Transcriptional profiling enables molecular classification of adrenocortical tumours.
OBJECTIVE
Tumours in the adrenocortex are common human tumours. Malignancy is however, rare, the yearly incidence being 0.5-2 per million inhabitants, but associated with a very aggressive behaviour. Adrenocortical tumours are often associated with altered hormone production with a variety of clinical symptoms. The aggressiveness of carcinomas together with the high frequency of adenomas calls for a deeper understanding of the underlying biological mechanisms and an improvement of the diagnostic possibilities.


METHODS
Microarray gene expression analysis was performed in tumours of adrenocortex with emphasis on malignancy as well as hormonal activity. The sample set consisted of 17 adenomas, 11 carcinomas and 4 histological normal adrenocortexes. RNA from these was hybridised according to a reference design on microarrays harbouring 29 760 human cDNA clones. Confirmation was performed with quantitative real time-PCR and western blot analysis.


RESULTS
Unsupervised clustering to reveal relationships between samples based on the entire gene expression profile resulted in two subclusters; carcinomas and non-cancer specimens. A large number of genes were accordingly found to be differentially expressed comparing carcinomas to adenomas. Among these were IGF2, FGFR1 and FGFR4 in growth factor signalling the most predominant and also the USP4, UBE2C and UFD1L in the ubiquitin-proteasome pathway. Moreover, two subgroups of carcinomas were identified with different survival outcome, suggesting that survival prediction can be made on the basis of gene expression profiles. Regarding adenomas with aldosterone overproduction, OSBP and VEGFB were among the most up-regulated genes compared with the other samples.


CONCLUSIONS
Adrenocortical carcinomas are associated with a distinct molecular signature apparent in their gene expression profiles. Differentially expressed genes were identified associated with malignancy, survival as well as hormonal activity providing a resource of candidate genes for an exploration of possible drug targets and diagnostic and prognostic markers.
Laurell
Cecilia
C
School of Biotechnology, KTH-Royal Institute of Technology, 11427 Stockholm, Sweden. claurell@kth.se
Velázquez-Fernández
David
D
Lindsten
Kristina
K
Juhlin
Christofer
C
Enberg
Ulla
U
Geli
Janos
J
Höög
Anders
A
Kjellman
Magnus
M
Lundeberg
Joakim
J
Hamberger
Bertil
B
Larsson
Catharina
C
Nilsson
Peter
P
Bäckdahl
Martin
M
D000236:Adenoma / Q000145:classification* / Q000235:genetics* / Q000401:mortality; D000306:Adrenal Cortex Neoplasms / Q000145:classification* / Q000235:genetics* / Q000401:mortality; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000145:classification / Q000235:genetics / Q000401:mortality; D020411:Oligonucleotide Array Sequence Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016019:Survival Analysis; D014158:Transcription, Genetic; D043222:Ubiquitin Thiolesterase / Q000235:genetics; D064570:Ubiquitin-Specific Proteases
C486203:USP4 protein, human; D043222:Ubiquitin Thiolesterase; D064570:Ubiquitin-Specific Proteases