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Colorectal Cancer and Risk Factors
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This entry is adapted from the peer-reviewed paper 10.3390/cancers13092025

colorectal cancer (CRC) is one of the most common malignant neoplasms. Depending on the location, type of cancer or gender, it is ranked 2nd to 4th in terms of incidence in the world. CRC, year by year, shows an increasing tendency in terms of both morbidity and deaths. 

Colorectal Cancer Risk Factors

1. Introduction

The most common cancer diagnosed in both sexes is lung cancer (11.6% of the total cases), followed by breast cancer in women (11.6%) and prostate cancer in men (7.1%). Colorectal cancer (CRC) is third in terms of recognition (6.1%) and second in terms of mortality (9.2%). It is estimated that by the year 2035, the total number of deaths from rectal and colon cancer will increase by 60% and 71.5%, respectively [1]. These figures may differ from country to country depending on the degree of economic development. Therefore, the disease is widely recognized as a marker of the country’s socioeconomic development [2]. The increase in morbidity is also influenced by lifestyle, body fatness and dietary patterns [3]. There is convincing evidence that physical activity has a protective effect. The risk of developing the disease is increased by more frequent red and processed meat and alcohol drinks [2][4]. The progress of civilization and economic development, apart from improving socioeconomic conditions, also causes a change in dietary patterns, referred to as the westernization of the lifestyle. This means higher consumption of animal fats, processed meats, refined grains or sweets, a low supply of dietary fibers, fruits, vegetables and low physical activity. The occurrence of overweight or obesity is often the result of such a lifestyle [5]. Overweight and obesity are associated with an increased risk of many civilization diseases. Visceral obesity has been reported to adversely affect the prognosis of CRC in men [6]. About a quarter of a contributor to genetic predisposition. The development time of CRC usually lasts from several to several years; therefore, it is very important to diagnose it early in developing the disease. Based on follow-up examinations and nutrition prevention based on a balanced diet, secondary prevention is also important [7].
Considering all the aspects, we made efforts to systematize the available literature data in terms of epidemiology, risk factors, type and nature of symptoms, stages of development and available diagnosis of colorectal cancer.

2. Risk Factors

Multiple factors have been implicated in the development of colorectal cancer (Figure 1). It was demonstrated that individuals are at increased risk for CRC if they (or their relatives) have had cancer, a history of colon polyps, inflammatory bowel diseases, diabetes mellitus or cholecystectomy. Lifestyle factors also play important roles in CRC etiology. The evidence shows that overweight and obesity, physical inactivity, cigarette smoking, alcohol consumption and inappropriate dietary patterns (a diet low in fiber, fruits, vegetables, calcium and dietary products and high in red and processed meat) increase CRC risk. In addition, gut microbiome, age, gender and race and socioeconomical status are known to influence colorectal cancer risk.
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Figure 1. The main risk factors associated with colorectal cancer.

2.1. Family and Personal Medical History

2.1.1. Family History and Genetics

A family history of colorectal cancer significantly increased the risk of developing colorectal cancer. This phenomenon shares both inherited genetic predisposition and lifestyle factors. The information relevant for future colorectal cancer occurrence, among other, include: (i) the generational distance of the relatives to the individuals at risk; (ii) the age at which the first-degree relatives developed colorectal cancer; (iii) the number of family members diagnosed with colorectal cancer; (iv) family co-occurrence of other neoplasms (e.g., endometrial, ovarian and urinary tract, pancreatic) and (v) personal history of cancer. Previous studies indicated that people with one affected first-degree relatives (parents, siblings and children) have, on average, two times higher risk of CRC in comparison to those with no family history. The risk of CRC development is significantly higher if a relative is diagnosed before the age of 60. Moreover, a higher number of affected relatives (not only first-degree but also second- and third-degree) also increases the disease risk [8][9][10][11].
It is estimated that 2–8% of colorectal cancer cases arise as a result of inherited syndromes. The two most common hereditary syndromes that predispose for colorectal cancer development are hereditary nonpolyposis colorectal cancer (HNPCC), also known as Lynch syndrome, and familial adenomatous polyposis coli (FAP). HNPCC is an autosomal dominant disease caused by mutations in genes known as mismatch repair errors. Proteins encoded by these genes are responsible for reaper errors in DNA that occur during cell division. Most cases of HNPCC are associated with mutations in MLH1 and MSH2 genes. However, there are several other genes mutations in which give rise to HNPCC (e.g., MSH6, MLH3, TGBR2, PMS1 and PMS2). Patients with HNPCC have about 20% risk of developing CRC by the age of 50 and about 80% risk of developing CRC by the age of 85 [9][12][13][14][15].
Similar to HNPCC, FAP also presents an autosomal dominant pattern of heredity. It is caused by adenomatous polyposis coli (APC) gene defects. APC is classified as a tumor suppressor gene. It encodes a protein that plays a significant role in regulating DNA replication and cell division. Individuals with FAP start to develop hundreds or even thousands of colon polyps in their mid-teens and, with high-probability, most of these colon polyps evolve into cancer. It is assumed that almost all patients with the earlier unrecognized and untreated FAP syndrome will be diagnosed with colorectal cancer before the age of 35–40 [13][14][15][16].
The increased risk of CRC development is also linked with the occurrence of Peutz-Jeghers syndrome, Juvenile polyposis syndrome, PTEN hamartoma tumors syndrome and MUTYH-associated polyposis (MAP) [15].

