Serum levels of insulin-like growth factor-I and insulin-like growth factor-I binding protein-3: quality control for studies of stored serum.

The insulin-like growth factor (IGF) axis, particularly IGF-I and IGF binding protein-3 (IGFBP-3), has been the subject of much attention because of its role in juvenile growth and their association with cancers at several sites. However, epidemiologic studies of IGF-I and IGFBP-3 have had mixed results and several authors have speculated that quality control (QC), sample storage history, and other methodologic concerns could play a role in this heterogeneity. This article documents the results of storage history and QC efforts for a study of IGF-I and IGFBP-3 in 6,226 serum samples from the National Health and Nutrition Examination Survey III (NHANES III). The study was carried out on site at Diagnostic Systems Laboratories in Webster, Texas, using the IGF-I ELISA (DSL 10-5600) and the IGFBP-3 immunoradiometric assay (DSL 6600). A run-in study of assay performance suggested that plates, days, and weeks significantly affected the variance of both assays. Analysis of samples with different storage histories also indicated strong effects of storage history. Serum samples disbursed to laboratories for measurement of diverse analytes and then returned for storage showed reductions in serum IGF-I level averaging 43% and reductions in IGFBP-3 of 25% compared with samples shipped immediately to the repository for long-term storage at -80 degrees C. Therefore, the main study was carried out using samples that had been shipped directly to the National Center for Health Statistics/NHANES collection center for storage. Laboratory analyses of NHANES III and QC samples were carried out over approximately 10 months. QC was monitored through repeated testing of blood samples from six individuals, with two individuals tested twice on each plate. Assay performance was stable over the entire study and coefficients of variation averaged 2% to 3% within plates and approximately 14% for IGF-I and approximately 11.5% for IGFBP-3 over the entire study. Coefficients of variation varied significantly among individual QC subjects, ranging from 12.3% to 17.6% for IGF-I and 8.9% to 12.8% for IGFBP-3. Based on Levy-Jennings plots, approximately 5% of the plates used for IGF-I in the main study were out of compliance. Finally, location on a plate had small but significant effects on IGF-I level. Together, these results highlight the need for care in large studies of putative biomarkers for cancer risk and illustrate some probable sources of heterogeneity in past epidemiologic studies of the IGF axis and cancer.     

Association between insulin-like growth factor-I: insulin-like growth factor-binding protein-1 ratio and metabolic and anthropometric factors in men and women.

Several prospective observational studies have suggested that elevated circulating IGF-I levels are associated with an increased risk of cancer. These observations may provide a potential mechanism through which previously identified metabolic and anthropometric factors, such as obesity and elevated insulin and glucose levels, may operate. We therefore examined metabolic and anthropometric influences on circulating levels of insulin-like growth factor-I (IGF-I), insulin-like growth factor-binding protein-1 (IGFBP-1), and the IGF-I:IGFBP-1 ratio in a middle-aged population of 349 men and 492 women. IGF-I showed only modest inverse associations with indices of adiposity. However, we found that low IGFBP-I levels and an increased IGF-I:IGFBP-1 ratio were strongly associated with increased levels of insulin and glucose in men and women. Body mass index was also positively related to the IGF-I:IGFBP-1 ratio in men (P < 0.001) and women (P < 0.001), independent of metabolic correlates of IGFBP-1 and IGF-I. Similarly, waist:hip ratio and waist circumference were also associated with an increased IGF-I:IGFBP-1 ratio and low circulating IGFBP-1 levels. These findings suggest that individuals with greater fat mass and upper body obesity may have elevated levels of bioavailable or free IGF-I, which could, in part, mediate the reported associations among metabolic and anthropometric factors and cancer risk.     

