Circulating insulin-like growth factor axis and the risk of pancreatic cancer in four prospective cohorts.
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ABSTRACT:
SUBMITTER: Wolpin BM
PROVIDER: S-EPMC2359655 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description: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.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.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<or=.007). Two haplotypes containing the variant allele of either IRS1 G972R or IVS1-10949G>A, and an IRS2 haplotype predicted worse OS (P<or=.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.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 IGF(1)R-targeted agents.
| S-EPMC2910789 | biostudies-literature
Project description:AIMS/HYPOTHESIS:Metabolomics technologies have identified numerous blood biomarkers for type 2 diabetes risk in case-control studies of middle-aged and older individuals. We aimed to validate existing and identify novel metabolic biomarkers predictive of future diabetes in large cohorts of young adults. METHODS:NMR metabolomics was used to quantify 229 circulating metabolic measures in 11,896 individuals from four Finnish observational cohorts (baseline age 24-45 years). Associations between baseline metabolites and risk of developing diabetes during 8-15 years of follow-up (392 incident cases) were adjusted for sex, age, BMI and fasting glucose. Prospective metabolite associations were also tested with fasting glucose, 2 h glucose and HOMA-IR at follow-up. RESULTS:Out of 229 metabolic measures, 113 were associated with incident type 2 diabetes in meta-analysis of the four cohorts (ORs per 1 SD: 0.59-1.50; p<?0.0009). Among the strongest biomarkers of diabetes risk were branched-chain and aromatic amino acids (OR 1.31-1.33) and triacylglycerol within VLDL particles (OR 1.33-1.50), as well as linoleic n-6 fatty acid (OR 0.75) and non-esterified cholesterol in large HDL particles (OR 0.59). The metabolic biomarkers were more strongly associated with deterioration in post-load glucose and insulin resistance than with future fasting hyperglycaemia. A multi-metabolite score comprised of phenylalanine, non-esterified cholesterol in large HDL and the ratio of cholesteryl ester to total lipid in large VLDL was associated with future diabetes risk (OR 10.1 comparing individuals in upper vs lower fifth of the multi-metabolite score) in one of the cohorts (mean age 31 years). CONCLUSIONS/INTERPRETATION:Metabolic biomarkers across multiple molecular pathways are already predictive of the long-term risk of diabetes in young adults. Comprehensive metabolic profiling may help to target preventive interventions for young asymptomatic individuals at increased risk.
| S-EPMC6861432 | biostudies-literature
Project description:Previous in vitro and case-control studies have found an association between the insulin-like growth factor (IGF)-axis and bladder cancer risk. Circulating concentrations of IGF-I have also been found to be associated with an increased risk of several cancer types; however, the relationship between pre-diagnostic circulating IGF-I concentrations and bladder cancer has never been studied prospectively. We investigated the association of pre-diagnostic plasma concentrations of IGF-I with risk of overall bladder cancer and urothelial cell carcinoma (UCC) in a case-control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. A total of 843 men and women diagnosed with bladder cancer between 1992 and 2005 were matched with 843 controls by recruitment centre, sex, age at recruitment, date of blood collection, duration of follow-up, time of day and fasting status at blood collection using an incidence density sampling protocol. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using conditional logistic regression with adjustment for smoking status. No association was found between pre-diagnostic circulating IGF-I concentration and overall bladder cancer risk (adjusted OR for highest versus lowest fourth: 0.91, 95% CI: 0.66-1.24, ptrend = 0.40) or UCC (n of cases = 776; 0.91, 0.65-1.26, ptrend = 0.40). There was no significant evidence of heterogeneity in the association of IGF-I with bladder cancer risk by tumour aggressiveness, sex, smoking status, or by time between blood collection and diagnosis (pheterogeneity > 0.05 for all). This first prospective study indicates no evidence of an association between plasma IGF-I concentrations and bladder cancer risk.
| S-EPMC6220964 | biostudies-literature
Project description:Experimental and epidemiologic evidence supports the role of circulating insulin-like growth factor-1 (IGF-1) levels with the risk of prostate cancer. Most circulating IGF-1 is bound to specific binding proteins, and only about 5% circulates in a free form. We explored the relation of free IGF-1 and other components of the IGF system with lethal prostate cancer. Using prospectively collected samples, we undertook a nested case-only analysis among 434 men with lethal prostate cancer and 524 men with indolent, nonlethal prostate cancer in the Physicians' Health Study and the Health Professionals Follow-up Study. Prediagnostic plasma samples were assayed for free IGF-1 and total IGF-1, acid labile subunit, pregnancy-associated plasma protein A (PAPP-A), and intact and total IGF binding protein 4. We estimated odds ratios (ORs) and corresponding 95% confidence intervals (CIs) for the associations between IGF-1-related biomarkers and lethal prostate cancer using unconditional logistic regression models adjusted for age, height, and body mass index. Men in the highest quartile of PAPP-A levels had 42% higher odds of lethal prostate cancer (pooled adjusted OR = 1.42, 95% CI = 1.04 to 1.92) compared with men in the lowest 3 quartiles. There were no statistically significant differences in the other plasma analytes. The positive association between PAPP-A and lethal prostate cancer was present among men with intact PTEN but not among those with tumor PTEN loss (2-sided Pinteraction = .001). Our study provides suggestive evidence that among men who later develop prostate cancer, higher plasma PAPP-A levels measured prior to diagnosis are associated with increased risk of lethal compared with indolent disease.
