Nitrosyl-heme and heme iron intake from processed meats and risk of colorectal cancer in the EPIC-Spain cohort

The International Agency for Research on Cancer classified processed meats (PMs) as “carcinogenic” and red meat as “probably carcinogenic” for humans (1) . The possible relationship between colorectal cancer (CRC) risk and processed meats (PMs), along with the specific compound contributing to this association have not been established yet. Nitrosyl-heme and heme iron have been proposed as potential-related compounds. The aim of this study was to assess the association of nitrosyl-heme and heme iron intake with CRC risk among participants from the European Prospective Investigation into Cancer and Nutrition (EPIC) Spain study. This prospective study included 38,262 subjects (61.5% females) from the EPIC-Spain study. Food consumption was assessed by a validated diet history questionnaire (2) . Dietary intake of nitrosylheme and heme iron was estimated by matching PMs intake and composition data based on laboratory analyses conducted using a High Performance Liquid Chromatography method (3) . In brief, the daily intake of nitrosyl-heme and heme iron was determined by multiplying the intake of each PM (in grams/day) by its corresponding content of nitrosyl-heme and heme iron, and then summing up the estimated intakes from all PMs. The proportional hazards models were used to examine the association between sex-specific tertiles of nitrosyl-heme and heme iron intake and CRC risk and 95% confidence intervals (CIs) were computed using Cox regression. Age served as the time scale, stratified by age and centre with adjustments for sex, energy intake, body mass index (BMI), waist circumference, education, smoking, physical activity in MET-h/week, lifetime alcohol consumption, dietary fibre, calcium intake, and family CRC history. Homogeneity of location subtype risk was also assessed. Interactions with smoking, BMI, physical activity, and alcohol were examined and sensitivity analyses were also conducted excluding the first three years of follow-up. During a mean follow-up of 16.7 years, 577 CRC were identified. We found no overall association between nitrosyl-heme (T3 vs T1; HR: 0.98 (95% CI: 0.79-1.21)) or heme iron intakes (T3 vs T1; HR: 0.88 (95% CI: 0.70-1.10)) with CRC risk, nor according to tumour subtypes. However, we found a non-statistically significant positive association between nitrosyl-heme intake and proximal colon, HR = 1.03; 95% CI, (0.65-1.61) and rectum cancer, HR = 1.04; 95% CI, (0.70-1.56). Our study found no evidence supporting a link between nitrosyl-heme or heme iron intake and CRC risk in Spanish subjects from the EPIC cohort. As these results are novel and preliminary, more heterogeneous studies are necessary to provide more convincing evidence on their role in colorectal carcinogenesis.