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Colorectal cancer

Colon cancer (colorectal cancer (CRC)) it is a malignant tumor that develops from epithelial tissue.

Epithelial tissue is present everywhere in the body and covers all internal organs. Also, the mucous membrane of the gastrointestinal tract consists of epithelial tissue.

This pathology in the field of malignant neoplasms occupies one of the leading places in industrialized countries (such as the United States and Japan) and is less common in developing countries in Africa and Asia. The incidence rate is higher in the male population than in the female population. Despite the fact that colon cancer most often affects the elderly, this pathology can also be detected in young people.

In most cases, colorectal cancer (CRC) is an adenocarcinoma, a malignant tumor that develops from the glandular epithelial cells of the colon and rectum, in almost 90% of cases. In addition, but much less often, squamous cell, cricoid and undifferentiated cancer can occur. Approximately 60-65% of all cases of CRC occur sporadically (that is, in individuals without a family history of CRC or in the presence of non-hereditary genetic mutations that increase the risk of CRC) through acquired somatic genetic and epigenetic aberrations. Colorectal cancers are hereditary in nature, with twin studies showing heritability at 35-40%. Approximately 25% of CRRs have a family history in the absence of genetic syndromes. And only 5% are hereditary cancer syndromes, which include hereditary nonpolyposis colorectal cancer (HNPCC - hereditary nonpolyposis colorectal cancer, also known as Lynch syndrome), or familial adenomatous polyposis (FAP - familial adenomatous polyposis), caused by mutations in rare but highly penetrant genes (MLH1 and APC). Detectable mutations in common genetic variations with low penetrance are associated with only 1% of CRC. It should be noted that CRC with an inherited component is not completely hereditary, and environmental factors are also involved in carcinogenesis. 

Over the past decades, our understanding of the epidemiology, etiology, molecular biology, and clinical aspects of CRC has expanded.  And despite this, about 1.8 million new cases of CRC are registered annually in the world. Due to the fact that CRC is often diagnosed in the late stages of the disease, about 900 thousand patients die every year. Although CRC is considered a disease of developed countries, a rapid increase in the incidence occurs in countries experiencing economic development, which is accompanied by changes in diet and lifestyle. Unfortunately, Russia also belongs to such countries. In developed countries, screening and modern treatment methods reduce morbidity and mortality, but despite this, these indicators remain at a fairly high level (morbidity 30.8 per 100 thousand population, mortality-10.6 per 100 thousand population), the global average morbidity and mortality rates from CRC are 19.7 and 8.9, respectively. In less affluent countries, existing screening programs (and sometimes the lack of them) and affordable medical treatment are currently insufficient to contain the steady increase in these rates. 
Therefore, for government, health organizations, and policy makers, understanding the drivers of CRC incidence and the primary and secondary prevention strategies needed to counter the rise in CRC is critical. It is also important to understand that an increase in morbidity does not necessarily lead to an increase in mortality. Despite the increase in morbidity, in some countries (for example, Italy and Slovenia), mortality rates from CRC are decreasing, probably due to high-quality screening, which leads to early detection of CRC and improved treatment. Conversely, in some countries with rising morbidity rates but limited medical resources (such as Brazil and Russia), mortality rates are rising.

 
Age, gender, and racial predisposition. 

Since cancer is a disease of aging, the rate of disease development and death increases after the age of 50, with about 90% of cases of morbidity and death occurring after the age of 50. The age-adjusted rates are higher for men than for women, giving approximately a 1.4-fold and 1.5-fold difference in morbidity (23.6 vs. 16.3 cases per 100,000 people per year) and mortality (10.8 vs. 7.2 deaths per 100,000 people per year), with the difference becoming significant in the age group after 50 years. The higher incidence of CRC in men is probably due to the fact that men are more likely to be influenced by environmental factors than by genetic factors in colorectal carcinogenesis, the significance of the hereditary factor in men is estimated at 28%, in women – 45%. The study of population migration represents a large contribution of environmental factors to the risk of developing CRC in men. Interestingly, among men who migrated to Sweden before the age of 30, after five decades of living in Sweden, the incidence of CRC decreased for male immigrants from higher-risk countries, such as Norway, but increased for male immigrants from lower-risk countries, such as Finland. However, the shift in the risk of CRC towards the host country was less pronounced in women. In addition to their potentially higher vulnerability to environmental risk factors, men have a higher exposure to risk factors such as obesity, alcohol use, smoking, and poor diet, but a lower propensity to use screening diagnostic methods (fecal occult blood tests). In addition, women have a mechanism for the protective effect of endogenous estrogen. 