Serum insulin-like growth factor-I and insulin-like growth factor binding protein-3 levels with risk of malignant melanoma

We examined the relationship of insulin-like growth factor-I (IGF-I) and its primary growth factor, IGF binding protein-3 (IGFBP-3) with malignant melanoma using interview data and sera from cases (n = 286) and controls (n = 289) in a population-based case–control study conducted in 1986–1992 on Oahu, Hawaii. Serum IGF-I and IGFBP-3 concentrations were measured by ELISA. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by unconditional logistic regression and adjusting for age, sex, education, number of blistering sunburns, ability to tan, hair color, energy intake, BMI, height, smoking status, and drinking status. An inverse relationship was found between IGF-I concentration and melanoma (OR for upper vs. lower tertile: 0.44, 95% CI: 0.25–0.79), but clear associations were not observed between malignant melanoma and upper tertiles of IGFBP-3 and the IGF-1/IGFBP-3 molar ratio. The inverse association with IGF-I was strongest among subjects who did not report a history of non-melanoma skin cancer (NMSC) (OR for ≥ vs. < median: 0.39, 95% CI: 0.24–0.65), and a positive association was found among those with such a history (OR: 3.6, 95% CI: 1.0–13; p _interaction = 0.0035). Our findings observed here between serum IGF-I and malignant melanoma warrants replication in studies with a larger sample size and a prospective design.     

Dietary and lifestyle correlates of plasma insulin-like growth factor-I (IGF-I) and IGF binding protein-3 (IGFBP-3): the multiethnic cohort.

High circulating concentration of insulin-like growth factor-I (IGF-I) and low circulating concentration of IGF binding protein-3 (IGFBP-3) have been associated with increased risk for breast, prostate, and colorectal cancers. Building on previous work in the Multiethnic Cohort (MEC) showing significant differences in IGF-I levels across racial/ethnic groups, we investigated which lifestyle and dietary factors are associated with levels of IGF-I and IGFBP-3 in a random sample of 1,000 MEC participants, which included Native Hawaiian, African American, Japanese, Latino, and White men and women. Crude analyses confirmed the existence of differences in protein levels with race/ethnicity, sex, age, and body size. Reproductive, physical activity, smoking, and diet variables had less consistent effects. In multivariate analyses, IGF-I levels were lower and IGFBP-3 were higher in females versus males. IGF-I and IGFBP-3 declined with increasing age in both genders. Women in the highest quartile of body mass index showed depressed IGF-I and IGFBP-3 levels; in men, height was significantly positively associated with both proteins. In women, alcohol was directly associated with IGFBP-3. Both proteins were lowest among female Latinos. IGF-I was highest among female African Americans. In men, IGFBP-3 was lowest among African Americans. Overall, although these factors were statistically significant determinants of IGF-related protein levels, they did not explain much of the variation in these levels. A positive correlation was found between IGF-I levels (ng/mL) and colon cancer incidence rates (per 100,000) within the MEC by race/ethnicity for both sexes but not for either breast or prostate cancer.     

Effects of alcohol and menstrual cycle on insulin-like growth factor-I and insulin-like growth factor binding protein-3.

Alcohol ingestion and insulin-like growth factor-I (IGF-I) have been associated with increased breast cancer risk, the latter primarily in premenopausal women. We investigated whether alcohol ingestion altered IGF-I or its major binding protein (BP), IGFBP-3, in a controlled feeding study in premenopausal women. We also determined whether IGF-I or IGFBP-3 was affected by menstrual cycle phase. Serum was collected from 31 individuals who were randomly assigned to consume either 0 or 30 g (two drinks) of alcohol daily for three menstrual cycles and who then crossed over to the other alcohol level for three cycles. All calories were provided and weight was maintained during the study. For both alcohol levels, serum was collected during the final cycle at early follicular, periovulatory, and luteal phases. Relative to the follicular phase, IGF-I levels increased by 3.3% and 7.6% in the periovulatory and luteal phases, respectively (P for trend = 0.004). Although alcohol ingestion did not affect this increase, it significantly reduced IGF-I concentrations at all phases (9.5%; P < 0.001), whereas IGFBP-3 was unaffected by either menstrual phase or alcohol. This is the first controlled diet study to show that alcohol decreases serum IGF-I in premenopausal women and that IGF-I significantly increases over the course of the menstrual cycle whether or not alcohol is present.     

