Investigating the Mutual Influence of Colorectal Cancer and Metabolic Syndrome at the Molecular Level Through the Integration of Whole Exome Sequencing and Systems Biology Approach
Colorectal cancer (CRC) is the third most common cancer worldwide, accounting for 10.2% of all cancers. According to global statistics, more than 1.8 million people were diagnosed with colorectal cancer in 2018. In Iran, its incidence has increased significantly in recent years. The age-standardized incidence rate (ASR) is 15.9/100,000 for men and 11.9/100,000 for women. The major risk factors for CRC include genetic predisposition, Western dietary habits, lifestyle (smoking, drinking alcohol, physical activity, etc.) and metabolic diseases (obesity, insulin resistance, etc.). Metabolic syndrome (MetS) is a cluster of metabolic risk factors that includes abdominal obesity, hypertension, hyperglycemia, and dyslipidemia, for which several definitions have been proposed using different criteria. It is worth noting that in the past decades, the prevalence of metabolic syndrome has increased dramatically worldwide due to urbanization, increasing obesity, and sedentary lifestyle. It has been reported that more than 20% of adults have metabolic syndrome, but its global prevalence varies depending on ethnic and environmental factors. The prevalence of metabolic syndrome in Iran is high. A systematic survey of the Iranian population has shown that the highest and lowest incidence rates of metabolic syndrome were obtained by the International Diabetes Federation (144.07 per 1000) and JIS (89.73 per 1000).
Metabolic syndrome It is closely associated with various cancers, as it increases the risk of tumorigenesis and cancer-related mortality. In addition, cancer survivors are at risk of developing metabolic syndrome. Several studies have shown an association between obesity and a variety of cancers. It has also been reported that metabolic syndrome is associated with an approximately 13% increased risk of CRC. Obesity and diabetes mellitus (DM) are associated with an increased risk of colorectal cancer, and both have been suggested as factors that influence the prognosis of colorectal cancer. The metabolic phenotype of cancer cells is heterogeneous in different cancer types. For example, while some malignant tumors rely on glycolysis, others present a metabolic phenotype mediated by oxidative phosphorylation. In general, through the reprogramming of the tumor microenvironment, catabolic and anabolic metabolism are essential for cancer cells to maintain energy supply and synthesize biomass. It is also noteworthy that the increase in metabolic syndrome leads to drug dysregulation and increases the likelihood of chemotherapy side effects. Therefore, investigating the metabolic mechanism of colorectal cancer is essential for further prediction and implementation of personalized treatment. With the increasing application of bioinformatics analysis in the diagnosis and prognosis of malignant tumors, several researchers have linked the metabolome to the genome, which allows for the detection of extensive and accurate metabolite profiles. Whole-exome sequencing allows researchers to identify mutations and genetic variants that may be susceptible to colorectal cancer and metabolic syndrome. In parallel, systems biology approaches investigate the interactions between genes, proteins, and molecules to elucidate broader layers of disease development. Such comprehensive insights may reveal the complex molecular pathways linking metabolic syndrome to colorectal cancer and provide new perspectives for novel therapeutic avenues. Some studies have been reported on the association between metabolic syndrome and colorectal cancer, but these studies have been limited to Western countries and ethnicities, and studies on Asian ethnicities are limited to East Asian countries such as Taiwan and Japan. On the other hand, there is a lack of knowledge of prognostic and predictive molecular factors to guide treatment decisions in many clinical situations in colorectal cancer, and therefore there is a clinical need to uncover these factors in order to improve treatment and outcomes. In this study, we use whole-exome sequencing and systems biology to comprehensively investigate the association between metabolic syndrome and colorectal cancer at the molecular level to address these knowledge gaps, which are critical for the etiology, prevention, and early detection of colorectal cancer.
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