In terms of racial or ethnic disparity, a study conducted in the 2000s showed the highest rates of morbidity in blacks, and the lowest in people with Asian and Pacific ancestry (43.2 vs. 28.8 cases per 100,000 people per year) and death (18.6 vs. 9.9 cases per 100,000 people per year). Genetic factors play a role in this racial disparity, for example, new nucleotide polymorphisms (SNPs) associated with the risk of CRC have been identified in several studies conducted in the black population, although current understanding of racial differences in the genetic architectonics of CRC is limited due to the predominance of the Caucasian population in genome-wide association searches (GWAS). However, there are no data on racial differences in the frequency of somatic mutations in known genes (APC, KRAS,TP53, BRAF) and microsatellite instability (MSI) – a high-risk CRC, a molecular subtype of CRC caused by a mutation in the MMR genes (mismatch repair genes).  In addition, among individuals with Lynch syndrome, the cumulative risk of CRC was similar between that of the black and European populations. Moreover, the highest rates of CRC among African Americans are in sharp contrast to the lowest rates observed in Africa compared to other continents. Taken together, the evidence suggests that disproportionate exposure to modifiable risk factors and medical care (such as screening and treatment) may most likely lead to racial differences in the incidence rate. 
Subtypes of KRR. 

Although CRC develops in one organ, namely the colon, it is a very heterogeneous disease consisting of subtypes with different etiologies and clinical outcomes. Traditionally, the subtypes of CRC are divided according to the location of the tumor in three segments of the colon and rectum: the proximal colon (caecum, ascending colon, liver bend, and transverse colon), the distal colon (spleen bend, descending colon, and sigmoid colon), and the rectum. Studies have shown that CRC in different anatomical regions has different risk factors (for example, smoking was associated with an increased risk of proximal colon cancer and rectal cancer, but not with distal colon cancer). The etiological heterogeneity of CRC, depending on the localization, may partially vary and depend on the characteristics of the microbiota, as well as the anatomical and physiological characteristics of the colon. From the proximal colon to the rectum, there is a progressive increase in pH, microbial load, and the abundance of short-chain fatty acids (namely, microbial metabolites), which can have various consequences for colorectal carcinogenesis. 

As described earlier, the exposure to the main risk factors of CRC is also heterogeneous by demographic characteristics. Thus, the etiological heterogeneity in the anatomical localities of the CRR inevitably leads to variations in the distribution on a demographic basis. Cancer of the proximal colon is more common in women than in men (34% vs. 25%, respectively), this was demonstrated in a multinational European study and its proportion increases with age (from 35% in the age group under 60 years to 60% in the group after 70 years).  Although cancer of the proximal colon is the most common subtype among whites and blacks (for the proximal, 44% and 49%, respectively; for the distal, 27% and 26%, respectively; for the rectum, 29% and 25%, respectively), rectal cancer accounts for the highest proportion among Asians (for the proximal, 22%; for the distal, 26%; and for the rectum, 52%). 
Notably, the molecular subtypes of CRC are also disproportionately distributed across the colon. The MSI-high and CIMP-high subtypes are more common in the proximal colon, whereas the CIN-positive subtype is predominantly found in the distal colon. Further refinement of this concept was made thanks to the discovery of the Cancer Genome Atlas project, which described in detail genomic changes in 20 types of cancer (hypermethylation, high MSI, high CIMP, and BRAF mutation in the proximal colon was limited to hypermuted CRC-the mutation rate was more than 12 per 106 bases), which was 16%. In contrast to hypermuted CRC, non-hypermuted CRC (the mutation rate was less than 8.24 per 106 bases) is characterized by frequent mutations in known genes (for example, APC and TP53) associated with the CIN-positive subtype. The molecular classification of CRC provides an understanding of the prognosis and response to treatment. Currently, there is evidence in the literature that MSI-high (despite the fact that in this case, low differentiation with mucus formation is more often observed) has a better prognosis than CRR without MSI-high. And in connection with this postulate, tumors with high MSI often do not respond to adjuvant chemotherapy, but at the same time have a good prognosis when treated with targeted drugs. In 2015, the Colorectal Cancer Subtyping Consortium introduced four molecular subtypes based on gene expression profiles. However, later, in 2018, based on a systematic review, scientists came to the conclusion that the prognostic value and applicability of the proposed classification is not optimal enough for routine use in clinical practice. 
Genetic risk factors.

