Dataset Information

A let-7 microRNA-binding site polymorphism in the KRAS 3' UTR is associated with reduced survival in oral cancers.

ABSTRACT: MicroRNA (miRNA)-binding site polymorphisms that could contribute to disease risk and prognosis are rapidly being identified and investigated as this genetic variation may have a potentially profound impact on human health. A recently described variant allele in the KRAS 3' untranslated region that arises in the let-7 miRNA complementary site (KRAS-LCS6) and leads to increased KRAS expression in lung cancer was examined for its association with the occurrence of head and neck squamous cell carcinoma (HNSCC). We examined the prevalence of the KRAS-LCS6 variant allele in a population-based case-control study of HNSCC to determine if this KRAS-LCS6 genotype was associated with disease occurrence and patient survival. Although the KRAS-LCS6 variant genotype was not associated with the overall risk of HNSCC, cases with the KRAS-LCS6 variant genotype had significantly reduced survival [hazard ratio (HR), 1.6; 95% confidence interval (CI), 1.0-2.5] in models controlled for confounders of survival. This risk was greatest in cases of oral cavity carcinoma (HR, 2.7; 95% CI, 1.4-5.3). These data demonstrate that cases with the KRAS-LCS6 variant have significantly reduced survival time and suggest that this variant may alter the phenotype or therapeutic response of this disease.

SUBMITTER: Christensen BC

PROVIDER: S-EPMC2691138 | biostudies-literature | 2009 Jun

REPOSITORIES: biostudies-literature

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A let-7 microRNA-binding site polymorphism in the KRAS 3' UTR is associated with reduced survival in oral cancers.

Christensen Brock C BC Moyer Benjamin J BJ Avissar Michele M Ouellet Lauren G LG Plaza Silvia L SL McClean Michael D MD Marsit Carmen J CJ Kelsey Karl T KT

Carcinogenesis 20090420 6

MicroRNA (miRNA)-binding site polymorphisms that could contribute to disease risk and prognosis are rapidly being identified and investigated as this genetic variation may have a potentially profound impact on human health. A recently described variant allele in the KRAS 3' untranslated region that arises in the let-7 miRNA complementary site (KRAS-LCS6) and leads to increased KRAS expression in lung cancer was examined for its association with the occurrence of head and neck squamous cell carci ...[more]

PMID: 19380522

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Project description: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.

Dataset Information

A let-7 microRNA-binding site polymorphism in the KRAS 3' UTR is associated with reduced survival in oral cancers.

Publications

A let-7 microRNA-binding site polymorphism in the KRAS 3' UTR is associated with reduced survival in oral cancers.

Similar Datasets

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