Dietary heme iron and the risk of colorectal cancer with specific mutations in KRAS and APC

Abstract

Red meat intake has been linked to increased colorectal cancer (CRC) risk. Although the underlying mechanisms remain unclear, experimental studies suggest a role for dietary heme iron. Because heme iron was shown to promote specific mutations, it would be insightful to link heme iron data to CRC with mutations in key genes in an observational, population-based study. We investigated the association between dietary heme iron intake and risk of CRC with mutations in APC (adenomatous polyposis coli) and KRAS (Kirsten ras) and P53 overexpression in the Netherlands Cohort Study. After 7.3 years of follow-up, excluding the first 2.3 years due to incomplete coverage of the pathology registry and to avoid preclinical disease, adjusted hazard ratios (including adjustment for total meat) and 95% confidence intervals were calculated, using 4026 subcohort members (aged 55-69 years at baseline), 435 colon and 140 rectal cancer patients. When comparing the highest with the lowest tertile of intake, heme iron intake was associated with an increased risk of CRC harboring activating mutations in KRAS (hazard ratio = 1.71, 95% confidence interval: 1.15-2.57; P for trend = 0.03) and CRC without truncating mutations in APC (hazard ratio = 1.79, 95% confidence interval: 1.23-2.60; P for trend = 0.003). We observed a positive association between heme iron intake and the risk of CRC with activating G>A mutations in KRAS (P for trend = 0.01) and overall G>A mutations in APC (P for trend = 0.005). No associations were found with CRC harboring G>T mutations in KRAS/APC. Heme iron intake was positively associated with the risk of P53 overexpressed tumors but not with tumors without P53 overexpression (Pheterogeneity = 0.12). Heme iron intake was associated with an increased risk of colorectal tumors harboring G>A transitions in KRAS and APC and overexpression of P53. These novel findings suggest that alkylating rather than oxidative DNA-damaging mechanisms are involved in heme-induced colorectal carcinogenesis.

Mechanisms of Oxidative Processes in Meat and Toxicity Induced by Postprandial Degradation Products: A Review

“…Jakszyn and others () demonstrated a potential association between higher intakes of heme iron and the risk of esophageal adenocarcinoma. Gilsing and others () studied the interrelationship between dietary heme iron and the risk of colorectal cancer with specific mutations in Kristen‐ras (KRAS) and adenomatous polyposis coli (APC), and they observed a positive association between heme iron intake and risk of colorectal cancer with the activating G > A mutation in KRAS and overall G > A mutation in APC.…”

Heme, an Essential Nutrient from Dietary Proteins, Critically Impacts Diverse Physiological and Pathological Processes

“…Heme is more bioavailable and readily absorbed as compared to non-heme. However, detrimental effects are associated with heme specifically, which includes cytotoxicity and the increased formation of endogenous N -nitroso compounds (NOCs), which may increase the overall mutation rate in the DNA of colonic tissue [55,56,57]. Heme in red meat may catalyze the production of endogenous NOCs within the colon and thereby catalyze the formation of cytotoxic and genotoxic aldehydes by lipoperoxidation [43,44,51,56].…”

Meat and Colorectal Cancer: Associations and Issues

“…In a recent study, a molecular genetic epidemiological approach was used to understand the association between heme iron intake and colorectal cancer risk by examining specific mutations in colon tumors in the adenomatous polyposis coli (APC) tumor suppressor gene and Kirsten ras (KRAS) oncogene [26]. In this nested case-control study, no difference was found between cases and controls in daily heme intake in women.…”