Colorectal cancer

The signs and symptoms of colorectal cancer depend on the location of the tumor in the bowel, and whether it has spread elsewhere in the body (metastasis). The classic warning signs include worsening constipation, blood in the stool, a decrease in stool caliber (thickness), loss of appetite, loss of weight, and nausea or vomiting in someone over 50 years old. Around 50% of people who have colorectal cancer do not report any symptoms. Rectal bleeding or anemia are high-risk symptoms in people over the age of 50. Weight loss and changes in a person's bowel habit are typically only concerning if they are associated with rectal bleeding. Gastroenterologist Dr. Trisha Pasricha advises that understanding personal "normal" bowel habits and watching for unchanging, sausage-like stool consistency is crucial for early detection. ==Cause==

75–95% of colorectal cancer cases occur in people with little or no genetic risk. Risk factors include older age, male sex, Approximately 10% of cases are linked to insufficient physical activity. Diet Diet is the largest environmental risk factor. Whole grain intake is inversely related to risk. The consumption of calcium (e.g. dairy products) is protective against colorectal cancer. Associated with a diet high in saturated fats, elevated levels of bile acids appear to increase the risk of colorectal cancer. The bile acid deoxycholic acid particularly is elevated in the colonic contents of humans in response to a high fat diet. Bacteria Streptococcus gallolyticus is associated with colorectal cancer. Some strains of Streptococcus bovis/Streptococcus equinus complex are consumed by millions of people daily and thus may be safe. 25 to 80% of people with Streptococcus bovis/gallolyticus bacteremia have concomitant colorectal tumors. Seroprevalence of Streptococcus bovis/gallolyticus is considered as a candidate practical marker for the early prediction of an underlying bowel lesion at high-risk population. Inflammatory bowel disease People with inflammatory bowel disease (ulcerative colitis and Crohn's disease) are at increased risk of colon cancer. The risk increases the longer a person has the disease, and the worse the severity of inflammation. In these high risk groups, both prevention with aspirin and regular colonoscopies are recommended. Endoscopic surveillance in this high-risk population may reduce the development of colorectal cancer through early diagnosis and may also reduce the chances of dying from colon cancer. For people with these syndromes, cancer almost always occurs and makes up 1% of the cancer cases. A total proctocolectomy may be recommended for people with FAP as a preventive measure due to the high risk of malignancy. Colectomy, the removal of the colon, may not suffice as a preventive measure because of the high risk of rectal cancer if the rectum remains. The most common polyposis syndrome affecting the colon is serrated polyposis syndrome, which is associated with a 25–40% risk of colorectal cancer (CRC). Mutations in the pair of genes POLE and POLD1 have been associated with familial colon cancer. Most deaths due to colon cancer are associated with metastatic disease. A gene that appears to contribute to the risk of metastatic disease, metastasis-associated in colon cancer 1 (MACC1), has been isolated. It is a transcriptional factor that influences the expression of hepatocyte growth factor. This gene is associated with the proliferation, invasion, and scattering of colon cancer cells in cell culture, and tumor growth and metastasis in mice. MACC1 may be a potential target for cancer intervention, but this possibility needs to be confirmed with clinical studies. Epigenetic factors, such as abnormal DNA methylation of tumor suppressor promoters, play a role in the development of colorectal cancer. The Rectal Cancer Survival Calculator developed by the MD Anderson Cancer Center also considers race a risk factor; however, there are equity issues concerning whether this might lead to inequity in clinical decision making. Ashkenazi Jews have a 6% higher risk rate of getting adenomas and then colon cancer due to mutations in the APC gene being more common. ==Pathogenesis==