2.1.2. Inflammatory Bowel Disease (Crohn’s Disease; Ulcerative Colitis)

Inflammatory bowel disease (IBD) is ranked as the third-highest risk condition for the development of colorectal cancer, behind HNPCC and FAP. IBD is a group of chronic and incurable diseases, which affect the immune system of the gastrointestinal tract and, in consequence, lead to the development of uncontrolled inflammation. The two major forms of IBD are Crohn’s disease and ulcerative colitis. The etiology of IBD is unknown, it is considered that the development of IBD is a result of interactions between genetic, immunological and environmental factors [14][17]. Due to the fact that chronic inflammation promotes tumor growth and progression, individuals with IBD have about 2–6 times higher risk of developing CRC in comparison to healthy individuals. The risk of CRC increases with the duration of IBD and the anatomic extent and severity of the disease [8][18][19].

2.1.3. Colon Polyps

Colon polyps (precancerous neoplastic lesions) are defined as an abnormal growth of tissue projecting from a mucous layer of the colon. They are histologically classified into two main categories: non-neoplastic (hamartomatous, hyperplastic and inflammatory polyps) and neoplastic (adenomatous, Figure 2). The adenomatous polyps are of great importance because they harbor the potential to become malignant. It is estimated that about 95% of colorectal cancer is developed from adenomatous polyps. Despite the fact that almost all cancer arises from adenomas, it is estimated that only about 5% of polyps progress to colorectal cancer [10][20]. The period for the transition of adenomatous polyps into invasive adenocarcinoma is 5–15 years and the risk of malignant transformation increases with polyp size, degree of dysplasia and the age of individuals. Polyps greater than 1–2 cm in diameter, a high degree of dysplasia and increasing age are unfavorable prognostic factors. Due to the fact that approximately 40% of people at the age of 50 or older have one or more adenomatous polyps, it is of great importance to identify these polyps and remove them prior to cancer transition [8][20].
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Figure 2. Representative histopathological appearance of adenomatous (A,B) and serrated (C,D) changes in the colon.

2.1.4. Diabetes Mellitus

Diabetes mellitus is a metabolic disorder characterized by chronic hyperglycemia, which results from defects in insulin secretion and/or action. It is estimated that around 460 million people globally are currently suffering from diabetes and the number will continue to grow. Epidemiological data indicate that diabetes is an independent risk factor for several gastrointestinal cancers, including colorectal cancer [21][22]. Individuals with type 2 diabetes have about two-three times greater risk of developing colorectal cancer in comparison to the non-diabetic population [23][24]. The development of colorectal cancer is thought to be related to an increase in insulin concentration and an inflammatory condition associated with the disease. Hyperinsulinemia may contribute to colorectal cancerogenesis directly by stimulating colonic cell proliferation and indirectly by increasing the level of insulin-like growth factor 1 (IGF-1). IGF-1 is a mitogenic factor that enhances cell growth and decreases cell death [21][25]. Moreover, chronic inflammation associated with diabetes favors carcinogenesis, malignant transformation, tumor growth, invasion and metastasis through the action of proinflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α) and interleukin-6 (Il-6) [25][26].

2.1.5. Cholecystectomy

The possible association between cholecystectomy, the surgical removal of the gallbladder from the body and subsequent colorectal cancer incidence has still not been firmly established or refuted. The results from some studies indicated an increased risk of CRC development after cholecystectomy [27][28][29], whereas others have reported no increased risk [30][31][32]. The possible increased risk of CRC after cholecystectomy is thought to be associated with changes in the secretion and composition of bile acids. Under physiological conditions bile acids are released periodically in response to food intake. In the absence of a gallbladder, there is a continuous flow of bile to the intestine, which results in increased bacterial biotransformation of bile acids into secondary bile acids. The secondary bile acids have the potential to generate reactive oxygen and nitrogen species, disturb the cell membrane and induce DNA damage and apoptosis in the colonic mucosa cells, which increase the risk of developing colon carcinomas [33][34].