The cumulative risk of developing CRC in people under 75 years of age is 5% in the general population of people in countries with a high incidence (Korea, Norway, Russia). The risk of life-long CRC increases significantly when people have a family history or inherited cancer syndromes. According to the literature, it was proved that the risk of developing CRC increases 2.24 times in the presence of one first–line relative (parents, brothers, sisters or children) with an established diagnosis of CRC (95% CI 2.06–2.43), and 3.97 times in the presence of two relatives (95% CI 2.60-6.06). The dependence increases in the presence of a relative with an established diagnosis of CRC at the age of 50 years. With the exception of rare cancer syndromes, most known hereditary mutations, although genetically predisposing to the development of CRC, have low penetrance. Thus, a significant part of the "cluster" CRC is not inherited, but occurs through acquired genomic aberrations, which indicates the importance of environmental factors in the modulation of the risk of CRC. At any age, people suffering from hereditary cancer syndromes are at a higher risk of CRC than the general population, because they have germ-line mutations in genes with high penetrance, mainly in the autosomal dominant type. 
Notably, people can develop hereditary CRC without a family history of syndromes or CRC. In this situation, the parents probably have mutations only in the germ cells or the mutations occurred shortly after fertilization. The PMS2 mutation in hereditary nonpolypose CRC has a reduced penetrance compared to mutations in other genes. Thus, even if an individual inherited the PMS2 mutation and developed CRC, the family history might not be present if the parents carrying the PMS2 mutation did not develop cancer during their lifetime. Hereditary nonpolypose CRC is the most common hereditary CRC syndrome (1 in 300), which is characterized by the presence of MSI-high and tumors of the proximal colon. High-MSI hereditary nonpolypose CRC is mainly caused by genetic germ-line mutations in any of the mismatch repair genes, including MLH1, MSH2,MSH6, and PMS2. Although the term "non-polypous" is used, people develop one or more polyps that become malignated within 2-3 years, as opposed to 8-10 years in the general population. Hereditary nonpolypose CRC is usually characterized by low differentiation, mucus formation, and pronounced lymphocytic infiltration. The presence of this hereditary syndrome increases the risk of developing CRC to 60%, but its share of all cases of CRC is not more than 2-3%. The second most common form of hereditary CRC syndrome is familial adenomatous polyposis (FAP), which occurs in 1 in 11,000-30,000 people. Caused by hereditary germ-line APC gene mutations (as opposed to acquired somatic mutations), FAP is characterized by the development of hundreds to thousands of adenomas, located mainly in the distal part of the colon, starting from adolescence. The presence of such a number of adenomas guarantees a 100% chance that a person will develop CRC by the age of 40, if a preventive colectomy or colproktectomy has not been performed. However, FAP occurs in less than 1% of CRC cases. 
Previously, the development of the KRR.