Colorectal cancer is a disease originating from the epithelial cells lining the colon or rectum of the gastrointestinal tract, most frequently as a result of genetic mutations in the Wnt signaling pathway that increases signaling activity. The Wnt signaling pathway normally plays an important role for normal function of these cells including maintaining this lining. Mutations can be inherited or acquired, and most probably occur in the intestinal crypt stem cell. The most commonly mutated gene in all colorectal cancer is the APC gene, which produces the APC protein. Beyond the defects in the Wnt signaling pathway, other mutations must occur for the cell to become cancerous. The p53 protein, produced by the TP53 gene, normally monitors cell division and induces programmed death if Wnt pathway defects are present. Eventually, a cell line acquires a mutation in the TP53 gene and transforms the tissue from a benign epithelial tumor into an invasive epithelial cell cancer. Sometimes the gene encoding p53 is not mutated, but another protective protein named BAX is mutated instead. Approximately 70% of all human genes are expressed in colorectal cancer, with just over 1% having increased expression in colorectal cancer compared to other forms of cancer. PTEN, a tumor suppressor, normally inhibits PI3K, but can sometimes become mutated and deactivated. In addition to the oncogenic and inactivating mutations described for the genes above, non-hypermutated samples also contain mutated CTNNB1, FAM123B, SOX9, ATM, and ARID1A. Progressing through a distinct set of genetic events, hypermutated tumors display mutated forms of ACVR2A, TGFBR2, MSH3, MSH6, SLC9A9, TCF7L2, and BRAF. The common theme among these genes, across both tumor types, is their involvement in Wnt and TGF-β signaling pathways, which results in increased MYC activity, a central player in colorectal cancer. This is caused by a deficiency in MMR proteins – which are typically caused by epigenetic silencing and/or inherited mutations (e.g., Lynch syndrome). 15 to 18 percent of colorectal cancer tumours have MMR deficiencies, with 3 percent developing due to Lynch syndrome. The role of the mismatch repair system is to protect the integrity of the genetic material within cells (i.e., error detecting and correcting). In this adenoma-carcinoma sequence, normal epithelial cells progress to dysplastic cells such as adenomas, and then to carcinoma, by a process of progressive genetic mutation. Central to the polyp to CRC sequence are gene mutations, epigenetic alterations, and local inflammatory changes. Since then, the terms "field cancerization", "field carcinogenesis", "field defect", and "field effect" have been used to describe pre-malignant or pre-neoplastic tissue in which new cancers are likely to arise. Field defects are important in the progression of colon cancer. However, as pointed out by Rubin, "The vast majority of studies in cancer research has been done on well-defined tumors in vivo, or on discrete neoplastic foci in vitro. Yet there is evidence that more than 80% of the somatic mutations found in mutator phenotype human colorectal tumors occur before the onset of terminal clonal expansion." Similarly, Vogelstein et al. An expanded view of field effect has been termed "etiologic field effect", which encompasses not only molecular and pathologic changes in pre-neoplastic cells but also the influence of exogenous environmental factors and molecular changes in the local microenvironment on neoplastic evolution from tumor initiation to death. Epigenetics As described by Vogelstein et al., an average cancer of the colon has only 1 or 2 oncogene mutations and 1 to 5 tumor suppressor mutations (together designated "driver mutations"), with about 60 further "passenger" mutations. The oncogenes and tumor suppressor genes are well-studied and described above under Pathogenesis. Epigenetic alterations are much more frequent in colon cancer than genetic (mutational) alterations. Epigenetic alterations, distinct from mutations, change how genes express proteins without changing the DNA sequence. One frequent type of epigenetic alteration in colorectal cancers is changed expression levels of particular microRNAs. microRNAs (miRNAs) are small RNAs that bind the 3′ untranslated regions of their target messenger RNAs and cause suppression of protein translation. Down-regulation and up-regulation of microRNAs are epigenetic alterations since their altered regulation of messenger RNAs does not directly involve changing the DNA sequence. MicroRNAs are important epigenetic factors in colorectal cancer, with 164 microRNAs significantly altered in colorectal cancers. miRNAs have an average of 300 target genes per miRNA. About 60% of human protein-coding genes appear to be under the epigenetic control of miRNAs. As an example, miRNA-143 is downregulated in 88% of colorectal colon cancers and down-regulation of miRNA-143 causes up-regulation of protein expression of its target oncogene KRAS as well as its target DNA methylating protein DNMT3A As an example, 147 hypermethylations and 27 hypomethylations of protein-coding genes were frequently associated with colorectal cancers. Of the hypermethylated genes, 10 were hypermethylated in 100% of colon cancers, and many others were hypermethylated in more than 50% of colon cancers. In addition, 11 hypermethylations and 96 hypomethylations of miRNAs were also associated with colorectal cancers. The source and trigger of this age-related methylation is unknown. Approximately half of the genes that show age-related methylation changes are the same genes that have been identified to be involved in the development of colorectal cancer. Genomics and epigenomics Consensus Molecular Subtypes (CMS) classification of colorectal cancer was first introduced in 2015. CMS classification is considered the most robust classification system available for CRC. It has a clear biological interpretability and basis for future clinical stratification and subtype-based targeted interventions. A novel Epigenome-based Classification (EpiC) of colorectal cancer was proposed in 2021, introducing 4 enhancer subtypes in people with CRC. Chromatin states using 6 histone marks are characterized to identify EpiC subtypes. A combinatorial therapeutic approach based on the previously introduced consensus molecular subtypes (CMSs) and EpiCs could significantly enhance current treatment strategies. Microbiome and infectious agents Several studies show that tumors are consistently associated with reduced microbial diversity and the enrichment of specific taxa that promote inflammation and immune modulation. Fusobacterium species are enriched in colorectal cancer tissue compared with adjacent normal mucosa, suggesting a selective tumor microenvironment for these bacteria. Recent experimental work has shown that membrane vesicles derived from selected Clostridioides difficile strains can induce epithelial–mesenchymal transition in colonic epithelial cells, providing mechanistic insights into how this pathogen may contribute to colorectal carcinogenesis. Other pathogens have also been linked to colorectal carcinogenesis. Studies report enrichment of Clostridia and other pro-inflammatory taxa in tumor tissue, accompanied by production of metabolites with mutagenic potential and changes in host gene expression. Other studies similarly suggest that patients with a higher "dysbiosis index," characterized by expansion of pathogenic taxa such as Escherichia coli and Fusobacterium nucleatum and depletion of beneficial genera like Bifidobacterium and Lactobacillus, may carry an increased risk of developing colorectal cancer. Collectively, these findings support the view that disturbances in the gut microbiome can influence colorectal carcinogenesis through multiple mechanisms. ==Diagnosis==