2.2. Lifestyle

2.2.1. Dietary Patterns

  • Diet high in red and processed meat
According to the International Agency for Research on Cancer Group, red meat and processed meat were classified as probably carcinogenic to humans (Group 2A) and carcinogenic to humans (Group 1), respectively. Red meat is defined as the meat derived from the muscle of farm animals (e.g., beef, lamb, game and pork). Processed meat refers to the meat that has been preserved by curing, salting, smoking or adding chemical preservatives in order to improve favor or extend the shelf life. Studies have shown that regular consumption of red and processed meat is an important risk factor for the development of colorectal cancer [14][35]. It is estimated that the risk of CRC may increase by about 17% for every 100 grams portion of red meat and by approximately 18% for every 50 grams of processed meat eaten daily [36][37][38]. The exact mechanism by which consumption of red and processed meat may contribute to the development of colorectal cancer is still under investigation. Several factors that are believed to influence the occurrence of cancer are heterocyclic amines (HACs), polycyclic aromatic hydrocarbons (PAHs) and N-nitroso compounds (NOCs)—harmful substances that may be produced during high-temperature or open-fire cooking of meat (e.g., pan-frying, grilling and roasting). HACs are formed during the specific reaction of free amino acids, carbohydrates and creatinine or creatine (substances found in muscle). PAHs, in turn, are formed when fat and juice from meat come into contact with open flames. The smoke that contains PAHs attaches to the surface of the cooked meat. HACs and PAHs are considered genotoxic substances that have the potential to cause point mutations (deletions, insertions and substitutions) and, in consequence, initiate the process of carcinogenesis. Similarly, NOCs (nitrosamine and nitrosamide) are potent carcinogenic agents that can react with DNA. These substances are synthesized from amines or amides and oxides of nitrogen (nitrites or nitrates, i.e., substances used as a food additive to inhibit the growth of bacteria and gives the meat the desirable cured) during high-heat cooking of processed meat [39][40]. The other factor that is believed to contribute to the malignant transformation of colon cells is heme, an iron-containing porphyrin presents in large amounts in red meat. It was demonstrated that heme increases oxidative stress and induce lipid peroxidation of intestinal cells. Reactive oxygen species contribute to DNA damage and gene mutations. Reactive lipid peroxides, in turn, exert a cytotoxic effect on epithelial cells. The damage of the cell surface results in hyperproliferation of the cells and leads to epithelial hyperplasia, which may evolve to dysplasia and cancer. In addition, heme irons stimulate the endogenous formation of the above-mentioned NOCs and induce alternation in the gut microbiota leading to a state of dysbiosis [5][35][38]. It should be also emphasized that consumption of high-fat red and processed meat contributes to obesity, insulin resistance and an increase of bile acid secretion, which acts as an aggressive surfactant for the mucosa and increase the risk of developing colorectal cancer.
  • Diet low in fiber, fruits and vegetables
It was shown that the high consumption of dietary fiber could reduce the risk of colorectal cancer development by up to 50% [8]. However, currently available results of epidemiologic studies not unequivocally support the protective effects of fiber against CRC and the precise mechanism of anticancer fiber action has not been clearly established. The potential mechanism of the protective effect of fiber consumption on CRC development includes: (i) reduction of transit time for stool throughout the colon and, in consequence, reduction of contact between potential carcinogenic substances and colonic epithelium, (ii) increase in the amount of water in fecal content and thus dilution of carcinogens and procarcinogens present in fecal, (iii) binding sterols and bile acids metabolites, which may be implicated in carcinogenesis, and (iv) stimulation the growth of beneficial gut microbiota, which, in turn, ferment fiber and produce short-chain fatty acids—substances suggested to exert tumor-suppressive effects. Therefore, dietary guidelines recommend people consume at least 20–30 g of fiber per day [5][10][11][35]. Naturally great sources of fiber are fruits and vegetables. In addition to fiber intake, consumption of fruits and vegetables provides a large number of bioactive compounds, such as vitamins, minerals, folate, plant sterols and protease inhibitors. Many of these compounds exhibit potent antioxidant and anti-inflammatory properties, which could inhibit DNA and cellular damage. The results from several studies demonstrated that a high intake of fruits and vegetables may be linked with a lower CRC risk development [11][18][35].
  • Diet low in calcium, vitamin D and dairy products
According to the World Cancer Research Fund/American Institute for Cancer Research [35], the high consumption of dairy products (in particular milk) is probably inversely associated with the risk of developing colorectal cancer. The suggested protective effect of dairy products has been largely attributed to their content of calcium. It was demonstrated that calcium binds secondary bile acids and fatty acids diminishing their ability to modify intestinal mucosa and, in consequence, limiting their carcinogenic potential. Moreover, calcium was found to inhibit proliferation and to induce apoptosis of tumor cells and reduce distinct patterns of mutation in proto-oncogene KRAS [5][35][41]. In addition to calcium, the other milk component, i.e., vitamin D is also suggested to play a beneficial role against CRC development. The roles of vitamin D and calcium are closely related since the primary function of vitamin D is the maintenance of calcium homeostasis by enhancing its intestinal absorption. It is hypothesized that the anticancer effect of vitamin D may be a result of the increased level of serum calcium concentration. It should be emphasized, however, that vitamin D exerts many other physiological functions that may play an important part in cancer control. The results of the studies showed that vitamin D alters the expression of a variety of genes involved in the regulation of growth, proliferation, differentiation and apoptosis of epithelial cells. Moreover, it exhibits anti-inflammatory action, improved immune function and inhibits angiogenesis [42][43]. Due to the fact that the major source of vitamin D for humans is skin exposure to sunlight, there are some studies to determine if the distribution of colorectal cancer incidence depends on amounts of natural light. It was demonstrated the colorectal cancer mortality rates were higher in the northern regions of the United States and Europe. It is assumed that people who live at higher latitudes are exposed to less amount of solar ultraviolet-B dose, synthesize less vitamin D and therefore have a higher risk of developing and die from colorectal cancer [42]. On the other hand, the results of the study performed in Norway showed that there is no significant north–south gradient for the death rate for colon cancer. However, the survival rate of colon cancer depended on the season of diagnosis and was the lowest in the cancers diagnosed in the autumn. Recent meta-analyses of prospective cohorts demonstrated that, regardless of geographic location, higher serum vitamin D level was related to a statistically significant, substantially lower colorectal cancer risk in women and non-statistically significant lower risk in men [44]. According to World Cancer Research Fund/American Institute for Cancer Research [35], the evidence for vitamin D was limited and there is a need to perform research assessing the anticancer activity of vitamin D.

