Diabetes mellitus, genetic variants in the insulin‐like growth factor pathway and colorectal cancer risk. Issue 7 (6th May 2019)

• Record Type: Journal Article
• Authors: de Kort, Sander; Simons, Colinda C.J.M.; van den Brandt, Piet A.; Janssen‐Heijnen, Maryska L.G.; Sanduleanu, Silvia; Masclee, Ad A.M.; Weijenberg, Matty P.
• Is Part Of: International journal of cancer. Volume 145:Issue 7(2019)
• Page Start: 1774
• Page End: 1781
• Publication Date: 2019-05-06
• Subjects: cohort studies -- colorectal cancer -- insulin‐like growth factors -- gene–environment interactions -- diabetes mellitus; Cancer -- Periodicals; Cancer -- Prevention -- Periodicals; 616.994
• DOI: 10.1002/ijc.32365
• Languages: English
• ISSNs: 0020-7136

Abstract

Abstract : Genetic variation in the insulin‐like growth factor (IGF) pathway may further increase the risk of colorectal cancer (CRC) associated with type 2 diabetes mellitus (T2DM). Joint effects of T2DM and genetic variation in the IGF pathway on CRC risk can increase mechanistic insights. Participants from the Netherlands Cohort Study ( n = 120, 852) completed a baseline questionnaire in 1986 when 55–69 years old (case–cohort, n subcohort = 5, 000, n cases = 3, 441 after 16.3 years follow‐up). Self‐reported DM at baseline with onset at ≥30 years was classified as T2DM. Eighteen single nucleotide polymorphisms (SNPs) from the IGF pathway were aggregated in a genetic risk score (GRS). Cox proportional hazard ratios (HRs) for CRC were estimated according to combinations of T2DM status with GRS tertiles and categories of an IGF1 19‐CA repeat polymorphism. Baseline T2DM prevalence was 3.1% in subcohort members and 3.8% in CRC cases. Comparison of combined categories with non‐T2DM individuals in the lowest GRS tertile as reference showed that those in the highest GRS tertiles with and without T2DM had significantly increased CRC risks, particularly those with T2DM (HR = 2.28, 95% CI: 1.11, 4.66). As compared to IGF1 19‐CA wild‐type carriers without T2DM, carrying two IGF1 19‐CA variant repeat alleles were associated with a significantly decreased CRC risk in those without T2DM (HR = 0.76, 95% CI: 0.63–0.91). This association was absent when T2DM was present. Our study of joint effects indicated that the presence of unfavorable alleles in the IGF pathway may further increase the risk of CRC associated with T2DM. Abstract : What's new? Colorectal cancer (CRC) and type‐2 diabetes mellitus (T2DM) have several risk factors in common (high BMI, physical inactivity, etc.). In this study, the authors identified several SNPs in the insulin‐like growth factor (IGF) pathway that further increase CRC risk, particularly in people with T2DM. These results support the hypothesis that T2DM increases CRC risk by influencing the IGF pathway. Screening for these unfavorable genetic variations in the IGF pathway may also help to improve the assessment of personalized CRC risk.