Circulating insulin-like growth factor-I and binding protein-3 and risk of prostate cancer.

Some recent epidemiologic studies have failed to confirm positive associations between insulin-like growth factor-I (IGF-I) and the risk of prostate cancer observed in earlier studies but have reported suggestive evidence for a positive association between IGF-binding protein-3 (IGFBP-3) and prostate cancer risk, a result contradicting the earlier assumption that high levels of IGFBP-3 would be protective against prostate cancer. We tested the association between IGF-I and IGFBP-3 and prostate cancer risk by measuring the two peptides in plasma samples collected at baseline in a prospective cohort study of 17,049 men. We used a case-cohort design, including 524 cases diagnosed during a mean of 8.7 years follow-up and a randomly sampled subcohort of 1,826 men. The association between each peptide level and prostate cancer risk was tested using Cox models adjusted for country of birth and alcohol consumption. The risk of prostate cancer was not associated with baseline levels of IGF-I or the molar ratio IGF-I/IGFBP-3 (all odds ratios are between 0.82 and 1.08; P(trend) > or = 0.2), whereas the risk increased with baseline levels of IGFBP-3 (P(trend) = 0.008), the hazard ratio (HR) associated with a doubling of the concentration of IGFBP-3 being 1.70 (95% confidence interval, 1.15-2.52). The HR for quartile 4 relative to quartile 1 of IGFBP-3 was 1.49 (95% confidence interval, 1.11-2.00). The HRs did not differ by tumor aggressiveness or age at onset (all Ps > or = 0.4). In our study, high levels of IGFBP-3 but not IGF-I were associated with an increased risk of prostate cancer.     

Relation of serum insulin-like growth factor-I (IGF-I) and IGF binding protein-3 to risk of prostate cancer (United States)

Objective: Insulin-like growth factor I (IGF-I) exerts potent mitogenic and antiapoptotic effects on prostatic epithelial cells. Insulin-like growth factor binding protein-3 (IGFBP-3) modulates the effects of IGF-I, and independently induces apoptosis and inhibits cell growth. Previous studies have inconsistently associated IGF-I and IGFBP-3 with prostate cancer. To try and further clarify these potential associations, we undertook a sibling-matched case–control study. Methods: Serum IGF-I and IGFBP-3 were determined for 845 men (408 cases and 437 sibling controls). Conditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between the serum IGF levels and prostate cancer. Results: Among all study subjects, only the molar ratio of IGF-I to IGFBP-3 was associated with prostate cancer: comparing those in the highest to lowest quartiles gave an OR = 1.62 (95% CI = 1.02–2.57, trend-p = 0.04). Among men with clinically less aggressive disease, we observed positive associations between prostate cancer and high levels of IGF-I (OR = 2.78, 95% CI = 1.06–6.80, trend-p = 0.03), and IGFBP-3 (OR = 2.68, 95% CI = 1.08–6.80, trend-p = 0.04). Simultaneously modeling both left the IGF-I result essentially unchanged, while substantially weakening the IGFBP-3 association. Conclusions: We found that a high IGF-I to IGFBP-3 molar ratio was associated with an increased risk of prostate cancer. Furthermore, high IGF-I was associated with increased risk of prostate cancer among men with less advanced disease at diagnosis. These results lend support to the hypothesis that IGF-I, or the IGF-I to IGFBP-3 molar ratio, is an important risk factor for prostate cancer.     

Circulating insulin-like growth factor-I and binding protein-3 and the risk of breast cancer.

