Integrated genomic analysis of nodular tissue in macronodular adrenocortical hyperplasia: progression of tumorigenesis in a disorder associated with multiple benign lesions.
BACKGROUND
Massive macronodular adrenocortical disease or ACTH-independent macronodular adrenal hyperplasia (AIMAH) is a clinically and genetically heterogeneous disorder.


OBJECTIVE
Whole-genome expression profiling and oligonucleotide array comparative genomic hybridization changes were analyzed in samples of different nodules from the same patients with AIMAH. Quantitative RT-PCR and staining were employed to validate the mRNA array data.


RESULTS
Chromosomal gains were more frequent in larger nodules when compared with smaller nodules from the same patients. Among the 50 most overexpressed genes, 50% had a chromosomal locus that was amplified in the comparative genomic hybridization data. Although the list of most over- and underexpressed genes was similar between the nodules of different size, the gene set enrichment analysis identified different pathways associated with AIMAH that corresponded to the size; the smaller nodules were mainly enriched for metabolic pathways, whereas p53 signaling and cancer genes were enriched in larger nodules. Confirmatory studies demonstrated that BCL2, E2F1, EGF, c-KIT, MYB, PRKCA, and CTNNB1 were overexpressed in the larger nodules at messenger and/or protein levels. Chromosomal enrichment analysis showed that chromosomes 20q13 and 14q23 might be involved in progression of AIMAH from smaller to larger tumors.


CONCLUSIONS
Integrated transcriptomic and genomic data for AIMAH provides supporting evidence to the hypothesis that larger adrenal lesions, in the context of this chronic, polyclonal hyperplasia, accumulate an increased number of genomic and, subsequently, transcript abnormalities. The latter shows that the disease appears to start with mainly tissue metabolic derangements, as suggested by the study of the smaller nodules, but larger lesions showed aberrant expression of oncogenic pathways.
Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892, USA.
Madson Q
MQ
Almeida
Michelle
M
Harran
Eirini I
EI
Bimpaki
Hui-Pin
HP
Hsiao
Anelia
A
Horvath
Chris
C
Cheadle
Tonya
T
Watkins
Maria
M
Nesterova
Constantine A
CA
Stratakis
D000302:Adrenal Cortex / Q000378:metabolism / Q000473:pathology*; D000306:Adrenal Cortex Neoplasms / Q000235:genetics* / Q000473:pathology; D000328:Adult; D002277:Carcinoma / Q000235:genetics* / Q000473:pathology; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000473:pathology; D055028:Comparative Genomic Hybridization; D018450:Disease Progression; D005260:Female; D020869:Gene Expression Profiling; D023281:Genomics / Q000379:methods; D006801:Humans; D006965:Hyperplasia; D008297:Male; D009378:Neoplasms, Multiple Primary / Q000235:genetics* / Q000473:pathology; D018511:Systems Integration; D047368:Tumor Burden
Clin Endocrinol (Oxf). 2009 Jun;70(6):883-91
19018784
Trends Endocrinol Metab. 2004 Oct;15(8):375-82
15380809
Trends Endocrinol Metab. 2003 Nov;14(9):404-10
14580759
Best Pract Res Clin Endocrinol Metab. 2009 Apr;23(2):245-59
19500767
J Biol Chem. 1993 Mar 15;268(8):5774-82
8449943
Genes Chromosomes Cancer. 2000 Jun;28(2):145-52
10824999
J Clin Endocrinol Metab. 1999 Mar;84(3):1116-21
10084604
J Clin Endocrinol Metab. 2002 Jul;87(7):3467-74
12107267
Clin Endocrinol (Oxf). 2008 Sep;69(3):367-73
18419788
Oncogene. 2009 Aug 6;28(31):2773-83
19525976
Methods. 2001 Dec;25(4):402-8
11846609
Clin Endocrinol (Oxf). 2010 Jul;73(1):1-15
19719763
Nat Genet. 2000 Sep;26(1):89-92
10973256
Mol Cell Endocrinol. 2009 Mar 5;300(1-2):152-7
19063937
J Clin Invest. 2009 Sep;119(9):2795-806
19652362
Hum Mol Genet. 2010 Apr 15;19(8):1387-98
20080939
J Mol Diagn. 2003 May;5(2):73-81
12707371
Oncogene. 2004 Feb 26;23(8):1575-85
14767469
Cancer Res. 1994 Sep 15;54(18):4927-32
7915195
Nat Protoc. 2009;4(1):44-57
19131956
J Clin Endocrinol Metab. 2006 Feb;91(2):584-96
16278264
Cancer Cell. 2010 Jul 13;18(1):11-22
20579941
J Clin Endocrinol Metab. 2008 Oct;93(10):4135-40
18647815
Gynecol Oncol. 2010 Aug 1;118(2):160-6
20537689
Clin Endocrinol (Oxf). 1996 Apr;44(4):483-8
8706318
Cancer Res. 2006 Jul 15;66(14):7083-94
16849554
Eur J Endocrinol. 2003 Oct;149(4):273-85
14514341
Crit Rev Oncol Hematol. 2007 Jun;62(3):179-213
17324579
Nucleic Acids Res. 2007 Jul;35(Web Server issue):W169-75
17576678
Nature. 2008 Oct 23;455(7216):1069-75
18948947
J Clin Endocrinol Metab. 1993 Jan;76(1):189-91
8380604
Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50
16199517
Am J Hum Genet. 1983 Jul;35(4):635-44
6881140
J Pediatr. 1991 Feb;118(2):256-8
1993957
Cancer Res. 2009 Apr 15;69(8):3278-82
19351815
Am J Med Genet A. 2008 Oct 1;146A(19):2480-9
18666230
Cancer Res. 1996 Sep 15;56(18):4219-23
8797595
J Clin Endocrinol Metab. 1998 Apr;83(4):1163-7
9543134
Neoplasma. 2010;57(4):325-32
20429623
Am J Pathol. 1999 Oct;155(4):1039-45
10514385
Cancer Res. 2003 Sep 1;63(17):5308-19
14500362
Cancer Res. 2010 Feb 15;70(4):1668-78
20124479
PLoS One. 2010 Mar 17;5(3):e9738
20305816
J Clin Endocrinol Metab. 2009 Aug;94(8):2930-7
19509103
J Clin Endocrinol Metab. 2006 Sep;91(9):3626-32
16772351
Endocr Rev. 2001 Feb;22(1):75-110
11159817
Oncogene. 2010 May 27;29(21):3163-72
20305693