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Single nucleotide polymorphisms in the HIF-1? gene and chemoradiotherapy of locally advanced rectal cancer.

ABSTRACT: The aim of this study was to investigate the predictive impact of polymorphisms in the HIF-1? gene on the response to chemoradiotherapy (CRT) in rectal cancer. This study included two cohorts of patients with locally advanced rectal cancer receiving long-course CRT. The HIF-1? C1772T (rs11549465), G1790A (rs11549467) and c(*)191T>C (rs2057482) polymorphisms were investigated in the test cohort (n=65), and HIF-1? c(*)191T>C was analysed in the validation cohort (n=198). No correlations were identified between the polymorphisms and clinicopathological factors. The HIF-1? C1772T and HIF-1? G1790A polymorphisms demonstrated no correlation with tumour response to CRT in the test cohort. The HIF-1? c(*)191T>C CC genotype was marginally associated with a higher rate of complete tumour response (P=0.05) in the test cohort, while the HIF-1? c(*)191T>C CC genotype was associated with a poor tumour response (P=0.03) in the validation cohort. In conclusion, these results suggest that HIF-1? polymorphisms have no value as predictors of response to neoadjuvant CRT in rectal cancer. The results of the HIF-1? c(*)191T>C in two cohorts differ and emphasise the importance of biomarker validation.

SUBMITTER: Havelund BM

PROVIDER: S-EPMC3499484 | biostudies-literature | 2012 Nov

REPOSITORIES: biostudies-literature

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Single nucleotide polymorphisms in the HIF-1α gene and chemoradiotherapy of locally advanced rectal cancer.

Havelund Birgitte Mayland BM Spindler Karen-Lise Garm KL Ploen John J Andersen Rikke Fredslund RF Jakobsen Anders A

Oncology letters 20120731 5

The aim of this study was to investigate the predictive impact of polymorphisms in the HIF-1α gene on the response to chemoradiotherapy (CRT) in rectal cancer. This study included two cohorts of patients with locally advanced rectal cancer receiving long-course CRT. The HIF-1α C1772T (rs11549465), G1790A (rs11549467) and c(*)191T>C (rs2057482) polymorphisms were investigated in the test cohort (n=65), and HIF-1α c(*)191T>C was analysed in the validation cohort (n=198). No correlations were ident ...[more]

PMID: 23162650

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Project description:The aim of the present study was to investigate candidate genes for chemoradiotherapy (CRT) sensitivity in patients with locally advanced rectal cancer (LARC), and the potential mechanisms of their action. A microarray dataset (GSE98959) was obtained from the Gene Expression Omnibus database that included microRNA (miRNA, miR) expression profiling of 22 samples from patients with LARC who had received preoperative radiotherapy and chemotherapy. Of these patients, 10 responded to the treatment and 12 did not. Differentially expressed miRNAs (DEMs) were identified, followed by the construction of an miRNA-gene network. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and Gene Ontology (GO) function analyses were performed on the target genes in the miRNA-gene network. Furthermore, a protein-protein interaction (PPI) network was constructed on the basis of the target genes, followed by GO function enrichment and KEGG pathway analysis. A total of 30 DEMs were identified between the responder and non-responder groups. Thiamine metabolism (including miR-371a-3p) was the pathway with the highest enrichment of DEMs. The pathway that was most markedly enriched in the target genes of upregulated miRNAs was the pluripotency of stem cells pathway, as indicated by phosphoinositide-4,5-bisphosphate 3-kinase γ (PIK3CG) and anaphase-promoting complex subunit 2 (APC2). Pathways in cancer exhibited the highest enrichment in the set of target genes of downregulated miRNAs. KEGG pathway and GO function analysis indicated that target genes in the PPI network were enriched in the glioma pathway and assembled in the intracellular signaling cascade function, as indicated by the proto-oncogene NRAS. miR-371a-3p may be a candidate miRNA for CRT sensitivity in LARC via the thiamine metabolism pathway. PIK3CG and APC2 may contribute to CRT sensitivity via signaling pathways regulating the pluripotency of stem cells. Furthermore, NRAS may serve an important role in mediating CRT sensitivity via an intracellular signaling cascade.

Dataset Information

Single nucleotide polymorphisms in the HIF-1? gene and chemoradiotherapy of locally advanced rectal cancer.

Publications

Single nucleotide polymorphisms in the HIF-1α gene and chemoradiotherapy of locally advanced rectal cancer.

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