In countries such as Canada and the United States, where there is a natural decrease or stabilization of the incidence of CRC, in the last few decades there has been a trend towards an increase in early CRC (i.e., CRC diagnosed before the age of 50), with a predominance of rectal cancer. Although hereditary syndromes, a family history of CRC, and inflammatory bowel disease (IBD) predispose individuals to early development of CRC, most occur sporadically in individuals at medium risk. Among early-onset CRC diagnosed mainly in the white population of our planet, only 13% had germ-line mutations in the genes underlying hereditary CRC syndromes (MLH1, MSH2, MSH6, PMS2, and APC). Compared to CRC, which occurs after 50 years, sporadic CRC with early onset has a more frequent localization in the rectum and is characterized by the presence of histologically unfavorable subtypes, such as low-grade and mucinous adenocarcinomas. Early CRC is more often detected at a later stage, but a large prospective study did not reveal a statistically significant difference in the 5-year cancer-specific survival of the two forms of CRC depending on the stage (99% vs. 98 %, p=0.19 for stage I, 94% vs. 95%, p=0.77 for stage II, 78% vs. 83%, p=0.09 for stage III, 39% vs. 50%, p=0.14 for stage IV). Although the etiology of sporadic early CRC remains unclear, given the long time interval for the completion of carcinogenesis, exposure at an early age (in childhood and adolescence) is likely to be a determinant of the risk of early CRC. Since countries such as Australia, Canada, New Zealand, and the United States are countries with more Western "traditions," newborns in these countries may have been exposed to Western diets and lifestyles in recent decades, which are the dominant risk factors for CRC. This fact may be contributing to the growth of early CRR in these countries, although it should not be overlooked that the main risk factors for late-onset CRR are the same as for early-onset CRR. There is evidence, although scant, that the prevalence of childhood and adolescent obesity correlates with the incidence of CRC. Assessing the two facts that, on the one hand, rectal cancer predominates in the trend of increasing the frequency of early CRC, and on the other hand, obesity is a risk factor for developing colon cancer rather than rectal cancer, we can assume that these discrepancies indicate a multifactorial nature of early CRC. 
Lifestyle and alimentary factors. 

Genetics contribute to individual risk, and the frequency of CRC in the population is largely influenced by modifiable dietary and lifestyle factors, because indicators can vary greatly over short periods of time, low rates of CRC of migrants are quickly compared with those of the host country. Researchers at the World Cancer Foundation (WCRF) and the American Cancer Institute (AICR) concluded that obesity, low physical activity, poor nutrition (high in red meat, low in plant fiber and whole grains, and low in calcium in the diet), and alcohol consumption increase the risk of CRC. About half of the patients with CRC have modifiable risk factors in their lifestyle, in addition to which smoking can be included here. The combination of these factors is probably the driving force behind the increase in the incidence of CRC worldwide. 
Obesity. 

Excessive obesity is an established risk factor for CRC (more for the colon than for the rectum), which is confirmed by epidemiological studies. The two most commonly used indicators of obesity are body mass index (BMI) and waist circumference (OT), and there is evidence that the latter is a stronger prognostic risk factor for CRC. An increase in the OT index by 10 cm increases the risk of developing CRC by approximately 4%. The localization of adipose tissue is divided into two isolated divisions: visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT). Compared to subcutaneous adipose tissue, visceral adipose tissue secretes more pro-inflammatory adipokines (such as TNF) and less adiponectin (an insulin-sensitizing hormone), and is more strongly infiltrated by immune cells such as macrophages. This contributes to the development of low-grade chronic systemic inflammation and insulin resistance. Inflammatory changes in the intestinal wall are known to promote tumor growth and progression, but there is no data yet on whether obesity-related inflammation increases the risk of developing CRC directly or through secondary processes such as insulin resistance. Insulin resistance and subsequent hyperinsulinemia lead to an increase in free insulin-like growth factor (IGF1), suggesting that this pathway contributes to colorectal carcinogenesis by increasing cell proliferation and reducing apoptosis. For all BMI measures, visceral obesity is more common in Asians and in men, possibly due to genetic variations in sex hormones. Most of the available studies (obesity and CRC) have focused on obesity in adulthood, but obesity at a young age may also be significant in the development of CRC in women. Endogenous estrogens "protect" against CRC only in women, and adipocytes become the main site of estrogen after menopause, so as for overweight women in old age, the increasing carcinogenic effect of insulin can be balanced by the anti-cancer effect of estrogens. 
Physical activity and sedentary lifestyle.

