Molecular classification and prognostication of adrenocortical tumors by transcriptome profiling.
OBJECTIVE
Our understanding of adrenocortical carcinoma (ACC) has improved considerably, yet many unanswered questions remain. For instance, can molecular subtypes of ACC be identified? If so, what is their underlying pathogenetic basis and do they possess clinical significance?


METHODS
We did a whole genome gene expression study of a large cohort of adrenocortical tissues annotated with clinicopathologic data. Using Affymetrix Human Genome U133 Plus 2.0 oligonucleotide arrays, transcriptional profiles were generated for 10 normal adrenal cortices (NC), 22 adrenocortical adenomas (ACA), and 33 ACCs.


RESULTS
The overall classification of adrenocortical tumors was recapitulated using principal component analysis of the entire data set. The NC and ACA cohorts showed little intragroup variation, whereas the ACC cohort revealed much greater variation in gene expression. A robust list of 2,875 differentially expressed genes in ACC compared with both NC and ACA was generated and used in functional enrichment analysis to find pathways and attributes of biological significance. Cluster analysis of the ACCs revealed two subtypes that reflected tumor proliferation, as measured by mitotic counts and cell cycle genes. Kaplan-Meier analysis of these ACC clusters showed a significant difference in survival (P < 0.020). Multivariate Cox modeling using stage, mitotic rate, and gene expression data as measured by the first principal component for ACC samples showed that gene expression data contains significant independent prognostic information (P < 0.017).


CONCLUSIONS
This study lays the foundation for the molecular classification and prognostication of adrenocortical tumors and also provides a rich source of potential diagnostic and prognostic markers.
Giordano
Thomas J
TJ
Department of Pathology, 1150 West Medical Center Drive, MSRB-2, C570D, Ann Arbor, MI 48109-0669, USA. Giordano@umich.edu
Kuick
Rork
R
Else
Tobias
T
Gauger
Paul G
PG
Vinco
Michelle
M
Bauersfeld
Juliane
J
Sanders
Donita
D
Thomas
Dafydd G
DG
Doherty
Gerard
G
Hammer
Gary
G
D000302:Adrenal Cortex / Q000473:pathology; D000306:Adrenal Cortex Neoplasms / Q000175:diagnosis* / Q000235:genetics*; D045744:Cell Line, Tumor; D016000:Cluster Analysis; D015331:Cohort Studies; D019927:Cyclin E / Q000378:metabolism; D020869:Gene Expression Profiling; D016678:Genome; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D016016:Proportional Hazards Models; D014158:Transcription, Genetic
D019927:Cyclin E