D000368:Aged; D001483:Base Sequence; D014408:Biomarkers, Tumor / Q000235:genetics*; D002675:Child, Preschool; D019175:DNA Methylation / Q000235:genetics; D044127:Epigenesis, Genetic; D005260:Female; D014644:Genetic Variation / Q000235:genetics; D006801:Humans; D007265:Inhibins / Q000096:biosynthesis / Q000097:blood / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D011401:Promoter Regions, Genetic / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D017422:Sequence Analysis, DNA
chemical_list: D014408:Biomarkers, Tumor; D012333:RNA, Messenger; C094377:inhibin-alpha subunit; D007265:Inhibins
references.citation: J Endocrinol. 2006 Feb;188(2):305-10
references.pmid: 16461556
references.citation: Endocrinology. 2001 Mar;142(3):977-86
references.pmid: 11181509
references.citation: Cancer. 1993 Dec 1;72(11):3145-55
references.pmid: 8242539
references.citation: Eur J Endocrinol. 2012 Feb;166(2):281-9
references.pmid: 22127493
references.citation: Mol Cell Biol. 2003 Jun;23(11):3951-64
references.pmid: 12748296
references.citation: Nature. 1992 Nov 26;360(6402):313-9
references.pmid: 1448148
references.citation: J Endocrinol. 2000 May;165(2):223-9
references.pmid: 10810286
references.citation: J Clin Endocrinol Metab. 2002 Jul;87(7):3467-74
references.pmid: 12107267
references.citation: Mol Endocrinol. 2010 Mar;24(3):608-20
references.pmid: 20160125
references.citation: Am J Physiol Endocrinol Metab. 2013 Sep 15;305(6):E736-44
references.pmid: 23900415
references.citation: Mod Pathol. 1998 Dec;11(12):1160-4
references.pmid: 9872645
references.citation: J Med Genet. 2004 May;41(5):354-9
references.pmid: 15121773
references.citation: Mol Endocrinol. 2000 Jan;14(1):66-81
references.pmid: 10628748
references.citation: Mod Pathol. 1998 Jun;11(6):516-24
references.pmid: 9647588
references.citation: J Natl Cancer Inst. 1998 Apr 15;90(8):606-11
references.pmid: 9554443
references.citation: Nat Rev Genet. 2002 Jun;3(6):415-28
references.pmid: 12042769
references.citation: Fukuoka Igaku Zasshi. 2000 Jan;91(1):8-20
references.pmid: 10714012
references.citation: Br J Cancer. 1999 Sep;81(2):300-4
references.pmid: 10496356
references.citation: J Clin Pathol. 1998 Feb;51(2):114-6
references.pmid: 9602683
references.citation: World J Surg. 1992 Jul-Aug;16(4):663-7; discussion 668
references.pmid: 1413834
references.citation: Nature. 2010 Oct 28;467(7319):1061-73
references.pmid: 20981092
references.citation: Clin Endocrinol (Oxf). 2006 Dec;65(6):792-9
references.pmid: 17121532
references.citation: Eur J Endocrinol. 1995 Mar;132(3):290-1
references.pmid: 7889176
references.citation: J Clin Endocrinol Metab. 1998 May;83(5):1713-20
references.pmid: 9589681
references.citation: Mol Cell Endocrinol. 2012 Aug 15;359(1-2):92-100
references.pmid: 21722704
references.citation: N Engl J Med. 2008 Mar 13;358(11):1148-59
references.pmid: 18337604
references.citation: Proc Natl Acad Sci U S A. 1994 Sep 13;91(19):8817-21
references.pmid: 8090730
references.citation: Cancer Res. 2005 Sep 1;65(17):7622-7
references.pmid: 16140927
references.citation: Mol Endocrinol. 2006 Nov;20(11):2848-63
references.pmid: 16873442
references.citation: J Endocrinol. 1999 May;161(2):341-7
references.pmid: 10320833
references.citation: J Clin Endocrinol Metab. 1999 Mar;84(3):1116-21
references.pmid: 10084604
references.citation: Physiol Rev. 1988 Apr;68(2):555-607
references.pmid: 3282246
references.citation: Histopathology. 2007 Aug;51(2):239-45
references.pmid: 17593212
references.citation: Cancer. 2009 Jan 15;115(2):243-50
references.pmid: 19025987
references.citation: J Mol Endocrinol. 2004 Dec;33(3):651-62
references.pmid: 15591025
references.citation: Eur J Pediatr. 1983 Mar;140(1):5-12
references.pmid: 6873112
references.citation: J Clin Endocrinol Metab. 1994 Mar;78(3):790-4
references.pmid: 8126158
references.citation: Eur J Endocrinol. 1995 Mar;132(3):292-9
references.pmid: 7889177