Prediagnostic plasma IGFBP‐1, IGF‐1 and risk of prostate cancer

Abstract

Insulin-like growth factor (IGF)-1 is associated with a higher risk of prostate cancer. IGF-binding protein (IGFBP)-1, a marker for insulin activity, also binds IGF-1 and inhibits its action. Data on IGFBP-1 and prostate cancer risk are sparse and whether the IGF and insulin axes interact to affect prostate cancer carcinogenesis is unknown. We evaluated the independent and joint influence of prediagnostic plasma levels of IGFBP-1 (fasting) and IGF-1 on risk of prostate cancer among 957 cases and 1021 controls with fasting levels of IGFBP-1 and 1709 cases and 1778 controls with IGF-1 nested within the Health Professionals Follow-up Study. Unconditional logistic regression adjusting for matching factors were used to estimate the odds ratio (OR) and 95% confidence interval (CI). Higher prediagnostic fasting IGFBP-1 levels were associated with lower risk of prostate cancer (highest vs lowest quartile OR=0.67, 95% CI 0.52-0.86, Ptrend=0.003), which remained similar after adjusting for IGF-1. Prediagnostic IGF-1 was associated with increased risk of prostate cancer (highest vs lowest quartile OR=1.28, 95% CI=1.05-1.56, Ptrend=0.01). The associations with each marker were primarily driven by lower-grade and non-advanced prostate cancer. Being low in IGFBP-1 and high in IGF-1 did not confer appreciable additional risk (Pinteraction=0.42). In summary, prediagnostic fasting IGFBP-1 may influence prostate cancer carcinogenesis. Being low in IGFBP-1 or high in IGF-1 is sufficient to elevate the risk of prostate cancer.

Association between serum levels of insulin‐like growth factor‐1, bioavailable testosterone, and pathologic Gleason score

“…The present study had a robust sample size ( n  =   793) and clearly demonstrated a lower risk of high surgical GS in patients with high serum IGF‐1 level (highest vs lowest quartile, OR = 0.494; P trend  = 0.006; Table 3), whereas the risk of prostate cancer itself was positively associated with serum IGF‐1 level (OR = 3.35, P trend  < 0.001; Table 1). These findings are in agreement with those of previous epidemiologic studies, such as the HPFS,10, 11, 12 PHS,14 and EPIC15 studies.…”

“…A previous study reported that complete loss of the PTEN gene is more frequent in high‐grade prostate cancer,36 in which, the PI3K/AKT pathway is constitutively active and requires minimal activation by IGF‐1 or other hormones. In men of the HPFS10, 11, 12 and PHS14 cohorts, loss of PTEN was significantly associated with higher IGF1R expression ( P  =   0.03) 34. These findings suggest that high‐grade prostate cancer requires minimal activation by IGF‐1, and that the IGF‐1 threshold level for tumorigenesis might be lower.…”

“…Serial reports from the Health Professionals Follow‐up Study (HPFS), a large prospective cohort study comprising 51 529 male health professionals from the United States, aged 40‐75 years at enrollment in 1986, demonstrate that circulating IGF‐1 level is positively associated with low‐grade, but not with high‐grade, prostate cancer 10, 11, 12. Associations between serum IGF‐1 level and low‐grade prostate cancer have also been shown by a pooled analysis of 12 prospective studies,13 and the results of other large prospective cohort studies, such as the Physicians’ Health Study (PHS) 14 and the European Prospective Investigation into Cancer and Nutrition (EPIC) study 15.…”

Assessing the role of insulin‐like growth factors and binding proteins in prostate cancer using Mendelian randomization: Genetic variants as instruments for circulating levels

“…The lack of –or marginal‐ association with IGF‐I, IGF‐II and IGFBP‐3 levels of SNPs in or near IGFBP1 may mean that these variants are predominantly influencing IGFBP‐1 levels. Recently higher circulating IGFBP‐1 was found to be associated with lower prostate cancer risk 4, 36. It is also conceivable that these signals may all be linked to another, causal signal in the region.…”

“…A number of observational studies have consistently reported positive associations of circulating IGF‐I with prostate cancer, but inferences of causality are limited with observational studies 3, 4, 36. MR is designed to overcome these problems if the exposure is adequately instrumented.…”