title: Association of variants in genes encoding for macrophage-related functions with clinical outcome in patients with locoregional gastric cancer.
abstract: BACKGROUND
  Nuclear factor-kappaB (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 the 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.
  
  
  METHODS
  This study enrolled two cohorts which consisted of 160 Japanese patients and 104 US patients with locoregional 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
  The univariable analysis showed four 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 with those with the T/T genotype in both the Japanese and US cohort in the univariable analysis. In contrast, genotypes with the T allele of CCL2 rs4586 were significantly associated with shorter OS compared with the C/C genotype in the US cohort [hazard ratio (HR) 2.43; P = 0.015] but longer OS in the Japanese cohort (HR 0.58; P = 0.021), resulting in the statistically significant opposite impact on OS (P = 0.001).
  
  
  CONCLUSIONS
  Our study provides the first evidence that the NFKB1 rs230510 and CCL2 rs4586 are significantly associated with the clinical outcome in patients with locoregional 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.
authors.affiliation: Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles.
authors.forename: Y
authors.initials: Y
authors.lastname: Sunakawa
authors.affiliation: Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles.
authors.forename: S
authors.initials: S
authors.lastname: Stremitzer
authors.affiliation: Department of Preventive Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, USA.
authors.forename: S
authors.initials: S
authors.lastname: Cao
authors.affiliation: Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles.
authors.forename: W
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Preventive Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, USA.
authors.forename: D
authors.initials: D
authors.lastname: Yang
authors.affiliation: Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles.
authors.forename: T
authors.initials: T
authors.lastname: Wakatsuki
authors.affiliation: Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles.
authors.forename: Y
authors.initials: Y
authors.lastname: Ning
authors.affiliation: Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles.
authors.forename: S
authors.initials: S
authors.lastname: Yamauchi
authors.affiliation: Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles.
authors.forename: S
authors.initials: S
authors.lastname: Stintzing
authors.affiliation: Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles.
authors.forename: A
authors.initials: A
authors.lastname: Sebio
authors.affiliation: Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles.
authors.forename: R
authors.initials: R
authors.lastname: El-Khoueiry
authors.affiliation: Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles.
authors.forename: S
authors.initials: S
authors.lastname: Matsusaka
authors.affiliation: Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles.
authors.forename: A
authors.initials: A
authors.lastname: Parekh
authors.affiliation: Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles.
authors.forename: A
authors.initials: A
authors.lastname: Barzi
authors.affiliation: Department of Gastroenterology, School of Medicine, Kitasato University, Sagamihara.
authors.forename: M
authors.initials: M
authors.lastname: Azuma
authors.affiliation: Department of Surgery, School of Medicine, Kitasato University, Sagamihara, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Watanabe
authors.affiliation: Department of Gastroenterology, School of Medicine, Kitasato University, Sagamihara.
authors.forename: W
authors.initials: W
authors.lastname: Koizumi
authors.affiliation: Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles lenz@usc.edu.
authors.forename: H-J
authors.initials: HJ
authors.lastname: Lenz
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018932:Chemokine CCL2 / Q000235:genetics*; D015331:Cohort Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D053208:Kaplan-Meier Estimate; D008264:Macrophages / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D016016:Proportional Hazards Models; D054390:Receptors, CCR2 / Q000235:genetics*; D013274:Stomach Neoplasms / Q000235:genetics* / Q000276:immunology / Q000401:mortality; D051996:Transcription Factor RelA / Q000235:genetics*
chemical_list: C111835:CCL2 protein, human; C515334:CCR2 protein, human; D018932:Chemokine CCL2; D016328:NF-kappa B; C498143:RELA protein, human; D054390:Receptors, CCR2; D051996:Transcription Factor RelA
keywords: CCL2; NF-κB; ethnic difference; gastric cancer; single-nucleotide polymorphism