Circulating Levels of Insulin-like Growth Factor 1 and Insulin-like Growth Factor Binding Protein 3 Associate With Risk of Colorectal Cancer Based on Serologic and Mendelian Randomization Analyses

Abstract

BACKGROUND & AIMS: Human studies examining associations between circulating levels of insulin-like growth factor 1 (IGF1) and insulin-like growth factor binding protein 3 (IGFBP3) and colorectal cancer risk have reported inconsistent results. We conducted complementary serologic and Mendelian randomization (MR) analyses to determine whether alterations in circulating levels of IGF1 or IGFBP3 are associated with colorectal cancer development. METHODS: Serum levels of IGF1 were measured in blood samples collected from 397,380 participants from the UK Biobank, from 2006 through 2010. Incident cancer cases and cancer cases recorded first in death certificates were identified through linkage to national cancer and death registries. Complete follow-up was available through March 31, 2016. For the MR analyses, we identified genetic variants associated with circulating levels of IGF1 and IGFBP3. The association of these genetic variants with colorectal cancer was examined with 2-sample MR methods using genomewide association study consortia data (52,865 cases with colorectal cancer and 46,287 individuals without [controls]) RESULTS: After a median follow-up period of 7.1 years, 2665 cases of colorectal cancer were recorded. In a multivariableadjusted model, circulating level of IGF1 associated with colorectal cancer risk (hazard ratio per 1 standard deviation increment of IGF1, 1.11; 95% confidence interval [CI] 1.05-1.17). Similar associations were found by sex, follow-up time, and tumor subsite. In the MR analyses, a 1 standard deviation increment in IGF1 level, predicted based on genetic factors, was associated with a higher risk of colorectal cancer risk (odds ratio 1.08; 95% CI 1.03-1.12; P ¼ 3.3 Â 10-4). Level of IGFBP3, predicted based on genetic factors, was associated with colorectal cancer risk (odds ratio per 1 standard deviation increment, 1.12; 95% CI 1.06-1.18; P ¼ 4.2 Â 10-5). Colorectal cancer risk was associated with only 1 variant in the IGFBP3 gene region (rs11977526), which also associated with anthropometric traits and circulating level of IGF2. CONCLUSIONS: In an analysis of blood samples from almost 400,000 participants in the UK Biobank, we found an association between circulating level of IGF1 and colorectal cancer. Using genetic data from 52,865 cases with colorectal cancer and 46,287 controls, a higher level of IGF1, determined by genetic factors, was associated with colorectal cancer. Further studies are needed to determine how this signaling pathway might contribute to colorectal carcinogenesis.

Circulating insulin-like growth factor-I, total and free testosterone concentrations and prostate cancer risk in 200,000 men in UK Biobank

“…The findings of a likely causal effect of IGF-I in prostate cancer development may be due to its role in activating signalling pathways which regulate cell proliferation and apoptosis 2 . The positive relationship between IGF-I and incident prostate cancer observed is consistent with previous epidemiological evidence 4 , as well as associations observed with other cancers including breast and colorectal [35][36][37] . Further genetic epidemiology including fine mapping may help elucidate exactly by which mechanism variation at the IGF1 locus associates with risk prostate and some other cancers.…”

Insulin‐like growth factor‐1 and site‐specific cancers: A Mendelian randomization study

“…Our finding for colorectal cancer confirm those of a previous MR study which showed an OR of colorectal cancer of 1.08 (95% CI 1.03-1.12) per one SD increment of genetically-predicted IGF-1 levels. 6 That study further showed that directly measured serum IGF-1 levels were associated with increased risk of all colorectal tumor subsites, including proximal colon, distal colon, and rectal cancer. 6 Possible mechanisms underlying the increased colorectal cancer risk include direct actions of IGF-1 on cell growth or indirect effects via for example insulin resistance and elevated insulin levels.…”

“…6 That study further showed that directly measured serum IGF-1 levels were associated with increased risk of all colorectal tumor subsites, including proximal colon, distal colon, and rectal cancer. 6 Possible mechanisms underlying the increased colorectal cancer risk include direct actions of IGF-1 on cell growth or indirect effects via for example insulin resistance and elevated insulin levels. 25 The present MR results for IGF-1 and breast cancer based on BCAC data are similar to those obtained from another MR study also based on BCAC data which showed an OR of 1.05 (95% CI 1.01-1.10) per 5 nmol/L increase of genetically predicted IGF-1 levels based on 265 SNPs associated with serum IGF-1 levels in women.…”

Circulating liver function markers and colorectal cancer risk: A prospective cohort study in the UK Biobank

“…We then used the ICCs to recalibrate the multivariable HR estimates for regression dilution. 25,26 To assess the linearity in the associations of circulating liver function markers with CRC risk, we performed restricted cubic spline analysis with four knots and calculated the likelihood ratio test by comparing the model with only the linear term of these markers to the model with both the linear and the cubic spline terms.…”