Colorectal and gastric cancers are among the leading causes of death worldwide [1]. In Brazil, estimates for 2018–2019 from the National Cancer Institute (INCA) indicate more than 417000 new cases of these malignant neoplasms [2]. In the northern region of the country, where our target population resides, GC is the second most prevalent type of neoplasia in men and the fourth in women, whereas the CRC is the fourth most incident in men and the third in women [2].
Although the causes of cancer have not yet been completely elucidated, studies have shown that a large group of mutagen-carcinogenic agents require metabolic activation to allow them to bind to DNA, RNA and proteins; therefore, several environmental components are strong risk factors for GC and CRC development [13][14]. Tomasetti (2017) demonstrated that the percentage of influence of external factors on GC and CRC susceptibility is 55% and 26%, respectively [15], thus, association studies in genetic pathways related to the metabolism and transport of environmental risk factors have aided to better understand the carcinogenesis process in several organs [16][17][18]. Most genetic association studies on cancer are investigations about tumor suppressors or oncogenes. Our analysis, however, proposes the study of xenobiotic-metabolizing and transporter genes, which can also modulate the susceptibility to different types of cancer. Additionally, few of these studies have been performed in admixed populations such as the Brazilian one. The Brazilian population is composed, mainly, by the admixture of Amerindian, European, and African ancestral populations [11][12]. Case-control studies in such admixed populations may be influenced by the variation of allelic frequencies of markers found in each different ethnic groups, which may create biases in the outcomes, especially in investigations of susceptibility to complex diseases, such as cancer [19][20]. In this case, estimates of ethnic admixture must be taken into consideration. Our investigation of genomic ancestry analysis was based on the set of 61 AIMs used in previous genetic studies of complex human diseases[11]. Our research group have performed some studies that demonstrated the influence of population substructure present in the northern region of Brazil with several types of cancer, for example childhood B-cell Leukemia [20][21]and breast and gastric cancer [7]. In the present study, however, no significant difference was found in the ethnic profiles between the case and control groups.
In this study, the polymorphisms shown to be associated with colorectal or gastric cancers are related to xenobiotic metabolism. A major group of mutagenic-carcinogenic agents requires metabolic activation to enable them to bind to DNA, RNA, and proteins. Therefore, genetic polymorphisms in these xenobiotic-metabolizing and transporter genes may account for the individual variation observed in the individual response to exposure [18][19][20].
In our analysis, the rs2231142 variant of the ABCG2 gene increased approximately 3 times the risk forGC development. The ABCG2 gene encodes the Human Breast Cancer resistance protein (BCRP)/ATP-binding cassette subfamily G member 2 (ABCG2),, which is an ATP-binding cassette (ABC) transporter responsible for the active transport of several compounds through extra and intracellular membranes [22]. This protein expression occurs predominantly in the liver and in the apical membrane of the intestinal epithelium, playing an important role in intestinal absorption and mediation of hepatobiliary excretion of its substrates (such as potentially carcinogenic xenobiotics and anticancer drugs) [23]. The BRCP is known as a molecular cause of multidrug resistance (MDR) in several cancer cells, but recently some research has focused on understanding its role as a susceptibility biomarker of human carcinoma cells [24][25]. Gupta et al. found a decrease in mRNA expression of ABCG2 in colorectal and cervical cancer, suggesting a role of this gene in tumorigenesis through the accumulation of genotoxins and the excess of nitric oxide production, which the author suggests being a common phenomenon in other tissues where this gene is hypo-expressed [26]. Supporting this finding, the study by Liu et al. (2010) demonstrated a differential expression of the BCRP at each carcinogenesis stage [27]. For the promotion of carcinogenesis, the expression of BCRP would be decreased to allow the accumulation of genotoxins and nitric oxide, but in the more advanced stages, BRCP can be positively expressed to efficiently transport chemotherapeutic drugs out of the cancerous cells, protecting them. Therefore, the assessment of differential expressions of BRCP may lead the scientific community to create a new method to evaluate progression, metastasis and to predict therapeutic response of colorectal cancer. The results also corroborate with the findings of Wang and colleagues, who, through an in vitro experiment, demonstrated that the ABCG2 gene shows dysregulated expression in GC tissues and cells [28]. In this study, the high expression of ABCG2/BRCP was correlated with advanced stages and poor prognosis of GC. Deregulated expression of the ABCG2 gene has further been pointed as a promoter factor to GC that affects cell proliferation and induces resistance to cellular apoptosis. These results corroborate with our analyses, confirming the role of SNPs of the ABCG2 gene in the initiation and promotion of GC.
Polymorphisms in the DPYD gene have also been shown to play a role in gastric or colorectal carcinogenesis. Our data demonstrated that the rs1801159 and rs17116806 polymorphisms are associated with a higher risk of GC susceptibility. Additionally, the rs17116806 has been also associated to an increased susceptibility to colorectal carcinogenesis, demonstrating that the same polymorphism can act on tumorigenesis in different tissues. International regulatory agencies, such as the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA), strongly recommend the monitoring of polymorphisms on the DPYD gene for evaluation of therapeutic response in fluoropyrimidine-based treatment [29][30]. Nevertheless, few investigations have studied genetic variations in the DPYD gene regarding cancer susceptibility, thus, the variety of clinical manifestations resulting by mutations in DPYD is still not well understood [31]. To date, there are no genetic association studies with the rs1801159 and rs17116806 polymorphisms and the susceptibility to the neoplasms investigated hereby. Therefore, this study is the first to investigate the correlation between DPYD polymorphisms and the susceptibility to GC and CRC in the Brazilian Amazon population.
Previous studies have also shown that modifications of the pyrimidines homeostasis and the products of their degradation can result in a number of phenotypic manifestations, including neurological disturbances [32] and gastrointestinal disorders [31]. Tanaka et al. analyzed the rs1801265 variant and the risk to develop six different neoplasms: esophagus, gastric, colon, lung, breast, and lymphomas, suggesting an influence of this variant on the development of these types of cancer [33]. Matáková et al. (2017) demonstrated a significant association with the rs1801160 SNP of the DPYD and an increased risk for the CRC development (p = 0.003, OR = 3.264, 95% CI = 1.425–7.475) [34]. Edward et al. (2016) showed a comprehensive view of how the polymorphisms in the DPYD gene deregulate the pyrimidine and nucleic acid synthesis, consequently, promoting malignant progression of melanoma [35]. A multicenter study concluded that variations in genes involved in the metabolism of pyrimidines, particularly the DPYD, may also influence the susceptibility to ovarian carcinoma [36].
From the findings to date, we can infer that relevant clinical interventions is possible by enhancing the knowledge of the basic set of mutations that can lead to gastric and colorectal carcinogenesis. This outcomes creates a new expectation regarding the progress of studies related to the predictive diagnosis of cancer.