Association of variants in genes encoding for macrophage-related functions with clinical outcome in patients with loco-regional gastric cancer
Menée sur une cohorte japonaise et une cohorte américaine incluant au total 264 patients atteints d'un cancer gastrique de stade loco-régional, cette étude analyse l'association entre 11 polymorphismes à simple nucléotide de gènes codant pour des protéines impliquées dans les réponses immunitaires sollicitant les macrophages (
Background : NF-
κB and CCL2/CCR2 chemokine axis play a central role in tumor progression such as stimulation of angiogenesis, acceleration of tumor invasion and migration, and suppression of innate immunosurveillance in the macrophage-related functions. There have been few reports regarding association of the macrophage function-related genes with clinical outcome in gastric cancer. We hypothesized that variants in genes encoding for NF-κB and CCL2/CCR2 axis may predict prognosis in gastric cancer and tested whether the functional single-nucleotide polymorphisms (SNPs) will be associated with clinical outcome in patients with gastric cancer across two independent groups.
Patients and methods
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This study enrolled two cohorts which consisted of 160 Japanese patients and 104 U.S. patients with loco-regional gastric cancer. Genomic DNA was analyzed for association of 11 SNPs in NFKB1, RELA, CCL2, and CCR2 with clinical outcome using PCR-based direct DNA sequencing.
Results
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The univariable analysis showed 4 SNPs had significant association with clinical outcome in the Japanese cohort, NFKB1 rs230510 remained significant upon multivariable analysis. The patients with the A allele of the NFKB1 rs230510 had significantly longer overall survival (OS) compared to those with the T/T genotype in both the Japanese and U.S. cohort in the univariable analysis. In contrast, genotypes with the T allele of CCL2 rs4586 were significantly associated with shorter OS compared to the C/C genotype in the U.S. cohort (HR: 2.43; P=0.015) but longer OS in the Japanese cohort (HR: 0.58; P=0.021), resulting in the statistically significantly opposite impact on OS (P=0.001).
Conclusions
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Our study provides the first evidence that the NFKB1 rs230510 and CCL2 rs4586 are significantly associated with clinical outcome in patients with loco-regional gastric cancer. These results also suggest that the genetic predisposition of the host may dictate the immune-related component of the tumor for progression in gastric cancer.
Annals of Oncology , résumé, 2014