Four meta-analyses and literature reviews have concluded that a positive association exists between circulating levels of insulin-like growth factor-I (IGF-I) and IGF-binding protein-3 (IGFBP-3) and breast cancer risk for premenopausal but not postmenopausal women. Recently, a large prospective study reported an association with IGF-I and IGFBP-3 concentration for breast cancer diagnosed after, but not before, the age of 50 years; and in a large cohort of primarily premenopausal women, IGF-I and IGFBP-3 were not associated with breast cancer risk. We did a case-cohort study within the Melbourne Collaborative Cohort Study, which included a random sample of 1,901 women (subcohort) and 423 breast cancer cases diagnosed during a mean of 9.1 years of follow-up. IGF-I and IGFBP-3 concentrations were measured in plasma collected at baseline. The association between quartiles of IGF concentration and breast cancer risk was tested using a Cox model adjusted for known and potential confounders. The hazard ratio (HR) for breast cancer comparing the fourth with the first quartiles was 1.20 [95% confidence interval (95% CI), 0.87-1.65] for IGF-I and 1.09 (95% CI, 0.78-1.53) for IGFBP-3. Both associations varied with age: for IGF-I, the HRs for breast cancer comparing the fourth with the first quartiles were 0.60 (95% CI, 0.25-1.45) before age 50 and 1.61 (95% CI, 1.04-2.51) after age 60 (test for the log-linear trend of HR according to age, P = 0.05); for IGFBP-3, the HRs were 0.79 (95% CI, 0.34-1.83) before age 50 and 1.62 (95% CI, 1.03-2.55) after age 60 (test for log-linear trend, P = 0.08). IGF-I and IGFBP-3 were positively associated with breast cancer risk in older women but not in younger women. More prospective studies are needed to clarify the age dependence of the association between IGF-I and IGFBP-3 and breast cancer.     

Prostate cancer risk in relation to selected genetic polymorphisms in insulin-like growth factor-I, insulin-like growth factor binding protein-3, and insulin-like growth factor-I receptor.

We conducted a nested case-control study within a cohort of elderly Americans to examine the role of the insulin-like growth factor (IGF) signaling pathway in prostate cancer etiology. The distribution of genotypes of IGF-I (CA)n, IGF binding protein-3 (IGFBP-3) A-202C, and of the 2-bp deletion and (AGG)n polymorphisms in IGF-I receptor (IGF-IR) was compared between men with prostate cancer (n = 213) and equal number of controls matched on year of blood draw, survival until the date of diagnosis, race, and age. Among controls, the number of CA repeats in IGF-I was not correlated to any appreciable degree with plasma IGF-I concentration, whereas the IGFBP-3 CC genotype was associated with a relatively low level of plasma IGFBP-3. There was no association between prostate cancer risk and the number of CA repeats in IGF-I, IGFBP-3 genotype, or the presence of the 2-bp deletion in IGF-IR. There was a small increased risk among men who did not carry two copies of the (AGG)7 allele of IGF-IR. These results add to the evidence that the number of IGF-I CA repeats is not associated with prostate cancer risk. Our observation that men who do not carry two copies of the IGF-IR (AGG)7 allele are at increased risk of prostate cancer merits further investigation.     

Cord serum estrogens, androgens, insulin-like growth factor-I, and insulin-like growth factor binding protein-3 in Chinese and U.S. Caucasian neonates