Colorectal cancer, and in particular colon cancer, is one of the few cancers for which lack of physical activity is considered a risk factor. There is no clear answer to how much intense and regular physical activity should be for the prevention of CRC. The American Society for Cancer Research recommends that adults engage in at least 150 minutes (3-5. 9 metabolic equivalents of task) per week (moderate intensity) or 75 minutes of intense activity (more than 6 MET). Exercise intensity implies a certain level of energy expenditure through physical activity, rather than specific exercise regimens, so for example, increasing the amount of exercise by 5 METH hours per week reduces the risk of developing CRC by 8%. This can be achieved through the beneficial effects of exercise on intestinal motility, the immune system, inflammation, and metabolic hormones-this is a direct effect, but there can also be an indirect effect due to the loss of visceral adipose tissue (VAT). Among adults who were overweight or obese, 3-4 months of daily walking or jogging resulted in a significant reduction in VAT, even in the absence of overall weight loss. At the same time, according to the meta-analysis, a significant loss of visceral adipose tissue was associated with aerobic exercise, rather than with strength exercises. In a cohort study where participants were divided by aerobic exercise intensity and weight lifting, the greatest risk reduction occurred in the group with the most active exercise of about 30 METH-hours per week. Regardless of the level of physical activity, prolonged sitting or lying down (for example, watching TV) for about 2 hours a day increases the risk of developing CRC by 7% (95% Cl 1.05-1.10). 
 

The effect of diet. 
Since the diets of each population and individual region are diverse and unique, it is often very difficult to assess the impact of a particular product or dish. In this regard, it is necessary to divide diets into two types: healthy food (characterized by a high consumption of fresh vegetables and fruits, as well as cereals, including products based on whole grains, nuts, legumes, fish and other seafood, with a high content of red meat, sweetened beverages, baked goods, desserts, semi-finished products and is conditionally called the "Western diet"). As a rule, this division is relative, so the interaction of healthy and harmful products is very multifaceted and complex. The consumption of red and processed meat increases the risk of developing CRC by 12%, due to the presence of carcinogenic compounds, which can include heme iron, exogenous nitrates, ionized fatty acids, secondary bile acids, as well as heterocyclic amines and polycyclic hydrocarbons formed when cooking meat at high temperatures. The role of diet in the development of CRC is based on the presumed carcinogenic effect of insulin and the presence of inflammatory mediators. Thus, in a large population study, the level of C-peptide and inflammatory markers (C-reactive protein, IL6, and TNF receptor) were studied, and it was concluded that a diet with a high content of red meat and sweetened beverages, there is a high content of C-peptide and pro-inflammatory markers, on the basis of which it is concluded that hyperinsulinemia and inflammation can affect the risk of developing CRC. 

Fiber and whole grains. 
In 1970, D. Burkitt linked the relatively low incidence of CRC in rural Africans to the high consumption of dietary fiber. Dietary fiber, especially insoluble fiber, reduces the effect of carcinogenic substances on the cylindrical epithelium of the colon mucosa by reducing the transit time and increasing the volume of fecal matter in the colon. Another mechanism involves the interaction of dietary fiber with the intestinal microbiota, undigested fiber reaching the colon is easily fermented by the anaerobic intestinal microbiota to short-chain fatty acids (mainly acetate, propionate and butyrate). In vitro, butyrate has been shown to promote the survival of normal colonocytes and the apoptosis of tumor cells by suppressing the proinflammatory pathway. In addition, Fusobacterium nucleatum, found in the tumor tissue in a large titer compared to the adjacent normal tissue, contributes to the immunosuppression of the microenvironment. A diet rich in dietary fiber and whole-grain structures reduces the content of this bacterium. However, not everything is so simple, and if the data of the 2011 meta-analysis show a direct relationship between the amount of fiber consumed (vegetables, fruits, beans) and the risk of developing CRC, then when studying the influence of whole-grain structures, an inverse relationship was obtained. And when it comes to dietary fiber in general, the World Cancer Foundation consensus on its impact on the risk of CRC has changed its statement from "convincing" in 2011 to "probable" in 2017. 

