title: Host genetic variants in the IGF binding protein-3 impact on survival of patients with advanced gastric cancer treated with palliative chemotherapy.
abstract: OBJECTIVE
  IGF binding protein-3 (IGFBP-3) displays growth inhibitory/proapoptotic action and counteracts the IGF-1 tumor-promoting effects by downregulating its bioavailability. We investigated whether IGFBP-3 SNPs determining high IGFBP-3 circulating levels are associated with improved survival of patients with advanced gastric cancer treated with palliative chemotherapy.
  
  
  METHODS
  A total of 185 patients undergoing combination chemotherapy for relapsed/metastatic disease were considered eligible for the present clinical investigation. Four functional IGFBP-3 SNPs (rs3110697, rs2854746, rs2864744 and rs2960436) were studied for association with overall survival (OS).
  
  
  RESULTS
  In the multivariate model including SNPs and clinicopathologic features, the rs285744 A allele and the rs2960436 A allele showed favorable association with survival. The hazard ratios for rs285744 C/A and A/A genotypes were 0.38 (95% CI: 0.18-0.66) and 0.20 (95% CI: 0.09-0.39), respectively. The hazard ratios for rs2960436 G/A and A/A genotypes were 0.41 (95% CI: 0.25-0.68) and 0.35 (95% CI: 0.16-0.58), respectively. Bonferroni-corrected p-values for the rs285744 A/A genotype and the rs2960436 A/A genotype were 0.012 and 0.024, respectively. There was linkage disequilibrium between the four variants and there were four common haplotypes (>5% estimated frequency). The most common haplotype (GCAA) included all alleles causing IGFBP-3 upregulation and their carriers demonstrated the best outcome in the log-rank comparison of survival curves.
  
  
  CONCLUSIONS
  Genetic regulation of the IGFBP-3 impacts on survival of patients with advanced gastric cancer. This finding deserves additional studies because of its prognostic and therapeutic implications.
authors.affiliation: Department of Onco-Hematology, Division of Oncology, Azienda Ospedale San Salvatore, Pesaro, Italy. frada@tin.it
authors.forename: Francesco
authors.initials: F
authors.lastname: Graziano
authors.forename: Annamaria
authors.initials: A
authors.lastname: Ruzzo
authors.forename: Emanuele
authors.initials: E
authors.lastname: Canestrari
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Catalano
authors.forename: Daniele
authors.initials: D
authors.lastname: Santini
authors.forename: Nadia
authors.initials: N
authors.lastname: Galluccio
authors.forename: Fotios
authors.initials: F
authors.lastname: Loupakis
authors.forename: Paolo
authors.initials: P
authors.lastname: Alessandroni
authors.forename: Daniele
authors.initials: D
authors.lastname: Spada
authors.forename: Rita
authors.initials: R
authors.lastname: Ficarelli
authors.forename: Renato
authors.initials: R
authors.lastname: Bisonni
authors.forename: Silvia
authors.initials: S
authors.lastname: D'Emidio
authors.forename: Bruno
authors.initials: B
authors.lastname: Vincenzi
authors.forename: Silvia
authors.initials: S
authors.lastname: Angeletti
authors.forename: Lisa
authors.initials: L
authors.lastname: Salvatore
authors.forename: Chiara
authors.initials: C
authors.lastname: Cremolini
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Tonini
authors.forename: Alfredo
authors.initials: A
authors.lastname: Falcone
authors.forename: Mauro
authors.initials: M
authors.lastname: Magnani
mesh_terms: D000368:Aged; D004359:Drug Therapy, Combination; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000235:genetics*; D018969:Insulin-Like Growth Factor Binding Proteins; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D010166:Palliative Care / Q000379:methods*; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D012008:Recurrence; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality; D016019:Survival Analysis
chemical_list: C515497:IGFBP3 protein, human; D018972:Insulin-Like Growth Factor Binding Protein 3; D018969:Insulin-Like Growth Factor Binding Proteins; D007334:Insulin-Like Growth Factor I