Markedly lower breast cancer incidence rates in Asians than Caucasians are not explained by established adult risk factors. Migration studies suggest the importance of early-life exposures, including perhaps the in utero period. Concentrations of steroid hormones and insulin-like growth factors (IGF) were measured in umbilical cord sera from pregnancies in Shanghai, China (n = 121) and Boston, MA (n = 111). Pregnancy characteristics were ascertained by interview and medical records. Means and percent differences in hormone concentrations comparing Chinese with Caucasians and 95% confidence intervals were estimated from linear regression models. Cord concentrations of androstenedione (91.9%), testosterone (257%), estriol (48.6%), and IGF binding protein-3 (21.1%) were significantly higher in the Chinese than U.S. samples, and cord prolactin was lower (-14.9%). Cord estradiol and IGF-I concentrations did not differ by race/ethnicity. With adjustment for gestational length, maternal age, pre-pregnancy weight, and weight gain, androstenedione (60.5%), testosterone (185%), and IGF binding protein-3 (40.4%) remained significantly higher in the Chinese, whereas the higher estriol and lower prolactin concentrations were attenuated. In addition, estradiol levels became lower in the Chinese (-29.8%) but did not reach statistical significance. Results were generally similar when restricted to first full-term pregnancies, with reduced estradiol concentrations in the Chinese reaching statistical significance after adjustment. These data are consistent with the hypothesis that elevated prenatal androgen exposure could mediate reductions in breast cancer risk. The meaning of the change in findings for estrogens after controlling for factors related to the pregnancy is unclear with regard to explaining international breast cancer differences.     

Effect of the synthetic retinoid fenretinide on circulating free prostate-specific antigen, insulin-like growth factor-I, and insulin-like growth factor binding protein-3 levels in men with superficial bladder cancer.

PURPOSE: Fenretinide (4-HPR) is a synthetic retinoid that has shown a preventive activity in prostate cancer animal models. EXPERIMENTAL DESIGN: We measured the changes in total and free prostate-specific antigen (PSA) and its association with insulin-like growth factor I (IGF-I) and IGFBP-3 levels after 1 year of treatment in 24 subjects given 4-HPR and 24 control subjects enrolled in a randomized bladder cancer prevention trial. RESULTS: No significant effect of 4-HPR was observed on total and free fraction of PSA levels. The median percentage [95 confidence interval (95% CI)] change for % free PSA and total PSA in the 4-HPR and the control group were, respectively, 7.6 (95% CI, -4.0 to 69.3) versus 5.1 (95% CI, -21.4 to 59.8) and -7.8 (95% CI, -18.2 to 52.5) versus -12.3 (95% CI, -44.6 to 9.6). However, in patients ages <60 years, there was a trend to an increase of total free PSA and % free PSA after treatment with 4-HPR that was different from a trend to a decrease in the control group (P = 0.002 and 0.052, respectively). The interaction between age and treatment was statistically significant on free PSA (P = 0.001). A similar pattern was noted with smoking status (P = 0.011 for the interaction on free PSA). No association was observed between PSA levels and IGF-I or IGFBP-3 levels. CONCLUSIONS: We conclude that 4-HPR has no significant effect on circulating PSA, but it increases significantly free PSA levels in subjects younger than 60 years and in nonsmokers. These effects might support an activity in prostate cancer prevention but further studies are required.     

Genetic and nongenetic factors associated with variation of plasma levels of insulin-like growth factor-I and insulin-like growth factor-binding protein-3 in healthy premenopausal women.

Circulating levels of insulin-like growth factor-I (IGF-I) and insulin-like growth factor-binding protein 3 (IGFBP-3) vary considerably between normal individuals. Recent epidemiological studies have provided evidence that these levels are predictive of risk of several common cancers. To evaluate possible sources of variation of the levels of circulating IGF-I and IGFBP-3 in females, we studied specific candidate genetic and nongenetic factors in 311 nulliparous, premenopausal Caucasian women, 17-35 years of age. Women who used oral contraceptives (OC) had reduced levels of IGF-I (269 versus 301 ng/ml; P = 0.001 adjusted for age) and increased levels of IGFBP-3 (4213 versus 4009 ng/ml; P = 0.002, adjusted for age) compared with nonusers. The ratio of IGF-I:IGFBP-3 was associated with the dose of estrogen contained in the OC (P(trend) = 0.006, adjusted for age). We identified a novel single bp polymorphism in the promoter region of the gene encoding IGFBP-3. This polymorphism was related to the level of IGFBP-3 in the circulation. Mean IGFBP-3 levels were 4390, 4130, and 3840 ng/ml for the AA, AC, and CC genotypes, respectively (P(trend) = 0.006, adjusted for age and OC use). We observed no effect of a recently described polymorphism in the promoter region of the gene encoding IGF-I on the plasma IGF-I level, but there was evidence for a modifying effect of this locus on the influence of OC on the IGF-I level. Our results support the view that circulating IGF-I levels and IGFBP-3 levels are complex traits and are influenced by a number of interacting genetic and nongenetic factors.     