Colorectal cancer diagnosis is performed by sampling areas of the colon suspicious for possible tumor development, typically during colonoscopy or sigmoidoscopy, depending on the lesion's location. The presence of metastases is determined by a CT scan of the chest, abdomen, and pelvis. Patients selected for non-surgical treatment of rectal cancer should have periodic MRI scans, receive physical examinations, and undergo endoscopy procedures to detect any tumor re-growth, which can occur in a minority of these patients. When local recurrence occurs, periodic follow-up can detect it when it is still small and curable with salvage surgery. In addition, MRI tumor regression grades (mrTRG vs. pTRG = pathological tumor regression grade) can be assigned after chemoradiotherapy, which correlate with patients' long-term survival outcomes. Histopathology s. The histopathologic characteristics of the tumor are reported from the analysis of tissue taken from a biopsy or surgery. A pathology report describes the microscopic characteristics of the tumor tissue, including tumor cells and how the tumor invades into healthy tissues, and finally, whether the tumor appears to be completely removed. The most common form of colon cancer is adenocarcinoma, constituting between 95% and 98% of all cases of colorectal cancer. Other, rarer types include lymphoma, adenosquamous, and squamous cell carcinoma. Some subtypes are more aggressive. Immunohistochemistry may be used in uncertain cases. Staging Staging of the cancer is based on both radiological and pathological findings. As with most other forms of cancer, tumor staging is based on the TNM system, which considers how much the initial tumor has spread and the presence of metastases in lymph nodes and more distant organs. ==Prevention==