| S-EPMC8763370 | biostudies-literature
Project description:BACKGROUND:Resistin is a polypeptide hormone secreted by adipose tissue. A prior hospital-based case-control study reported serum resistin levels to be inversely associated with risk of multiple myeloma (MM). To date, this association has not been investigated prospectively. METHODS:We measured resistin concentrations for pre-diagnosis peripheral blood samples from 178 MM cases and 358 individually matched controls from three cohorts participating in the MM cohort consortium. RESULTS:In overall analyses, higher resistin levels were weakly associated with reduced MM risk. For men, we observed a statistically significant inverse association between resistin levels and MM (odds ratio, 0.44; 95% confidence interval (CI) 0.24-0.83 and 0.54; 95% CI 0.29-0.99, for the third and fourth quartiles, respectively, vs the lowest quartile; Ptrend=0.03). No association was observed for women. CONCLUSIONS:This study provides the first prospective evidence that low circulating resistin levels may be associated with an increased risk of MM, particularly for men.
| S-EPMC5674102 | biostudies-literature
Project description:Adiposity is associated with pancreatic cancer; however, the underlying mechanism(s) is uncertain. Leptin is an adipokine involved in metabolic regulation, and obese individuals have higher concentrations. We conducted a pooled, nested case-control study of cohort participants from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study, and the Cancer Prevention Study II Nutrition Cohort to investigate whether prediagnostic serum leptin was associated with pancreatic cancer. A total of 731 pancreatic adenocarcinoma cases that occurred between 1986 and 2010 were included (maximum follow-up, 23 years). Incidence density-selected controls (n = 909) were matched to cases by cohort, age, sex, race, and blood draw date. Conditional logistic regression was used to calculate odds ratios and 95% confidence intervals. Sex-specific quintiles were based on the distribution of the controls. Overall, serum leptin was not associated with pancreatic cancer (quintile 5 vs. quintile 1: odds ratio = 1.13, 95% confidence interval: 0.75, 1.71; Ptrend = 0.38). There was a significant interaction by follow-up time (P = 0.003), such that elevated risk was apparent only during follow-up of more than 10 years after blood draw (quintile 5 vs. quintile 1: odds ratio = 2.55, 95% confidence interval: 1.23, 5.27; Ptrend = 0.004). Our results support an association between increasing leptin concentration and pancreatic cancer; however, long follow-up is necessary to observe the relationship. Subclinical disease may explain the lack of association during early follow-up.
| S-EPMC4517697 | biostudies-literature
Project description:Insulin-like growth factor (IGF)-I has cancer promoting activities. However, the hypothesis that circulating IGF-I concentration is related to risk of lymphoma overall or its subtypes has not been examined prospectively. IGF-I concentration was measured in pre-diagnostic plasma samples from a nested case-control study of 1,072 cases of lymphoid malignancies and 1,072 individually matched controls from the European Prospective Investigation into Cancer and Nutrition. Odds ratios (ORs) and confidence intervals (CIs) for lymphoma were calculated using conditional logistic regression. IGF-I concentration was not associated with overall lymphoma risk (multivariable-adjusted OR for highest versus lowest third?=?0.77 [95% CI?=?0.57-1.03], ptrend ?=?0.06). There was no statistical evidence of heterogeneity in this association with IGF-I by sex, age at blood collection, time between blood collection and diagnosis, age at diagnosis, or body mass index (pheterogeneity for all ???0.05). There were no associations between IGF-I concentration and risk for specific BCL subtypes, T-cell lymphoma or Hodgkin lymphoma, although number of cases were small. In this European population, IGF-I concentration was not associated with risk of overall lymphoma. This study provides the first prospective evidence on circulating IGF-I concentrations and risk of lymphoma. Further prospective data are required to examine associations of IGF-I concentrations with lymphoma subtypes.
| S-EPMC5299544 | biostudies-literature
Project description:BackgroundHyperinsulinemia, high insulin-like growth factor 1 (IGF1) levels, and low IGF binding protein 1 (IGFBP1) levels have been implicated in the relationship between obesity and increased risk of colorectal cancer (CRC). However, it remains inconclusive whether circulating biomarkers of insulin and the IGF axis are associated with conventional adenoma and serrated polyp, the two distinct groups of CRC precursors.MethodsWe prospectively examined the associations of plasma C-peptide, IGF1, IGFBP1, IGFBP3, and IGF1 to IGFBP3 ratio with conventional adenoma and serrated polyp among 11 072 women from the Nurses' Health Studies. Multivariable logistic regression was used to calculate the odds ratio (OR) per 1-SD increase in each biomarker for overall risk of conventional adenoma and serrated polyp and according to polyp feature.ResultsDuring 20 years of follow-up, we documented 1234 conventional adenomas and 914 serrated polyps. After adjusting for various lifestyle factors (including body mass index), higher concentrations of IGFBP1 were associated with lower risk of serrated polyp (OR = 0.84, 95% confidence interval = 0.75 to 0.95, P = .005). The association was particularly strong for large serrated polyp (≥10 mm) located in the distal colon and rectum (OR = 0.59, 95% confidence interval = 0.39 to 0.87, P = .01). In contrast, we did not find any statistically significant association between the biomarkers and conventional adenoma.ConclusionsA higher plasma level of IGFBP1 was associated with lower risk of serrated polyp. Our findings support a potential role of IGFBP1 in the serrated pathway of CRC in women.