Serum insulin-like growth factor-I, insulin-like growth factor binding protein-3, and the risk of pancreatic cancer death

Recent epidemiological studies have shown that high serum levels of insulin-like growth factor-I (IGF-I) are associated with an increased risk of lung, colon, breast and prostate cancer. Since very few studies have addressed the role of serum levels of IGF-I in the development of pancreatic cancer, we conducted a nested case-control study to examine this association. The analysis involved 69 case subjects who died from pancreatic cancer during the follow-up period of the study, and 207 control subjects matched for sex, age(+/-1 year) and study area, selected randomly from a cohort of 10364 individuals. Serum levels of IGF-I and IGF binding protein-3 (IGFBP-3) were measured by immunoradiometric assay, using commercially available kits. The odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using conditional logistic models. The levels of IGF-I were positively correlated with IGFBP-3 (r=0.55). There was a positive, but statistically insignificant association between serum levels of IGF-I and risk of death from pancreatic cancer, with subjects in the highest quartile having an OR of 2.31 (95% CI=0.70-2.64) compared to those in the lowest quartile. The risk of pancreatic cancer death increased significantly with increasing serum levels of IGFBP-3 (trend p=0.03). Further adjustment for IGFBP-3 or IGF-I slightly attenuated the positive associations. This nested case-control study showed that high serum levels of IGF-I and IGFBP-3 may be associated with an increased risk of death from pancreatic cancer.     

Elevated serum insulin-like growth factor (IGF)-II and IGF binding protein-2 in patients with colorectal cancer

This study explored the relationships of serum insulin-like growth factors, IGF-I and IGF-II, and their binding proteins (IGFBP)-2 and IGFBP-3, with key clinicopathological parameters in 92 patients with colorectal cancer (cases). Comparisons were made with 57 individuals who had a normal colonoscopy (controls). Serial changes were examined in 27 cases. As IGF-related peptides are age- and sex-dependent, absolute concentrations were converted to standard deviation scores (SDS). Mean IGF-II SDS were elevated in Dukes A (n = 12, P< 0.001) and Dukes B (n = 25, P< 0.001) cases compared with controls, but not in advanced disease. Compared with controls, mean IGFBP-2 SDS were significantly elevated in patients with Dukes B (P< 0.001), Dukes C (n = 13, P< 0.001) and advanced disease (n = 42, P< 0.0001), with a significant trend from early to advanced disease (one-way ANOVA, P< 0.001). Furthermore, IGFBP-2 SDS were positively related to tumour size (P = 0.01) and fell significantly in patients following curative resection (P = 0.04), suggesting that circulating levels reflect tumour load. We tested the potential tumour marker characteristics of IGFBP-2 SDS against three endpoints: metastasis alone; local pelvic recurrence alone; and metastasis and recurrence combined. The sensitivities for IGFBP-2 alone (>/= + 2SD) were modest at 55%, 46%, and 52%, but in combination with CEA, increased substantially to 90%, 77% and 86%, respectively. We conclude that the serum IGF-II and IGFBP-2 profiles may provide insights into underlying biological mechanisms, and that serum IGFBP-2 may have an adjunct role in cancer surveillance in patients with colorectal cancer.     