2.2.2. Overweight and Obesity

A condition of abnormal or excessive fat accumulation (overweight and obesity) is a convincing risk factor for the development of colorectal cancer. Overweight/obese men and women have about 50% and 20% greater risk of developing colorectal cancer in comparison to people with normal weight, respectively. It is estimated that an overall CRC risk increase by 3% for every five kilograms of weight gain [11][14]. The mechanisms underlying the induction of carcinogenesis in overweight/obese people are not fully understood and still under intense study. Adipose tissue is an endocrine organ that plays a crucial role in the regulation of energy intake and inflammatory response. It was found that abnormal or excessive fat accumulation causes alternations in adipose tissue hormone and cytokine secretions. Adipose tissue of overweight/obese people release more factors (e.g., leptin, resistin, TNF-α, IL-1, IL-6, IL-7 and IL-8), which are known to exhibit mitogenic effects on epithelial cells, inhibit apoptosis of the cells, promote oxidative stress, suppress immune response and reduce the activity of IGF-1 axis and have been associated with cancer development and progression [5][35][45].

2.2.3. Physical Inactivity

Epidemiological data indicate that an increasing colorectal cancer incidence in developed and developing countries may be the result of a sedentary lifestyle. It is estimated that physically inactive people have up to 50% higher risk of developing colorectal cancer in comparison to the most physically active ones [11][46]. Regular physical exercises have been shown to improve immune system function, reduce inflammation, reduce stress, optimize metabolic rate, help regulate hormone level and prevent obesity and, as a result, may help protect against cancer development [41].

2.2.4. Cigarette Smoking

Tobacco smoke is an established risk factor for the development of many types of cancer, including colorectal cancer. The results of the studies indicated that people who smoke cigarettes have to 2–3-fold increase risk for developing CRC in comparison to non-smokers and the risk increases with dose and duration of exposure [25]. In addition, it is considered that cigarette smoking is attributed to up to 12% of colorectal cancer deaths [10]. Tobacco smoke contains a mixture of thousand chemicals, over 60 of which are well-established carcinogens (e.g., N-nitrosamines, polycyclic aromatic hydrocarbons, aromatic amines, aldehydes and metals) that are known to damage DNA. Mutations in colorectal epithelial cells may lead to polyposis development, which, in turn, may transit into invasive adenocarcinoma [47].

