title: Colorectal tumor molecular phenotype and miRNA: expression profiles and prognosis.
abstract: MiRNAs regulate gene expression by post-transcriptionally suppressing mRNA translation or by causing mRNA degradation. It has been proposed that unique miRNAs influence specific tumor molecular phenotype. In this paper, we test the hypotheses that miRNA expression differs by tumor molecular phenotype and that those differences may influence prognosis. Data come from population-based studies of colorectal cancer conducted in Utah and the Northern California Kaiser Permanente Medical Care Program. A total of 1893 carcinoma samples were run on the Agilent Human miRNA Microarray V19.0 containing 2006 miRNAs. We assessed differences in miRNA expression between TP53-mutated and non-mutated, KRAS-mutated and non-mutated, BRAF-mutated and non-mutated, CpG island methylator phenotype (CIMP) high and CIMP low, and microsatellite instability (MSI) and microsatellite stable (MSS) colon and rectal tumors. Using a Cox proportional hazard model we evaluated if those miRNAs differentially expressed by tumor phenotype influenced survival after adjusting for age, sex, and AJCC stage. There were 22 differentially expressed miRNAs for TP53-mutated colon tumors and 5 for TP53-mutated rectal tumors with a fold change of >1.49 (or <0.67). Additionally, 13 miRNAS were differentially expressed for KRAS-mutated rectal tumors, 8 differentially expressed miRNAs for colon CIMP high tumors, and 2 differentially expressed miRNAs for BRAF-mutated colon tumors. The majority of differentially expressed miRNAS were observed between MSI and MSS tumors (94 differentially expressed miRNAs for colon; 41 differentially expressed miRNAs for rectal tumors). Of these miRNAs differentially expressed between MSI and MSS tumors, the majority were downregulated. Ten of the differentially expressed miRNAs were associated with survival; after adjustment for MSI status, five miRNAS, miR-196b-5p, miR-31-5p, miR-99b-5p, miR-636, and miR-192-3p, were significantly associated with survival. In summary, it appears that the majority of miRNAs that are differentially expressed by tumor molecular phenotype are MSI tumors. However, these miRNAs appear to have minimal effect on prognosis.
authors.affiliation: Department of Medicine, University of Utah, Salt Lake City, UT, USA.
authors.forename: Martha L
authors.initials: ML
authors.lastname: Slattery
authors.affiliation: Department of Medicine, University of Utah, Salt Lake City, UT, USA.
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Herrick
authors.affiliation: Department of Medicine, University of Utah, Salt Lake City, UT, USA.
authors.forename: Lila E
authors.initials: LE
authors.lastname: Mullany
authors.affiliation: Department of Medicine, University of Utah, Salt Lake City, UT, USA.
authors.forename: Erica
authors.initials: E
authors.lastname: Wolff
authors.affiliation: Department of Medicine, University of Utah, Salt Lake City, UT, USA.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Hoffman
authors.affiliation: Department of Medicine, University of Utah, Salt Lake City, UT, USA.
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Pellatt
authors.affiliation: Department of Mathematics and Statistics, Utah State University, Logan, UT, USA.
authors.forename: John R
authors.initials: JR
authors.lastname: Stevens
authors.affiliation: Department of Medicine, University of Utah, Salt Lake City, UT, USA.
authors.forename: Roger K
authors.initials: RK
authors.lastname: Wolff
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics*; D002140:California; D016022:Case-Control Studies; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D019295:Computational Biology; D019175:DNA Methylation; D004252:DNA Mutational Analysis; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D053842:Microsatellite Instability; D008875:Middle Aged; D009154:Mutation; D009367:Neoplasm Staging; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D016016:Proportional Hazards Models; D012042:Registries; D012307:Risk Factors; D014589:Utah
chemical_list: D014408:Biomarkers, Tumor; D035683:MicroRNAs