Alcohol. 
Ethanol in alcoholic beverages of any type is already a proven risk factor for the development of CRC, due to its composition of acetaldehyde-a carcinogenic substance. According to a 2018 meta-analysis that included 14 cohort studies from North America, Europe, and Asia, it was shown that even small regular alcohol consumption (<1 drink per day) was associated with a small risk of developing CRC, but significantly more than with casual or no alcohol consumption (RR 1.04, 95% CI 1.01–1.06). This correlation is more common in men due to higher alcohol consumption. Ethanol in the intestinal lumen is metabolized with microbial alcohol dehydrogenase, which leads to mucosal damage and regenerative cell proliferation. The enzyme ADLH2, which is synthesized in the liver, leads to an increase in circulating acetaldehyde, which can reach the colonocytes. There is a subtype of this enzyme ADLH2 * 2, which is widely distributed in East Asia, and is practically absent in other parts of the world. Currently, there is no convincing evidence of the role of ADLH2*2 in the development of CRC. On the contrary, according to one meta-analysis, if carriers have a single ADLH2*2 allele, the risk of developing CRC decreases by approximately 20%. Perhaps due to adverse reactions when drinking alcohol (redness of the face, nausea, headache), this category of people do not abuse alcohol, and this fact probably affects the reduction in the risk of developing CRC. 

Smoking. 
Cigarette smoke contains a mixture of compounds that can easily reach the intestinal mucosa, either directly from food, or the circulatory system, and cause genetic and epigenetic aberrations. The risk of developing CRC in a smoker increases in direct proportion to the length of smoking experience, and decreases after quitting smoking, by about 4% for every 10 years. Smoking has different effects on the occurrence of cancer in different locations of the colon, for example, according to a 2018 cohort study, conclusions were made about a significant increase in the risk of developing cancer of the proximal colon (RR 1.19, 95% CI 1.05–1.34) and rectal cancer (RR 1.27, 95% CI 1.14–1.42). Cancer of the proximal colon is usually characterized by MSI-high, CIMP-positive. and a mutant type of BRAF. And interestingly, smoking increases the risk of developing CRC of these types of cancer twice and does not affect the risk of developing CIMP-negative. and wild-type BRAF KRR. Mutations in the BRAF and CIMP-negative genes are key molecular changes that determine the path of development of dentate adenomas, and smoking is associated with the risk of developing dentate polyps, rather than classical adenomas. I would like to add that when studying genomes, there are changes in the structure of DNA methylation of smokers and those who have never smoked, and it is noteworthy that there is evidence that when quitting smoking, aberrant methylation can be restored to normal. On the other hand, there is evidence of a long-term damaging effect of polycyclic aromatic hydrocarbons on the structure of DNA, and a possibly irreversible effect even after quitting smoking. 

Other risk factors. 
In addition to the existing proven risk factors for CRC, there are additional factors (promising but not proven) that may explain some features of the epidemiology of CRC. The high risk of CRC and the susceptibility to visceral obesity in men compared to women are not yet explained. The obvious answer to this question may be the influence of sex hormones, because it is known that high levels of endogenous estrogens "protect" against cancer in women, and high levels of endogenous testosterone can reduce the risk of CRC in men. Interestingly, an increase in obesity with aging has a differentiated effect on these hormones – adipocytes become the main site of estrogen production after menopause, and testosterone levels decrease with obesity in men. Thus, the association between obesity and the risk of CRC in women may be partially leveled in postmenopausal women with an increase in endogenous estrogen, and on the contrary, it may increase in men due to a decrease in the level of endogenous testosterone with the development of obesity. 

Another unresolved issue is the disproportionate distribution of the molecular subtypes of CRC across the anatomical locations of the colon, the probable cause of this is the microbiota, which also varies depending on the part of the colon. The samples of tumor tissue of different localization were compared, and different bacterial composition was obtained (for example, in the proximal parts a large amount of Cl. difficille, in the distal parts mainly bacteroids). A similar relationship is observed in the tissue samples of patients with polyps. The colon microbiota influences carcinogenesis through inflammation. In a study that compared the bacterial composition of mucosal samples in patients with adenomas, adenocarcinomas, and with a control group who were not diagnosed with neoplasms in the colon, as well as the level of CRP in plasma, it was shown that in the healthy-polyp-cancer sequence, the number of microorganisms, in particular F. nucleatum, increases and the level of CRP increases, and on the contrary, the number of Eubacterium eligens decreases. Currently, studies are being conducted on the role of fungi (Malasseziomycetes) and viruses (Orthobunyavirus), and there is already data on their possible impact on the risk of developing CRC, but it is too early to draw definite conclusions. 
Chemoprophylaxis of CRC.

