title: Prognostic significance and gene expression profiles of p53 mutations in microsatellite-stable stage III colorectal adenocarcinomas.
abstract: Although the prognostic value of p53 abnormalities in Stage III microsatellite stable (MSS) colorectal cancers (CRCs) is known, the gene expression profiles specific to the p53 status in the MSS background are not known. Therefore, the current investigation has focused on identification and validation of the gene expression profiles associated with p53 mutant phenotypes in MSS Stage III CRCs. Genomic DNA extracted from 135 formalin-fixed paraffin-embedded tissues, was analyzed for microsatellite instability (MSI) and p53 mutations. Further, mRNA samples extracted from five p53-mutant and five p53-wild-type MSS-CRC snap-frozen tissues were profiled for differential gene expression by Affymetrix Human Genome U133 Plus 2.0 arrays. Differentially expressed genes were further validated by the high-throughput quantitative nuclease protection assay (qNPA), and confirmed by quantitative real-time polymerase chain reaction (qRT-PCR) and by immunohistochemistry (IHC). Survival rates were estimated by Kaplan-Meier and Cox regression analyses. A higher incidence of p53 mutations was found in MSS (58%) than in MSI (30%) phenotypes. Both univariate (log-rank, P = 0.025) and multivariate (hazard ratio, 2.52; 95% confidence interval, 1.25-5.08) analyses have demonstrated that patients with MSS-p53 mutant phenotypes had poor CRC-specific survival when compared to MSS-p53 wild-type phenotypes. Gene expression analyses identified 84 differentially expressed genes. Of 49 down-regulated genes, LPAR6, PDLIM3, and PLAT, and, of 35 up-regulated genes, TRIM29, FUT3, IQGAP3, and SLC6A8 were confirmed by qNPA, qRT-PCR, and IHC platforms. p53 mutations are associated with poor survival of patients with Stage III MSS CRCs and p53-mutant and wild-type phenotypes have distinct gene expression profiles that might be helpful in identifying aggressive subsets.
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Venkat R
authors.initials: VR
authors.lastname: Katkoori
authors.forename: Chandrakumar
authors.initials: C
authors.lastname: Shanmugam
authors.forename: Xu
authors.initials: X
authors.lastname: Jia
authors.forename: Swaroop P
authors.initials: SP
authors.lastname: Vitta
authors.forename: Meenakshi
authors.initials: M
authors.lastname: Sthanam
authors.forename: Tom
authors.initials: T
authors.lastname: Callens
authors.forename: Ludwine
authors.initials: L
authors.lastname: Messiaen
authors.forename: Dongquan
authors.initials: D
authors.lastname: Chen
authors.forename: Bin
authors.initials: B
authors.lastname: Zhang
authors.forename: Harvey L
authors.initials: HL
authors.lastname: Bumpers
authors.forename: Temesgen
authors.initials: T
authors.lastname: Samuel
authors.forename: Upender
authors.initials: U
authors.lastname: Manne
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015179:Colorectal Neoplasms / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D005647:Fucosyltransferases / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D060588:LIM Domain Proteins / Q000235:genetics; D008297:Male; D008840:Microfilament Proteins / Q000235:genetics; D053842:Microsatellite Instability; D018895:Microsatellite Repeats / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D009367:Neoplasm Staging; D009419:Nerve Tissue Proteins / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D050480:Plasma Membrane Neurotransmitter Transport Proteins / Q000235:genetics; D011379:Prognosis; D060888:Real-Time Polymerase Chain Reaction; D049368:Receptors, Lysophosphatidic Acid / Q000235:genetics; D010959:Tissue Plasminogen Activator / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; D060588:LIM Domain Proteins; C545560:LPAR6 protein, human; D008840:Microfilament Proteins; D009419:Nerve Tissue Proteins; C108834:PDLIM3 protein, human; D050480:Plasma Membrane Neurotransmitter Transport Proteins; D049368:Receptors, Lysophosphatidic Acid; C094770:SLC6A8 protein, human; C087296:TRIM29 protein, human; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D005647:Fucosyltransferases; C019818:3-galactosyl-N-acetylglucosaminide 4-alpha-L-fucosyltransferase; C067262:PLAT protein, human; D010959:Tissue Plasminogen Activator