Energy Restriction At Young Age And Colorectal Cancer Risk: Involvement Of The Insulin-Like Growth Factor Pathway

Colinda SIMONS, Maastricht University, Netherlands
SCHOUTEN L. 1 , GODSCHALK R. 2 , VAN ENGELAND M. 3 , VAN DEN BRANDT P. 1 , VAN SCHOOTEN F. 2 , WEIJENBERG M. 1

1 Department of Epidemiology, GROW School for Oncology and Developmental Biology, Maastricht University, Maastricht, the Netherlands
2 Department of Toxicology, NUTRIM School for Nutrition and Toxicology, Maastricht University, Maastricht, the Netherlands
3 Department of Pathology, GROW School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, the Netherlands

Purpose: We investigated joint associations of energy restriction (ER) at young age and variation in insulin-like growth factor-related (IGF-related) genes with CRC risk.
Methods: Participants in the Netherlands Cohort Study completed a questionnaire (n=120,852) and provided toenail clippings (~90,000) in 1986. Those living in Western cities during the Hunger Winter (1944–45) were exposed to ER at young age. After 16.3 years follow-up, toenail DNA of 3,768 subcohort members and 2,580 CRC cases (case-cohort) was genotyped for IGF pathway gene variants. Hazard ratios for CRC were estimated across combined categories of ER exposure and a genetic sum score of unfavorable alleles (based on 18 SNPs in 8 IGF-related genes) by Cox regression. ER exposed individuals in the lowest genetic sum score tertile were hypothesized to be at lowest risk and used as reference. ER and IGF1 19-CA repeat status combinations were also analyzed.
Results: A pattern of increasing CRC risks was observed across combined ER-genetic sum score categories in men but not women, although interactions were nonsignificant. Compared to the reference, men who lived in a Western city and were in the highest genetic sum score tertile had a hazard ratio for CRC of 1.23 [95% confidence intervals (CI): 0.74 to 2.04]; men who lived in a non-Western area and were in the lowest tertile had a hazard ratio of 1.51 (95% CI: 1.03 to 2.20); and men who lived in a non-Western area and were in the highest tertile had a hazard ratio of 2.04 (95% CI: 1.39 to 3.00). Irrespective of ER, women, but not men, carrying variant versus wild type repeat alleles were at a ~50% CRC risk reduction.
Conclusions: Data indicate potential IGF pathway involvement in ER-CRC associations.
Funding source: World Cancer Research Fund; Dutch Cancer Society; Biobanking and Biomolecular Research Infrastructure Netherlands; Health Foundation Limburg.