It has been estimated that about half of colorectal cancer cases are due to lifestyle factors, and about a quarter of all cases are preventable. Increasing surveillance, engaging in physical activity, consuming a diet high in fiber, quitting smoking, and limiting alcohol consumption decrease the risk. Lifestyle Lifestyle risk factors with strong evidence include lack of exercise, cigarette smoking, alcohol, and obesity. The risk of colon cancer can be reduced by maintaining a normal body weight through a combination of sufficient exercise and eating a healthy diet. Current research consistently links eating more red meat and processed meat to a higher risk of the disease. Starting in the 1970s, dietary recommendations to prevent colorectal cancer often included increasing the consumption of whole grains, fruits and vegetables, and reducing the intake of red meat and processed meats. This was based on animal studies and retrospective observational studies. However, large-scale prospective studies have failed to demonstrate a significant protective effect, and due to the multiple causes of cancer and the complexity of studying correlations between diet and health, it is uncertain whether any specific dietary interventions will have significant protective effects. Consuming alcoholic drinks and consuming processed meat both increase the risk of colorectal cancer. The 2014 World Health Organization cancer report noted that dietary fiber has been hypothesized to help prevent colorectal cancer, but that most studies at the time had not yet studied the correlation. A 2019 review, however, found evidence of benefit from dietary fiber and whole grains. The World Cancer Research Fund listed the benefit of fiber for prevention of colorectal cancer as "probable" as of 2017. A 2022 umbrella review says there is "convincing evidence" for that association. Higher physical activity is recommended. Physical exercise is associated with a modest reduction in colon but not rectal cancer risk. High levels of physical activity reduce the risk of colon cancer by about 21%. Sitting regularly for prolonged periods is associated with higher mortality from colon cancer. Regular exercise does not negate the risk but does lower it. Medication and supplements Aspirin and celecoxib appear to decrease the risk of colorectal cancer in those at high risk. Aspirin is recommended in those who are 50 to 60 years old, do not have an increased risk of bleeding, and are at risk for cardiovascular disease to prevent colorectal cancer. It is not recommended in those at average risk. Adequate Vitamin D intake and blood levels are associated with a lower risk of colon cancer. Screening As more than 80% of colorectal cancers arise from adenomatous polyps, screening for this cancer is effective for both early detection and prevention. Diagnosis of cases of colorectal cancer through screening tends to occur 2–3 years before diagnosis of cases with symptoms. Flexible sigmoidoscopy, however, has the best evidence for decreasing the risk of death from any cause. Fecal occult blood (FOB) testing of the stool is typically recommended every two years and can be either guaiac-based or immunochemical. Immunochemical tests are accurate and do not require dietary or medication changes before testing. However, research in the UK has found that for these immunochemical tests, the threshold for further investigation is set at a point that may miss more than half of colorectal cancer cases. The research suggests that the NHS England's Bowel Cancer Screening Programme could make better use of the test's ability to provide the exact concentration of blood in feces (rather than only whether it is above or below a cutoff level). Other options include virtual colonoscopy and stool DNA screening testing (FIT-DNA). Virtual colonoscopy via a CT scan appears as good as standard colonoscopy for detecting cancers and large adenomas. However, it is expensive, associated with radiation exposure, and cannot remove any detected abnormal growths as a standard colonoscopy. The American Cancer Society recommends starting at the age of 45. For those between 76 and 85 years old, the decision to screen should be individualized. Several screening methods are recommended including stool-based tests every 2 years, sigmoidoscopy every 10 years with fecal immunochemical testing every two years, and colonoscopy every 10 years. For people with average risk who have had a high-quality colonoscopy with normal results, the American Gastroenterological Association does not recommend any type of screening in the 10 years following the colonoscopy. For people over 75 or those with a life expectancy of less than 10 years, screening is not recommended. It takes about 10 years after screening for one out of a 1000 people to benefit. The USPSTF list seven potential strategies for screening, with the most important thing being that at least one of these strategies is appropriately used. Some countries have national colorectal screening programs that offer FOBT screening for all adults within a certain age group, typically starting between ages 50 and 60. Examples of countries with organised screening include the United Kingdom, Australia, the Netherlands, Hong Kong, and Taiwan. The UK Bowel Cancer Screening Programme aims to find warning signs in people aged 50 to 74 by recommending a fecal immunochemical test (FIT) every two years. FIT measures blood in feces, and people with levels above a certain threshold may have bowel tissue examined for signs of cancer. Growths having cancerous potential are removed. ==Treatment==

The treatment of colorectal cancer can be aimed at cure or palliation. The decision on which aim to adopt depends on various factors, including the person's health and preferences, as well as the tumor stage. Assessment in multidisciplinary teams is a critical part of determining whether the patient is suitable for surgery or not. When colorectal cancer is caught early, surgery can be curative.1 centimeter, or high-grade dysplasia is found, it can be repeated after 3 years, then every 5 years. For other abnormalities, the colonoscopy can be repeated after 1 year. A phase 3 randomized trial of patients who had completed adjuvant chemotherapy for stage II–III colon cancer found that a structured 3-year exercise program improved disease-free survival and was associated with lower all-cause mortality at a median 7.9-year follow-up. ==Prognosis==

Fewer than 600 genes are linked to outcomes in colorectal cancer. These include both unfavorable genes, where high expression is related to poor outcome, for example the heat shock 70 kDa protein 1 (HSPA1A), and favorable genes where high expression is associated with better survival, for example the putative RNA-binding protein 3 (RBM3). The average five-year recurrence rate in people with rectal cancer where surgery is successful is 9% for stage 0 (after pre-treatment) cancers, 8% for stage I cancers, 18% in stage II, and 34% in stage III. Depending on the number of risk factors (0–2) the risk for distant metastasis in rectal cancer ranges from 4–11% in stage 0, 6–12% in stage I, 11–28% in stage II, and 15–43% in stage III. The recurrence rates have decreased over the past decades as a result of improvements in the colorectal cancer management. The risk of recurrence after five years of surveillance remain very low. Survival rates In Europe, the five-year survival rate for colorectal cancer is less than 60%.