Abstract
In an effort to identify the earliest molecular changes in tumorigenesis, we analyzed the gene and protein expression profile of morphologically normal epithelial cells bearing a single-hit in a tumor suppressor gene. This approach is based on the hypothesis that, while biallelic inactivation of the gatekeeper tumor suppressor gene is necessary to initiate tumorigenesis of a given target epithelium, heterozygous mutations of this gene might be associated with initial molecular alterations (preinitiation) present in the morphologically “normal” mucosa. In turn, the altered mRNA and protein expression repertoire of single-hit cells may identify targets for measures that could delay or even prevent progression to carcinoma.
We studied four different sites: breast, ovary (predisposing genotypes: BRCA1 and BRCA2), kidney (predisposing genotypes: VHL and TSC1/2), and colon (predisposing genotype: APC).
Our comparisons of epithelial cells from tumor suppressor gene mutation-carriers and controls identified multiple changes in gene expression, that were independently validated by real-time RT-PCR analysis. Several of the differentially expressed genes had been previously proposed as cancer markers, including mammaglobin in breast cancer and serum amyloid in ovarian cancer. These findings demonstrate that heterozygosity for a mutant tumor suppressor gene can alter the expression profiles of phenotypically normal epithelial cells in a gene-specific manner; these detectable effects of “one-hit” represent early molecular changes in tumorigenesis that may serve as novel biomarkers of cancer risk and as targets for chemoprevention.
Citation Information: Cancer Prev Res 2010;3(12 Suppl):PL04-04.
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