Insulin-like growth factor pathway genetic polymorphisms, circulating IGF1 and IGFBP3, and prostate cancer survival

Abstract

Background: The insulin-like growth factor (IGF) signaling pathway has been implicated in prostate cancer (PCa) initiation, but its role in progression remains unknown.

Methods: Among 5887 PCa patients (704 PCa deaths) of European ancestry from seven cohorts in the National Cancer Institute Breast and Prostate Cancer Cohort Consortium, we conducted Cox kernel machine pathway analysis to evaluate whether 530 tagging single nucleotide polymorphisms (SNPs) in 26 IGF pathway-related genes were collectively associated with PCa mortality. We also conducted SNP-specific analysis using stratified Cox models adjusting for multiple testing. In 2424 patients (313 PCa deaths), we evaluated the association of prediagnostic circulating IGF1 and IGFBP3 levels and PCa mortality. All statistical tests were two-sided.

Results: The IGF signaling pathway was associated with PCa mortality (P = .03), and IGF2-AS and SSTR2 were the main contributors (both P = .04). In SNP-specific analysis, 36 SNPs were associated with PCa mortality with P trend less than .05, but only three SNPs in the IGF2-AS remained statistically significant after gene-based corrections. Two were in linkage disequilibrium (r 2 = 1 for rs1004446 and rs3741211), whereas the third, rs4366464, was independent (r 2 = 0.03). The hazard ratios (HRs) per each additional risk allele were 1.19 (95% confidence interval [CI] = 1.06 to 1.34; P trend = .003) for rs3741211 and 1.44 (95% CI = 1.20 to 1.73; P trend < .001) for rs4366464. rs4366464 remained statistically significant after correction for all SNPs (P trend.corr = .04). Prediagnostic IGF1 (HRhighest vs lowest quartile = 0.71; 95% CI = 0.48 to 1.04) and IGFBP3 (HR = 0.93; 95% CI = 0.65 to 1.34) levels were not associated with PCa mortality.

Conclusions: The IGF signaling pathway, primarily IGF2-AS and SSTR2 genes, may be important in PCa survival.

Figure 1.

IGF signaling pathway. Genes included in this analysis were SST, SSTR1-5, GHRH, GHRHR, GHR, IGF1, IGF1R, IGFBP1-6, IGF2-AS, IGF2R, IGFALS, INSR, IRS1, IRS2 (shown in Figure 1) and POU1F1, GNRH1, and GNRHR (not shown); the insulin receptor is encoded by a single gene, INSR, from which alternate splicing during transcription results in either IRA or IRB isoforms; the insulin gene (INS) was not genotyped, and genes in PI3k/Akt/mTOR and Ras-MAPK pathway were not included in this analysis.

Figure 2.

Association of IGF2-AS single nucleotide polymorphism rs3741211 and rs4366464 with prostate cancer–specific mortality by study cohort. Hazard ratios (HRs; diamonds) and 95% confidence intervals (CIs; error bars) calculated for the association for the individual studies and the pooled analysis for rs3741211 (A) and rs4366464 (B) are shown. Size of gray square represents percentage weight of each study. RAF = risk allele frequency. ATBC = Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study; CI = confidence interval; CPS-II = American Cancer Society Cancer Prevention Study II; EPIC = European Prospective Investigation into Cancer and Nutrition; HPFS = Health Professionals Follow-up Study; HR = hazard ratio; MEC = Multiethnic Cohort Study; PHS = Physicians’ Health Study; PLCO = Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial.

Figure 3.

Gene map of IGF2-AS/IGF2/INS region and single nucleotide polymorphisms (SNPs) genotyped in IGF2-AS (n = 9). Only SNPs rs1004446 and rs3741211 have an r ² greater than 0.8, indicated by an asterisk (*).