Aspirin. Aspirin is a non-steroidal anti-inflammatory drug that has been studied for a long time as a preventive measure of CRC. According to the meta-analysis, daily use of aspirin significantly reduces the risk of CRC and mortality. Another population-based study concluded that women taking low-dose aspirin for 10 years had no effect on fluctuations in the frequency of CRC, but even after 8 years of taking aspirin, there was a decrease in the incidence of CRC (RR 0.58, 95% CI 0.42-0.80). The delayed effect of aspirin most likely implies its effective action in the early stages of carcinogenesis, and in particular, aspirin is more effective in preventing adenoma with 3-4 years of taking the drug. Currently, there is no convincing data on the optimal dose and time of taking aspirin. In a cohort study with a 32-year follow-up period, the minimum weekly dose of aspirin consumption (325 mg/week) was calculated for 6 years to obtain the desired effect. Aspirin has an anti-cancer effect partly through the inhibition of COX2, which stimulates inflammation and promotes the activation of T-cell immunity. 
Calcium. The inverse effect between calcium intake and CRC risk. Adding calcium to the diet at a dose of 300 mg per day was found to significantly reduce the risk of CRC (RR 0.92, 95% CI 0.89–0.95), but this study was not a randomized controlled trial (RCT). In observational studies, it has been shown that calcium intake, both with food and in the form of supplements, in the range (250-1900 mg per day), and this dosage is higher than the recommended daily dose for adults (1000-1200 mg per day), can be useful in preventing CRC. A large prospective study involving 47,740 men and 88,509 women found that it takes about 10 years of calcium intake to assess the effect on the risk of CRC. In another observational study, high-dose calcium intake was associated with a reduced risk of colorectal adenomas, a likely precursor to sporadic forms of cancer. It is believed that calcium prevents the progression of polyps (preadenomas) into adenomas, because the time required for the transformation of an adenoma into cancer can reach about 10 years. Therefore, studies whose end point is the occurrence of CRC with a 5-year period or less are insufficient to determine the effect of calcium. In contrast, studies that end with the occurrence of adenoma, such as a recent meta-analysis, demonstrated that daily calcium intake (1200-2000 mg) reduces the risk of developing adenoma by 12% over 3-5 years. On the basis of experimental studies, data were obtained that calcium precipitates secondary bile acids, ionized bile acids and heme iron into the lumen of the rectum, reducing their carcinogenic effect on the mucosa. 

Screening-secondary prevention.
Screening can reduce the incidence and mortality of CRC by early detection of CRC. There are several screening methods, one of them, this is known all over the world –fecal hemocult test (FOBT-fecal occult blood test, guaiac test), can detect a small amount of blood in a fecal sample, which indicates the presence of precancerous neoplasms and colon cancer. A variation of the FOBT is the immunochemical FOBT (known as the fecal immunochemical FIT test), which is more preferable than the older guaiac test. It does not require any dietary restrictions before use and has a higher sensitivity in detecting CRC (20 out of 34 per 100,000 population). A recent screening method is the multi-target fecal DNA test (FIT-DNA), which detects both latent bleeding (by immunoassay for hemoglobin) and molecular aberrations (by molecular analysis for biomarkers such as KRAS mutations. In a study in asymptomatic individuals with an average risk of CRC, FIT-DNA had a higher sensitivity in detecting common precancerous lesions (42.4% vs. 23.8%, p However, it has a lower specificity compared to the immunochemical method (86.6% vs. 94.9%, p In practical terms, the genetic method is more labor-intensive to use and has a higher cost, and therefore has a limited prevalence. 

Colonoscopy is the gold standard of screening, has almost 100% sensitivity, but at the same time it is quite expensive to perform it for everyone without exception. According to observational studies, the benefits of colonoscopy are obvious, but despite this, no RCTs have yet been performed in the world. Intestinal perforation and intestinal bleeding nab

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