Abstract 2599: IGF gene pathway and progression to fatal prostate cancer after diagnosis in men of European ancestry

Background: Substantial epidemiologic and experimental evidence implicated the role of insulin-like growth factor (IGF) pathway in prostate carcinogenesis. Many studies have demonstrated an increased risk of prostate cancer, especially advanced diseases among men with elevated IGF-I blood levels. Given limited evidence on the role of genetic variations in the IGF pathway on prostate cancer progression to fatal outcome, we comprehensively evaluated the association between genetic variants in 26 genes related to the insulin-like growth factor (IGF) pathway and prostate cancer specific mortality. Methods: Within the 7 cohort studies in the NCI Breast and Prostate Cancer Cohort Consortium (BPC3), a total of 590 tagging SNPs were successfully genotyped in 5887 men of European ancestry who were diagnosed with prostate cancer. SNPs were analyzed using Cox proportional hazards models under genotypic and additive allele models. Follow-up was defined from the date of prostate cancer diagnosis to the date of any death or last follow-up. Patients died from causes other than prostate cancer were censored. All analyses were adjusted for age at diagnosis and cohort. To account for multiple testing, the number of effective SNPs was calculated for each gene using a Spectral Decomposition approach. Results: In total, 704 prostate cancer deaths occurred during a median follow up of 8.9 years. After adjusting for age at diagnosis, cohorts and a gene-based correction for multiple testing, 3 SNPs in IGF2AS (insulin-like growth factor 2 antisense located in chromosome 11p15.5) were significantly associated with prostate cancer-specific mortality. Two of these SNPs (rs1004446 and rs3741211) were in linkage disequilibrium (r2=1) but they were not in linkage disequilibrium with the third SNP (rs4366464, r2=0.03). For rs3741211, each additional minor allele G was associated with 16% (HR 0.83; 95% CI 0.72-0.92; Pcorrected=0.02) lower risk of prostate cancer specific mortality. For rs4366464, each additional minor allele G was associated with 44% (HR 1.44; 95% CI 1.19-1.73) increased risk (Pcorrected=0.001). The association for SNP rs4366464 remained statistically significant after further adjusting for multiple testing on the 26 genes in the pathway. Conclusion: Germline variation in the IGF2AS gene was significantly positively and inversely associated with progression to fatal prostate cancer after diagnosis in this large cohort consortium of prostate cancer. These findings need to be confirmed by other studies. Given the link of this region in IGF2 imprinting, methylation and Wilms’ tumors, the role of IGF2AS in cancer progression deserves attention. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2599. doi:1538-7445.AM2012-2599