Body size, physical activity, genetic variants in the insulin-like growth factor pathway and colorectal cancer risk

Carcinogenesis. 2015 Sep;36(9):971-81. doi: 10.1093/carcin/bgv077. Epub 2015 May 29.


Insulin-like growth factors (IGFs) have been associated with growth, body size, physical activity and colorectal cancer (CRC). We hypothesized that variants in IGF-related genes increase the CRC susceptibility associated with a larger body size and a lack of physical activity. We assessed this in The Netherlands Cohort Study. Participants (n = 120852) completed a baseline questionnaire on diet and cancer. ~75% returned toenail clippings. Using a case-cohort approach and 16.3 years of follow-up, toenail DNA from 3768 subcohort members and 2580 CRC cases was genotyped. We aggregated unfavorable alleles (potentially increasing CRC risk) for 18 single nucleotide polymorphisms in 8 genes into a sum score. The sum score (in tertiles) and an IGF1 19-CA repeat polymorphism (19/19, 19/non-19 and non-19/non-19 repeats) in combination with body size (mostly in tertiles) and (non-)occupational physical activity (>12, 8-12 and <8 kJ/min in the job and >90, >60-90, >30-60 and ≤30 min/day) were analyzed by Cox regression. Increasingly higher hazard ratios (HRs) for CRC were observed for a larger adult body mass index, larger trouser size and tallness in the presence of more unfavorable alleles in men. HRs (95% confidence intervals) for joint effects were 1.55 (1.06-2.25), 1.78 (1.29-2.46) and 1.48 (1.01-2.17), respectively. In women, variant repeat alleles halved CRC risk irrespective of body size and physical activity. Almost no interactions tested significant. To conclude, a larger body size was a CRC risk factor in men in the presence of an accumulation of unfavorable alleles in IGF-related genes, but interactions were generally nonsignificant.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Body Mass Index
  • Body Size / physiology*
  • Cohort Studies
  • Colorectal Neoplasms / epidemiology*
  • Colorectal Neoplasms / genetics
  • Diet
  • Female
  • Genetic Predisposition to Disease
  • Humans
  • Insulin-Like Growth Factor I / genetics*
  • Male
  • Middle Aged
  • Motor Activity / physiology*
  • Netherlands
  • Polymorphism, Single Nucleotide / genetics
  • Risk Factors
  • Surveys and Questionnaires


  • IGF1 protein, human
  • Insulin-Like Growth Factor I