Higher circulating levels of insulin-like growth factor 1 (IGF1) may be associated with colorectal cancer (CRC) risk, according to study results published in Gastroenterology.
IGF1 and insulin-like growth factor-binding protein 3 (IGFBP3) have been associated with the development and progression of many cancers, including CRC. However, many studies examining the relationship between IGF1, IGFBP3, and CRC have been relatively small and had inconsistent results. The objective of this study was to examine the role of circulating IGF1 and IGFBP3 in the development of CRC.
Researchers measured serum levels of IGF1, testosterone, and various other proteins in blood samples collected from 397,380 patients in the UK Biobank — a prospective cohort study that investigated the genetic, lifestyle, and environmental causes of a range of diseases. Data were gathered from 2006 to 2010. Researchers linked to national cancer and death registries to identify cancer cases from this cohort. Complete follow-up was available through March 31, 2016.
Mendelian randomization (MR) analyses identified genetic variants related to circulating levels of IGF1 and IGFBP3, then examined these associations with a 2-sample MR approach using genome-wide association data for patients with CRC (n=52,865) and healthy controls (n=46,287).
2665 CRC cases (1539 in men and 1126 in women) were recorded after a median follow-up of 7.1 years. The multivariable-adjusted model showed that higher circulating IGF1 levels were associated with higher CRC risk (hazard ratio [HR] per 1 standard deviation [SD] increment of IGF1, 1.11; 95% CI, 1.05-1.17).
In the MR analyses, a 1 SD increment of IGF1 (predicted based on genetic factors) was associated with an 8% higher CRC risk (odds ratio [OR] 1.08; 95% CI, 1.03-1.12; P =3.3 x 10⁻⁴). IGFBP3 levels were associated with a 12% higher CRC risk (OR per 1 SD increment, 1.12; 95% CI, 1.06-1.18; P =4.2 x 10⁻⁵). The positive association between IGFBP3 and CRC was driven mainly by one variant in the IGFBP3 gene region (rs11977526).
There were 2 main limitations. First, levels of IGF1 were measured only one time at baseline and may not have accurately reflected exposure levels across time. Second, the use of summary-level data prevented researchers from investigating nonlinear effects and subgroup analyses by other risk factors including smoking, age, and body mass index.
The researchers concluded that higher circulating levels of IGF1 were associated with a higher risk for CRC and that lifestyle, diet, and/or pharmacological interventions that target the IGF system may help reduce disease risk.
Murphy N, Carreras-Torres R, Song M, et al. 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 [published online December 26, 2019] Gastroenterology. doi: 10.1053/j.gastro.2019.12.020