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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.

SUBMITTER: Cao Y

PROVIDER: S-EPMC4081624 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature

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

Cao Yin Y Lindström Sara S Schumacher Fredrick F Stevens Victoria L VL Albanes Demetrius D Berndt Sonja S Boeing Heiner H Bueno-de-Mesquita H Bas HB Canzian Federico F Chamosa Saioa S Chanock Stephen J SJ Diver W Ryan WR Gapstur Susan M SM Gaziano J Michael JM Giovannucci Edward L EL Haiman Christopher A CA Henderson Brian B Johansson Mattias M Le Marchand Loïc L Palli Domenico D Rosner Bernard B Siddiq Afshan A Stampfer Meir M Stram Daniel O DO Tamimi Rulla R Travis Ruth C RC Trichopoulos Dimitrios D Willett Walter C WC Yeager Meredith M Kraft Peter P Hsing Ann W AW Pollak Michael M Lin Xihong X Ma Jing J

Journal of the National Cancer Institute 20140601 6

<h4>Background</h4>The insulin-like growth factor (IGF) signaling pathway has been implicated in prostate cancer (PCa) initiation, but its role in progression remains unknown.<h4>Methods</h4>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 gen ...[more]

PMID: 24824313

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Project description:BackgroundInsulin-like growth factor 1 (IGF1) stimulates mitosis and inhibits apoptosis. Some published results have shown an association between circulating IGF1 and breast-cancer risk, but it has been unclear whether this relationship is consistent or whether it is modified by IGF binding protein 3 (IGFBP3), menopausal status, oestrogen receptor status or other factors. The relationship of IGF1 (and IGFBP3) with breast-cancer risk factors is also unclear. The Endogenous Hormones and Breast Cancer Collaborative Group was established to analyse pooled individual data from prospective studies to increase the precision of the estimated associations of endogenous hormones with breast-cancer risk.MethodsIndividual data on prediagnostic IGF1 and IGFBP3 concentrations were obtained from 17 prospective studies in 12 countries. The associations of IGF1 with risk factors for breast cancer in controls were examined by calculating geometric mean concentrations in categories of these factors. The odds ratios (ORs) with 95% CIs of breast cancer associated with increasing IGF1 concentrations were estimated by conditional logistic regression in 4790 cases and 9428 matched controls, with stratification by study, age at baseline, and date of baseline. All statistical tests were two-sided, and a p value of less than 0.05 was considered significant.FindingsIGF1 concentrations, adjusted for age, were positively associated with height and age at first pregnancy, inversely associated with age at menarche and years since menopause, and were higher in moderately overweight women and moderate alcohol consumers than in other women. The OR for breast cancer for women in the highest versus the lowest fifth of IGF1 concentration was 1.28 (95% CI 1.14-1.44; p<0.0001). This association was not altered by adjusting for IGFBP3, and did not vary significantly by menopausal status at blood collection. The ORs for a difference in IGF1 concentration between the highest and lowest fifth were 1.38 (95% CI 1.14-1.68) for oestrogen-receptor-positive tumours and 0.80 (0.57-1.13) for oestrogen-receptor-negative tumours (p for heterogeneity=0.007).InterpretationCirculating IGF1 is positively associated with breast-cancer risk. The association is not substantially modified by IGFBP3, and does not differ markedly by menopausal status, but seems to be confined to oestrogen-receptor-positive tumours.FundingCancer Research UK.

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

Publications

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

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