Insulin-Like Growth Factor Axis Gene Polymorphisms and Clinical Outcomes in Pancreatic Cancer

Background & Aims

Insulin-like growth factor (IGF)–axis mediated signaling pathways play an important role in pancreatic cancer development and progression. We examined whether IGF-axis gene variants are associated with clinical outcomes in pancreatic cancer.

Methods

We retrospectively genotyped 41 single-nucleotide polymorphisms from 10 IGF-axis genes in 333 patients with localized pancreatic adenocarcinoma and validated the findings in 373 patients with advanced disease. Associations between genotype and overall survival (OS) were evaluated using multivariable Cox proportional hazard regression models.

Results

IGF1 *8470T>C, IGF1R IVS2+46329T>C, IGFBP3 A32G, IRS1 G972R in patients with localized disease; IGF1R IVS20-3431A>G, IGF1R T766T, IGFBP3−202A>C, IRS1 IVS1+4315C>G, IRS1 G972R in patients with advanced disease; and IGF1R T766T, IGF2R L252V, IGFBP3 −202A>C, IRS1 IVS1+4315C>G, IRS1 G972R, IRS2 IVS1+5687T>C in all patients were significantly associated with OS (P ≤ .007). Two haplotypes containing the variant allele of either IRS1 G972R or IVS1-10949G>A, and an IRS2 haplotype predicted worse OS (P ≤ .002). A significant correlation between increased number of unfavorable genotypes and decreased OS was observed; patients with 0–1 (n = 247), 2 (n = 237), 3 (n = 145), 4 (n = 60), and 5–8 (n = 17) unfavorable genotypes had median survival time of 24.2, 16.4, 14.4, 9.6, and 7.4 months, respectively (P < .001). Several single-nucleotide polymorphisms of IGF1R, IGF2R, and IRS1 gene were significantly associated with tumor response to therapy and disease stage.

Conclusions

These data suggest that individual genetic variations in the IGF axis pathway may predict worse survival in patients with pancreatic cancer. This information may identify population subgroups that could benefit from IGF₁R-targeted agents.

Keywords: Pancreatic Cancer, Insulin-Like Growth Factor–Axis, Single-Nucleotide Polymorphism, Overall Survival

Abbreviations used in this paper: AKT, v-akt murine thymoma viral oncogene homolog, ERK, extracellular signal-regulated kinase, FDR, false discovery rate, IGF, insulin-like growth factor, IGFBP, insulin-like growth factor binding protein, IRS, insulin-receptor substrate, MAF, minor allele frequency, MAPK, mitogen-activated protein kinase, mTOR, mammalian target of rapamycin, OS, overall survival, PI3K, phosphatidylinositol-3′-kinase, SNP, single-nucleotide polymorphism