Host genetic variants in the IGF binding protein-3 impact on survival of patients with advanced gastric cancer treated with palliative chemotherapy.
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.
Graziano
Francesco
F
Department of Onco-Hematology, Division of Oncology, Azienda Ospedale San Salvatore, Pesaro, Italy. frada@tin.it
Ruzzo
Annamaria
A
Canestrari
Emanuele
E
Catalano
Vincenzo
V
Santini
Daniele
D
Galluccio
Nadia
N
Loupakis
Fotios
F
Alessandroni
Paolo
P
Spada
Daniele
D
Ficarelli
Rita
R
Bisonni
Renato
R
D'Emidio
Silvia
S
Vincenzi
Bruno
B
Angeletti
Silvia
S
Salvatore
Lisa
L
Cremolini
Chiara
C
Tonini
Giuseppe
G
Falcone
Alfredo
A
Magnani
Mauro
M
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
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