MicroRNA Expression Signatures Associated With BRAF-Mutated Versus KRAS-Mutated Colorectal Cancers. Issue 15 (April 2016) - Choi, Yong Won
Abstract : Supplemental Digital Content is available in the text Abstract : Abstract: BRAF and KRAS genes are known to play a similar role in the activation of RAS-RAF-MEK-ERK signaling pathway in colorectal tumorigenesis. However, BRAF -mutated colorectal cancers (CRCs) have distinct clinicopathologic characteristics different from those of the KRAS mutated ones as in comparison the BRAF -mutated CRCs are associated with a much worse prognosis for the afflicted patients. This study aimed to determine the different miRNA expression signatures associated with BRAF -mutated CRCs in comparison to KRAS -mutated ones, and to identify the specific miRNAs possibly mediating the aggressive phenotype of the BRAF -mutated CRCs. We screened 535 formalin-fixed paraffin-embedded CRC tissue samples for the BRAF V600E mutation, and selected 7 BRAF -mutated and 7 KRAS -mutated CRCs that were tumor size, stage, and microsatellite status-matched. Affymetrix GeneChip® miRNA 4.0 Array was used for detection of miRNA expression differences in the selected samples. We validated the array results by quantitative reverse transcription polymerase chain reaction (qRT-PCR) for selected miRNAs. A total of 10 differentially expressed (DE) miRNAs associated with BRAF -mutated CRCs were obtained, including miR-31-5p, miR-877-5p, miR-362-5p, and miR-425-3p. miR-31-5p showed the highest fold change (8.3-fold) among all of the miRNAs analyzed. From the analyses of GO biological processes, the DE-miRNAs were functionally relevant to cellular proliferation such as positive regulation of gene expression ( P = 1.26 × 10 −10 ), transcription ( P = 9.70 × 10 −10 ), and RNA metabolic process ( P = 1.97 × 10 −9 ). Bioinformatics analysis showed that the DE-miRNAs were significantly enriched in cancer-associated pathways including neutrophin signaling ( P = 6.84 × 10 −5 ), pathways in cancer ( P = 0.0016), Wnt signaling ( P = 0.0027), and MAPK signaling pathway ( P = 0.0036). Our results suggest that the DE-miRNAs in BRAF -mutated CRCs in comparison to KRAS -mutated CRCs are implicated in the aggressive phenotype of the BRAF -mutated CRCs. Further experimental validation is required to confirm these results.