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Altered gene expression in phenotypically normal renal cells from carriers of tumor suppressor gene mutations
Radka Stoyanova1, Margie L Clapper, Alfonso Bellacosa
1Division of Population Science, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA.
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.
Insights
Early molecular changes in normal kidney cells from individuals with inherited cancer predisposition genes, like von Hippel-Lindau (VHL) and tuberous sclerosis complex (TSC), were identified. These "one-hit" alterations may offer targets for cancer prevention.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Tumorigenesis involves complex signaling networks driven by genetic and epigenetic alterations.
- Inherited mutations in tumor suppressor genes predispose individuals to specific cancers, often following a
- two-hit
- model.
- Early molecular events in tumorigenesis are not fully understood.
Purpose of the Study:
- To identify early molecular changes in phenotypically normal renal epithelial cells from individuals with germline mutations in VHL or TSC genes.
- To compare gene expression profiles between cells from mutation carriers and non-carriers.
- To explore potential targets for chemopreventive strategies.
Main Methods:
- Microarray analysis was used to compare gene expression profiles.
- Phenotypically normal renal epithelial cells were cultured from individuals with VHL or TSC germline mutations and from control non-mutation carriers.
- Real-time RT-PCR and Principal Component Analysis were employed for data validation and analysis.
Main Results:
- Gene expression profiles of renal epithelial cells differed significantly between VHL/TSC mutation carriers and controls.
- Microarray data confirmed known cellular pathways affected by VHL and TSC mutations.
- Heterozygosity for mutant tumor suppressor genes altered gene expression in a gene-specific manner.
Conclusions:
- Germline mutations in tumor suppressor genes can lead to detectable molecular changes in phenotypically normal cells.
- These early molecular alterations, or
- one-hit
- effects, represent potential targets for chemoprevention.
- Understanding these early changes is crucial for developing strategies to prevent cancer development in individuals with inherited predispositions.
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