Factors associated with circulating levels of insulin-like growth factor-I and insulin-like growth factor binding protein-3 in 740 women at risk for breast cancer

Prospective studies have shown an association between elevated plasma levels of insulin-like growth factor-I (IGF-I) and/or decreased levels of its major circulating carrier protein insulin-like growth factor binding protein-3 (IGFBP-3) and increased risk of major cancers. Identifying the factors which affect these biomarkers is of particular interest as subjects at increased risk could benefit from lifestyle changes, and/or chemoprevention intervention. We evaluated the association between constitutional, hormonal and clinical factors and IGF-I and IGFBP-3 in 740 women, including 376 unaffected women and 364 women with intraepithelial neoplasia (IEN) or early invasive breast cancer enrolled in breast cancer chemoprevention trials, conducted at a single institution. Age, body mass index (BMI), height, waist to hip girth ratio (WHR), parity, menopausal status, age at menarche, number of affected first degree relatives, number of biopsies and breast cancer status were considered in the analysis. Women with early breast cancer had 21% higher IGF-I levels ( p=0.033) and 19% higher IGF-I/IGFBP-3 molar ratio ( p=0.047) than unaffected women. In unaffected women, age was negatively associated with IGF-I ( p=0.002) and IGF-I/IGFBP-3 ( p=0.001), while age at menarche was negatively associated with IGFBP-3 levels ( p=0.043). In women with IEN or early breast cancer, IGF-I levels were negatively associated with age ( p < 0.001), and positively associated with prior biopsies for benign disease ( p=0.013), while age, parity and menopausal status were significant predictors of IGF-I/IGFBP-3 molar ratio. We conclude that circulating IGF-I levels are higher in women with prior breast cancer compared to unaffected women, and that IGF-I and/or IGFBP-3 levels are influenced by age and by reproductive and hormonal factors. These findings support their putative role as breast cancer risk biomarker.     

Variation in plasma insulin-like growth factor-1 and insulin-like growth factor binding protein-3: genetic factors.

Insulin-like growth factors (IGFs) play key roles in cell proliferation and apoptosis. Whereas relatively stable within individuals, IGFs vary substantially between individuals, and a large component of this variation may be determined by genetic factors. Several polymorphisms in IGF genes have been identified, although their functional significance is not clear. We evaluated the association of polymorphisms in IGF-1 and IGFBP-3 and circulating levels of IGF-1 and IGFBP-3 in 323 population-based control subjects enrolled in a case-control study of colorectal cancer from September 1999 through February 2002. Total IGF-1 and IGFBP-3 levels were measured using ELISA assays, and all subjects were genotyped for a microsatellite polymorphism in IGF-1 and a single nucleotide polymorphism in IGFBP-3. Multiple linear regression was used to assess the association of genotype with circulating IGFs. IGF-1 levels were unrelated to either polymorphism. IGFBP-3 was significantly associated with IGFBP-3 genotype, with IGFBP-3 levels increasing from CC (1,895 ng/mL) --> GC (2,029 ng/mL) --> GG (2,182 ng/mL), (p-trend < 0.001). Having an IGF-1 genotype other than homozygous for the 19-repeat allele was associated with higher IGFBP-3 levels (1,945 versus 2,052 ng/mL). Furthermore, both IGF-1 and IGFBP-3 genotypes modified the relationship between postmenopausal hormone use and IGFs. This analysis provides evidence that common variation in IGF genes may contribute to the variation in circulating levels observed between individuals.     

