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  • However some limitations should be acknowledged First only m


    However, some limitations should be acknowledged. First, only missense variants with MAF ≥ 0.05 were inspected in this study. Other polymorphisms within PTP genes including copy number variant and rare variants should also be investigated in future researches. Second, for the scope of designed probes on the CRC exome chip, we only analyzed 18 candidate variants identified by the bioinformatic analysis. The remaining candidate variants not designed on the exome chip should be further explored. Third, our study was a retrospective observational research based on hospital population, which was inevitably influenced by selection bias and recall bias. At last, other confounders such as body mass index (BMI) and red meat intake were not evaluated in this study. Independent studies with better design and larger-scale are desiderated to confirm our findings. In conclusion, we highlighted that PTPN12 rs3750050 significantly increased the risk of CRC via a two-stage case-control study. Following functional assays revealed that this variant could attenuate PTPN12’s inhibitory effect on Ras/MEK/ERK signaling, enhance Herboxidiene procession and proliferation, thus participating in CRC development. Our study provides a novel insight into the roles of variants within PTP genes in the pathogenesis of CRC.
    Conflicts of interest
    Introduction Cancer is the second leading cause of death in Brazil [1]. In 2012, 224,000 cancer deaths occurred and 437,000 new cancer cases were diagnosed [2]. By 2025, the burden of cancer is projected to increase by 50% due to population growth and aging [2]. Besides changes in the population structure, the increasing prevalence of lifestyle risk factors may pose additional challenges to cancer control [[3], [4], [5], [6]]. Lifestyle risk factors (tobacco smoking, alcohol consumption, overweight and obesity, unhealthy diet, and lack of physical activity) have been associated with increased risk of at least 20 types of cancer [[7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17]]. Therefore, cancer prevention through lifestyle modification is one of the most attractive and realistic approaches for cancer control in Brazil. Quantitative estimation of proportion of cancer that could be potentially avoided by eliminating or reducing lifestyle risk factors is restriction fragment length polymorphism (RFLP) useful to inform cancer prevention strategies [18]. In Brazil, previous studies on preventability of cancer have focused on single risk factors [6,19], cancer incidence or mortality [6,19], historical exposure profile [20], or single exposure estimate for all age groups [19,20].
    Discussion Our results are comparable to recent studies, using similar methods, conducted in the Australia, China, United Kingdom (UK), and United States (US) [[28], [29], [30], [31]] (Table 4). Tobacco smoking was the leading factor contributing to cancer cases in all countries: 19.0% in US, 15.5% in Brazil (our study), 15.1% in UK, 14.8% in China, and 13.4% in Australia [[28], [29], [30], [31]]. Smoking-related cancer cases were higher in men than women, ranging from 43% in UK to 20-fold in China [[28], [29], [30], [31]]. High BMI had the second highest PAF among lifestyle factors in US (7.8%), UK (6.3%), Australia (3.4%), and Brazil (4.9%), and the third highest PAF in China (2.9%) and [[28], [29], [30], [31]]. Alcohol consumption the third highest PAF in Australia (2.8%), UK (3.3%), Brazil (3.8%) and US (5.6%), and the fourth in China (2.9%) [[28], [29], [30], [31]]. Our findings slightly differ from previous studies quantifying the preventability of cancer due to lifestyle risk factors in Brazil [6,19,20]. For example, compared to our study, Azevedo e Silva and colleagues [20] reported lower proportion of cancer cases due to smoking in both men (14.4% vs 20.8% in our study) and women (7.2% vs 10.1%). Tobacco smoking is constantly declining in Brazil [32], and our study used the most recent prevalence data, which would lead to lower estimates. However, our study also considered RR of cancers among former smokers, relative to never smokers, which were not considered by Azevedo e Silva and colleagues [20]. RR of lung cancer among heavy former smokers may remain at least threefold higher than never smokers after 25 years since quitting [33]. Azevedo e Silva and colleagues also reported lower PAF for all cancer cases due to high BMI (2.1% men; 3.3% women) compared to ours (3.3% men; 6.6% women). These differences could be relate to our use of continuous rather than categorical to estimates PAF, but mainly due to cancer sites considered with convincing evidence to be associated with high BMI (6 vs 13 cancer sites in our study) [9]. Indeed, BMI has constantly increased over the last years in Brazil [6], and anthropometrics measurements were considered five years apart (2008 vs 2013).