Altered gene expression in phenotypically normal renal cells from carriers of tumor suppressor gene mutations.
BACKGROUND
The inherently complex signaling networks of tumors result from genetic and epigenetic alterations that occur during cancer initiation and progression.


METHODS
In an attempt to identify early molecular changes associated with dominantly inherited predisposition to "two-hit" renal tumors, the expression profiles of primary cultures of phenotypically normal renal epithelial cells from individuals bearing a germline mutation in either the von Hippel-Lindau (VHL) or the tuberous sclerosis complex (TSC) gene were compared to that of renal epithelial cells from control nonmutation carriers by microarray analysis.


RESULTS
Reliability of the microarray data from pooled samples was confirmed by real-time RT-PCR. Principal Component Analysis revealed substantial differences in the gene expression profiles of the renal epithelial cells from VHL and TSC mutation carriers. In several instances, the microarray data confirm our present knowledge of the cellular pathways affected by biallelic VHL and TSC mutations.


CONCLUSIONS
These findings demonstrate that heterozygosity for a mutant tumor suppressor gene may alter the expression profiles of phenotypically normal epithelial cells in a gene-specific manner. Detectable effects of "one-hit" represent early molecular changes in tumorigenesis that may serve as targets for chemopreventive intervention.
Stoyanova
Radka
R
Division of Population Science, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA.
Clapper
Margie L
ML
Bellacosa
Alfonso
A
Henske
Elizabeth P
EP
Testa
Joseph R
JR
Ross
Eric A
EA
Yeung
Anthony T
AT
Nicolas
Emmanuelle
E
Tsichlis
Nicolaos
N
Li
Yue-Sheng
YS
Linehan
W Marston
WM
Howard
Sharon
S
Campbell
Kerry S
KS
Godwin
Andrew K
AK
Boman
Bruce M
BM
Crowell
James A
JA
Kopelovich
Levy
L
Knudson
Alfred G
AG
D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000235:genetics*; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D020869:Gene Expression Profiling; D018095:Germ-Line Mutation / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D006623:von Hippel-Lindau Disease / Q000235:genetics
D014408:Biomarkers, Tumor; D002135:Calcium-Binding Proteins; C486009:TESC protein, human; D025521:Tumor Suppressor Proteins; D044767:Ubiquitin-Protein Ligases; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C497446:VHL protein, human