The causal role of the nutritionally regulated insulin-like growth factor system in prostate cancer: Mendelian randomization study

  • Topic: Prostate cancer
  • Institution: University of Bristol
  • Country: United Kingdom
  • Status: Completed

Scientific abstract

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Background

Circulating insulin-like growth factors (IGFs) and their binding proteins (IGFBPs) have been associated with prostate cancer in several studies to date.

How the study was carried out

Using genetic variants as instruments for IGF peptides in a Mendelian randomization (MR) approach, we investigated whether these associations are likely to be causal. We identified from the literature 56 single nucleotide polymorphisms (SNPs) in the IGF axis previously associated with biomarker levels (eight from a genome-wide association study [GWAS] and 48 in candidate genes). In ~700 men without prostate cancer from the Prostate testing for cancer and Treatment (ProtecT) study and two replication cohorts (N ~ 900 and ~9,000), we examined the properties of these SNPs as instrumental variables (IVs) for IGF-I, IGF-II, IGFBP-2 and IGFBP-3. Those confirmed as strong IVs were tested for association with prostate cancer risk, low (<7) vs. high (≥7) Gleason grade, localised vs. advanced stage, and mortality, in 22,936 controls and 22,992 cases. IV analysis was used to estimate the causal effect of circulating IGF peptides on prostate cancer. Published SNPs in the IGFBP1/IGFBP3 gene region, particularly rs11977526, were strong instruments for IGF-II and IGFBP-3. Rs11977526 was associated with high (vs. low) Gleason grade (OR per IGF-II/IGFBP-3 level-raising allele 1.05; 95% CI: 1.00, 1.10). Using rs11977526 as an IV we estimated the causal effect of a one standard deviation (SD) increase in IGF-II (~265 ng/mL) on the risk of high vs. low grade disease as 1.14 (95% CI: 1.00, 1.31), and as 1.15 (95% CI 1.00, 1.32) per one SD (~1000 ng/ml) increase in IGFBP-3. Rs700752, a strong instrument for IGF-I and IGFBP-3, exhibited the most robust association with prostate cancer-specific mortality, with the causal estimates being HR 0.72 (95% CI 0.53, 0.98) per one SD (~50 ng/ml) increase in serum IGF-I and 0.76 (95% CI 0.29, 0.82) per one SD increase in IGFBP-3.

Since age at puberty is influenced by the IGF system we decided to use MR to examine whether the timing of puberty affects prostate cancer onset and progression. Epidemiological studies have shown a positive association between an earlier age at sexual development and prostate cancer, but markers of sexual maturation in boys are imprecise and observational estimates are likely to suffer from a degree of uncontrolled confounding. We derived a weighted genetic risk score for pubertal development, combining 13 SNPs associated with male Tanner stage identified in an earlier GWAS. A higher score indicated a later puberty initiation. In ProtecT, the puberty genetic score was inversely associated with prostate cancer grade (OR of high- vs low-grade cancer, per tertile of the score: 0.76; 95 % CI, 0.64–0.89). In an IV estimation of the causal OR, later physical development in adolescence (equivalent to a difference of one Tanner stage between pubertal boys of the same age) was associated with a 77 % (95 % CI, 43–91 %) reduced odds of high Gleason prostate cancer. In PRACTICAL, the puberty genetic score was associated with prostate cancer stage (OR of advanced vs. localized cancer, per tertile: 0.95; 95 % CI, 0.91–1.00) and prostate cancer-specific mortality (HR amongst cases, per tertile: 0.94; 95 % CI, 0.90–0.98), but not with disease grade.

Key findings and conclusions

Published SNPs in the IGFBP1/IGFBP3 gene region, particularly rs11977526, were strong instruments for IGF-II and IGFBP-3. Rs11977526 was associated with high (vs low) Gleason grade (OR per IGF-II/IGFBP-3 level-raising allele 1.05; 95% CI: 1.00, 1.10). Using rs11977526 as an IV we estimated the causal effect of a one standard deviation (SD) increase in IGF-II (~265 ng/mL) on the risk of high vs low grade disease as 1.14 (95% CI: 1.00, 1.31), and as 1.15 (95% CI 1.00, 1.32) per one SD (~1000 ng/ml) increase in IGFBP-3. Rs700752, a strong instrument for IGF-I and IGFBP-3, exhibited the most robust association with prostate cancer-specific mortality, with the causal estimates being HR 0.72 (95% CI 0.53, 0.98) per one SD (~50 ng/ml) increase in serum IGF-I and 0.76 (95% CI 0.29, 0.82) per one SD increase in IGFBP-3. Because of the potential for pleiotropy of the genetic instruments (seeing as they are associated with more than one peptide levels), these findings can only causally implicate the IGF pathway in general, not any one specific biomarker.

In summary, we found that older age at sexual maturation is causally linked to a lower risk of later prostate cancer, especially aggressive disease. Whether this is related to a reduced exposure to serum IGF during development remains to be proven.

Plain language summary

Background

Prostate cancer is now the most frequently detected cancer among men in westernized countries but there are as yet no distinct modifiable risk factors which can provide a reasonable prospect of prevention. Circulating insulin-like growth factors (IGF) and their binding proteins have been associated with prostate cancer risk in observational epidemiological studies but it is not clear whether there is a causal relationship with disease. The IGF axis plays a role in growth, with IGF hormone levels rising during puberty, and is nutritionally regulated, thus being an interesting candidate to consider as a potential target to implement preventative measures.

Aims and objectives

The aim of this study was to define whether hormones in the IGF pathway (ie IGF-I, IGF-II, IGFBP-2, IGFBP-3) cause prostate cancer.

How the study was carried out

The study first identified and validated genetic variants that were associated with circulating IGF hormones and then used those variants as proxies for the serum levels of the hormones. Subsequently the association of the genetic variants with prostate cancer was tested, and the effects of IGF levels on prostate cancer inferred using a novel methodology called Mendelian randomization (MR). We used the same methodology to additionally assess whether traits known to be influenced by the IGF pathway like puberty, height and BMI, were also associated with prostate cancer. We examined prostate cancer incidence, aggressiveness and mortality in all the analyses.

Key findings and conclusions

We found that some of the IGF proteins investigated were associated with prostate cancer risk and with its progression towards a more aggressive disease. Additionally, an earlier age at puberty also appeared to have an effect on high grade prostate cancer. On the other hand, there was no sufficient evidence to implicate height and BMI on prostate cancer risk.

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