2.2.5. Alcohol Consumption

Alcohol intake is one of the major contributors to colorectal cancer development. It is estimated that the consumption of 2–3 drinks daily increases the risk of CRC by about 20%, whereas drinking more than three alcoholic beverages increases this risk by about 40% [11][14]. Individuals who are used to drink four and more drinks every day increase their chance of developing colorectal cancer for up to 52% [48]. To date, the various mechanism by which alcohol may induce carcinogenesis have been proposed. They include the production of reactive oxygen species and nitrogen species (during the oxidative metabolism of ethanol), production of mutagenic acetaldehyde (the first metabolite of ethanol), depletion of S-adenosylmethionine (epigenetic alternations), inactivation of the tumor suppressor genes, hormonal imbalance, reduction in folate concentration and impairment of retinoic acid metabolism [41][49].

2.3. Others

2.3.1. Gut Microbiota

Recently, a growing number of studies indicated that gut microbiota may be a key factor that contributed to the development of many pathological processes, including cancer. The gut microbiota (microbiome) comprises a large population of diverse microorganisms (bacteria, viruses, fungi and protozoa) inhabiting the gastrointestinal tract of humans. In healthy people, the microbiome is involved in nutrient metabolism and absorption, drug metabolism and elimination of xenobiotics. In addition, normal gut microbiota participates in the maintenance of intestinal barrier integrity, protects against pathogens and plays an important role in immunomodulation. According to the latest research that explored the microbiome of the individuals with colorectal cancer, alternation in the composition and functionality of the normal gut microbiota may lead to initiation, promotion and progression of this cancer. It was demonstrated that toxic metabolites of bacteria cause DNA damage, affect cell cycles, stimulate immune response and lead to disturbance of the intestinal barrier function. As a result, impaired intestinal microbiota homeostasis contributes to the development of the microenvironment favorable to develop colorectal cancer [50][51][52][53][54].

2.3.2. Age

Due to the fact that about 90% of all new cases of colorectal cancer occurring in individuals over 50 years old, older age is considered to be one of the most significant factors influencing the risk of developing colorectal cancer [8][10]. It is estimated that people after the age of 65 have about three times greater risk to develop colorectal cancer in comparison to those at the age of 50–64 and about 30 times greater risk than people at the age of 25–49 [14]. The average age at diagnosis is 68 and 72 years old for men and women, respectively. The fact that colorectal cancer is the age-related disease is particularly evident in the developed countries where the rate of colorectal cancer is the highest. The number of colorectal cancer incidence in these countries is associated, among others, with longer life expectancy and, in consequence, increase number of old people in the population [55]. It should be emphasized, however, that the results of the newest studies indicated that the incidences of colorectal cancer rise among young adults (20–49 years old) in the United States and Europe [56][57]. Currently, it is recommended to begin screening for colorectal cancer in adults aged more than 50 years. According to the authors of the studies, if the mentioned trend continues, screening guidelines should be reconsidered.

2.3.3. Gender and Race

According to the American Cancer Society, men have about 30% higher risk of developing colorectal cancer in comparison to women. In addition, men who are diagnosed with colorectal cancer have a worse prognosis and approximately 40% higher mortality compared to women [11]. On the other hand, women are more prone to develop right-sided colon cancer, which is often diagnosed at a more advanced stage and seemed more aggressive than left-sided tumors [58][59]. The reasons for sex disparity are not fully understood, it is considered that they may be related to the differences in the exposure to risk factors (e.g., alcohol and tobacco), dietary patterns and sex hormones [11][41].
The incidence of colorectal cancer varied substantially by race also. The non-Hispanic Black individuals experience one of the highest incidence rates of all racial groups. It is estimated that colorectal cancer incidence rate in non-Hispanic Blacks is approximately 50% higher than in Asians/Pacific Islanders and about 20% higher than in non-Hispanic Whites [11][60].

2.3.4. Socioeconomics Factors

It is believed that people with low socioeconomic status (SES) generally have a higher risk of developing cancer than those with high SES. This may be explained in part by limited access to health care services and high-quality treatment resources and unhealthy dietary habits, sedentary lifestyle and smoking in the low socioeconomic status population [10][61]. It should be emphasized, however, that the results concerning the association of SES with the incidences of colorectal cancer are inconsistent. In North America, people with low SES exhibited a higher incidence of colorectal cancer in comparison to people with high SES, contrary, in Europe, high SES groups often show a higher risk of developing colorectal cancer. Therefore, there is a need to perform additional studies in order to establish the impact of socioeconomic status on colorectal cancer occurrence [62].

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Tomasz Sawicki
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