Insulin-like growth factor-I (IGF-I) and IGF binding protein-3 as predictors of advanced-stage prostate cancer

BACKGROUND: Plasma levels of insulin-like growth factor-I (IGF-I) have been associated with the risk of prostate cancer. However, the association of IGF-I with specific tumor stage and grade at diagnosis, which correlate with risk of recurrence and mortality, has not been studied rigorously. To determine whether plasma levels of IGF-I and its main circulating binding protein, IGF binding protein-3 (IGFBP-3), predict more aggressive forms of prostate cancer, we investigated the association between plasma levels of each and specific stages and grades of prostate cancer. METHODS: We examined 530 case patients and 534 control subjects in a nested case-control study in the prospective Physicians' Health Study. Patients with prostate cancer diagnosed from 1982 through 1995 were matched to control subjects by age and smoking status. IGF-I and IGFBP-3 were measured in prospectively collected plasma samples. Conditional logistic regression models were used to estimate the relative risks (RRs) for prostate cancer associated with IGF-I and IGFBP-3, stratified on grade (Gleason score > or = 7 versus <7) and stage (early = stage A or B prostate cancer versus advanced = stage C or D prostate cancer). All statistical tests were two-sided. RESULTS: Plasma levels of IGF-I and IGFBP-3 were predictors of advanced-stage prostate cancer (RR = 5.1, 95% confidence interval [CI] = 2.0 to 13.2 for highest versus lowest quartiles of IGF-I; RR = 0.2, 95% CI = 0.1 to 0.6 for highest versus lowest quartiles of IGFBP-3) but not of early-stage prostate cancer. Neither was differentially associated with Gleason score. Men with high IGF-I levels and low IGFBP-3 levels had an RR for advanced-stage prostate cancer of 9.5 (95% CI = 1.9 to 48.4) compared with men with low levels of both. Combining IGF-I and IGFPB-3 measurements with a standard prostate-specific antigen (PSA) measurement for prostate cancer screening increased the specificity (from 91% to 93%) but decreased sensitivity (from 40% to 36%) compared with measurement of PSA alone. CONCLUSIONS: Circulating levels of IGF-I and IGFBP-3 may predict the risk of developing advanced-stage prostate cancer, but their utility for screening patients with incident prostate cancer may be limited.     

Racial variation in insulin-like growth factor-1 and binding protein-3 concentrations in middle-aged men.

African-American men have the highest and Asian-American men have the lowest prostate cancer incidence rates in the United States; internationally, rates for the Asian continent are among the lowest. Higher insulin-like growth factor (IGF)-1, which participates in the control of cellular growth and differentiation and is modulated by IGF-binding protein-3 (IGFBP-3), was associated with an increased prostate cancer risk in three recent studies. We, therefore, investigated whether plasma levels of IGF-1 and IGFBP-3 vary by race in United States men selected from among members of the Health Professionals Follow-up Study who were 47-78 years old in 1993-1995 when they provided blood (n = 18,000). All of the men who described their major ancestry as African American (n = 63) and a random sample of 75 Asians and 75 Caucasians were invited to provide a second blood sample in 1997, of whom 42, 52, and 55, respectively, did so. IGF-1 and IGFBP-3 concentrations were determined by ELISA. We used nonparametric methods to assess racial variation in age-adjusted levels. Caucasians had the highest median IGF-1 level (224 ng/ml), followed by Asians (208 ng/ml) and African Americans (205 ng/ml). Median IGFBP-3 concentration was similar between Caucasians and Asians but was more than 13% lower in African Americans. Median molar IGF-1:IGFBP-3 ratio was greatest in Caucasians and lowest in Asians. The lower IGF-1 blood levels relative to IGFBP-3 levels among Asian men are consistent with their lower prostate cancer incidence. Although differences in circulating IGF-1 do not seem to account for the greater prostate cancer risk among African-American men, their absolute lower levels of IGFBP-3 may be contributory.     

Relationships between plasma insulin-like growth factor-I and insulin-like growth factor binding protein-3 and second breast cancer risk in a prevention trial of fenretinide.

PURPOSE: High circulating insulin-like growth factor (IGF) -I and/or low IGF-binding protein (IGFBP) -3 levels are associated with increased breast cancer risk in unaffected premenopausal women. We determined whether IGF-I and IGFBP-3 predict second breast cancer risk, and whether their changes during fenretinide explain observed reductions in second breast cancer in women 相似文献