Abstract
Obesity is a well-established risk factor for colorectal cancer (CRC), and accumulating evidence suggests a differential influence of sex and anthropometric factors on the molecular carcinogenesis of the disease. The aim of the present study was to investigate the relationship between height, weight, bodyfat percentage, waist- and hip circumference, waist-hip ratio (WHR), body mass index (BMI) and CRC risk according to KRAS and BRAF mutation status of the tumours, with particular reference to potential sex differences. KRAS and BRAF mutations were analysed by pyrosequencing in tumours from 494 incident CRC cases in the Malmö Diet and Cancer Study. Hazard ratios of CRC risk according to anthropometric factors and mutation status were calculated using multivariate Cox regression models. While all anthropometric measures except height were associated with an increased risk of KRAS-mutated tumours, only BMI was associated with an increased risk of KRAS wild type tumours overall. High weight, hip, waist, WHR and BMI were associated with an increased risk of BRAF wild type tumours, but none of the anthropometric factors were associated with risk of BRAF-mutated CRC, neither in the overall nor in the sex-stratified analysis. In men, several anthropometric measures were associated with both KRAS-mutated and KRAS wild type tumours. In women, only a high WHR was significantly associated with an increased risk of KRAS-mutated CRC. A significant interaction was found between sex and BMI with respect to risk of KRAS-mutated tumours. In men, all anthropometric factors except height were associated with an increased risk of BRAF wild type tumours, whereas in women, only bodyfat percentage was associated with an increased risk of BRAF wild type tumours. The results from this prospective cohort study further support an influence of sex and lifestyle factors on different pathways of colorectal carcinogenesis, defined by KRAS and BRAF mutation status of the tumours.
Highlights
It is well established that body size influences risk of colorectal cancer (CRC)
A Cox proportional hazards analysis was used in order to calculate relative risks of different anthropometric factors and subgroups of CRC defined by KRAS and BRAF mutation status, overall, and stratified for sex
High bodyfat percentage was significantly associated with an increased risk of BRAF wild type tumours. In this prospective cohort study, we have investigated the relationship between obesity, measured as several anthropometric factors, and risk of CRC according to KRAS and BRAF mutation status of the tumours, with particular reference to potential sex differences
Summary
It is well established that body size influences risk of colorectal cancer (CRC). It has been less investigated whether this risk differs according to molecular subsets of the disease. Colorectal carcinogenesis is a multistep process driven by accumulation of several genetic alterations, including chromosomal abnormalities, gene mutations, and epigenetic modifications involving regulation of proliferation, differentiation, apoptosis, and angiogenesis [1,2]. At least three distinct pathogenetic pathways have been identified, i.e. the chromosomal instability (CIN), microsatellite instability (MSI), and CpG island methylator phenotype (CIMP) pathways [3,4]. Somatic mutations in the KRAS (v-Ki-ras Kirsten rat sarcoma viral oncogene homolog) oncogene are identified in 30–40% of sporadic CRC and these mutations occur early in the carcinogenetic process [5,6]. While KRAS mutation predicts non-responsiveness to epidermal growth factor receptor (EGFR)-targeting agents, the prognostic relevance of KRAS mutations still remains controversial [7,8,9]
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