| S-EPMC7050032 | biostudies-literature
Project description:To characterize predictors of insulin-like growth factor-1 and insulin-like growth factor-binding protein-3 in acute critical illness with the hypothesis that acute factors associated with critical illness will more strongly predict circulating insulin-like growth factor-1 and insulin-like growth factor-binding protein-3 than chronic clinical or genetic factors.Observational study nested within a large prospective study using multivariable linear regression to model circulating insulin-like growth factor-1 and insulin-like growth factor-binding protein-3 with acute and chronic clinical variables, and genotype from five polymorphisms in insulin-like growth factor pathway genes.ICUs from two large academic medical centers.Five hundred forty-three Caucasian patients with risk factors for acute respiratory distress syndrome and available plasma from early in critical illness.None.Total insulin-like growth factor-1 and insulin-like growth factor-binding protein-3 were measured in plasma using IMMULITE assays (Siemens, Malvern, PA). We examined age, gender, body mass index, cirrhosis, and diabetes, as well as Acute Physiology, Age, and Chronic Health Evaluation III score, acute hepatic dysfunction, pneumonia and aspiration, sepsis/septic shock, acute respiratory distress syndrome, and receipt of corticosteroids. Body mass index, cirrhosis, and acute respiratory distress syndrome were strongly associated with insulin-like growth factor-1 and insulin-like growth factor-binding protein-3 levels; Acute Physiology, Age, and Chronic Health Evaluation III was strongly associated with insulin-like growth factor-1 levels; and age was strongly associated with insulin-like growth factor-binding protein-3. Five polymorphisms (IGF1: rs1520220, rs35767, rs2946834; IGFBP1: rs4619; IGFBP3: rs2854746) were analyzed for associations with plasma levels. When genotypes were added to models, rs2854746 was significantly associated with plasma insulin-like growth factor-binding protein-3. Genotype explained an additional 2% of variability with an overall adjusted R-square of 0.18.Despite the acute derangements of critical illness, both acute and chronic health factors significantly influence circulating levels of insulin-like growth factor-1 and insulin-like growth factor-binding protein-3 early in critical illness. rs2854746 is also significantly associated with insulin-like growth factor-binding protein-3 levels in this ICU cohort. Overall, phenotypic and genotypic factors explained only a modest amount of variability in insulin-like growth factor-1 and insulin-like growth factor-binding protein-3. Further research is needed to understand how to apply these findings to patient care.
| S-EPMC4651824 | biostudies-literature
Project description:Insulin-like growth factors (IGF-I, IGF-II) and their binding proteins (IGFBP-1-6) play a key role in cell proliferation, differentiation and apoptosis, suggesting possible involvement in carcinogenesis. Several epidemiological studies show associations of IGFs with prostate cancer. We searched the published literature for all studies relating levels of IGFs or IGFBPs with prostate cancer. We performed random effects meta-analysis to calculate summary odds ratios. The number of studies (prostate cancer cases) included in each meta-analysis were 42 (7,481) IGF-I; 10 (923) IGF-II; 3 (485) IGFBP-1; 5 (577) IGFBP-2; 29 (6,541) IGFBP-3 and 11 (3,545) IGF-1:IGFBP-3 ratio. The pooled odds ratios (95% confidence intervals) per standard deviation increase in peptide were: IGF-I, OR = 1.21 (1.07, 1.36); IGF-II, OR = 1.17 (0.93, 1.47); IGFBP-1, OR = 1.21 (0.62, 2.33); IGFBP-2, OR = 1.18 (0.90, 1.54); IGFBP-3, OR = 0.88 (0.79, 0.98); IGFI:IGFBP-3 ratio, OR = 1.10 (0.97, 1.24). For all exposures, there was substantial heterogeneity (all I(2) > 75%), partly explained by study design: the magnitude of associations was smaller in prospective vs. retrospective studies, and for IGFBP-3, the inverse association with prostate cancer risk was seen in retrospective but not prospective studies. There was weak evidence that associations of IGF-I and IGFBP-3 with prostate cancer were stronger for advanced disease. Our meta-analysis confirms that raised circulating lGF-I is positively associated with prostate cancer risk. Associations between IGFBP-3 and prostate cancer were inconsistent, and there was little evidence for a role of IGF-II, IGFBP-1 or IGFBP-2 in prostate cancer risk.
| S-EPMC2743036 | biostudies-literature