colorectal cancer colorectal cancer colorectal cancer (crc), also known as bowel cancer, colon cancer, or rectal cancer, is the development of cancer from the colon or rectum (parts of the large intestine). signs and symptoms may include blood in the stool, a change in bowel movements, weight loss, and fatigue. most colorectal cancers are due to old age and lifestyle factors, with only a small number of cases due to underlying genetic disorders. risk factors include diet, obesity, smoking, and lack of physical activity. dietary factors that increase the risk include red meat, processed meat, and alcohol. another risk factor is inflammatory bowel disease, which includes crohn's disease and ulcerative colitis. some of the inherited genetic disorders that can cause colorectal cancer include familial adenomatous polyposis and hereditary non-polyposis colon cancer; however, these represent less than 5% of cases. it typically starts as a benign tumor, often in the form of a polyp, which over time becomes cancerous. for cancer of the anus, see anal cancer. for cancer of the small intestine, see small intestine cancer. colorectal cancerother namescolon cancer, rectal cancer, bowel cancerlocation and appearance of two example colorectal tumorsspecialtygastroenterology general surgery oncologysymptomsblood in stool, change in bowel movements, unintentional weight loss, vomiting, fatiguecausesold age, lifestyle factors and genetic disordersrisk factorsdiet, obesity, smoking, lack of physical activity, alcohol usediagnostic methodtissue biopsy during a sigmoidoscopy or colonoscopypreventionscreening from age of 45 to 75treatmentsurgery, radiation therapy, chemotherapy, targeted therapyprognosisfive-year survival rate 65% (us)frequency9.4 million (2015)deaths551,000 (2018) colorectal cancer may be diagnosed by obtaining a sample of the colon during a sigmoidoscopy or colonoscopy. this is then followed by medical imaging to determine whether the disease has spread. screening is effective for preventing and decreasing deaths from colorectal cancer. screening, by one of a number of methods, is recommended starting from the age of 45 to 75. it was recommended starting at age 50 but it was changed to 45 due to increasing amount of colon cancers. during colonoscopy, small polyps may be removed if found. if a large polyp or tumor is found, a biopsy may be performed to check if it is cancerous. aspirin and other non-steroidal anti-inflammatory drugs decrease the risk of pain during polyp excision. their general use is not recommended for this purpose, however, due to side effects. treatments used for colorectal cancer may include some combination of surgery, radiation therapy, chemotherapy, and targeted therapy. cancers that are confined within the wall of the colon may be curable with surgery, while cancer that has spread widely is usually not curable, with management being directed towards improving quality of life and symptoms. the five-year survival rate in the united states was around 65% in 2014. the individual likelihood of survival depends on how advanced the cancer is, whether or not all the cancer can be removed with surgery, and the person's overall health. globally, colorectal cancer is the third most common type of cancer, making up about 10% of all cases. in 2018, there were 1.09 million new cases and 551,000 deaths from the disease. it is more common in developed countries, where more than 65% of cases are found. it is less common in women than men. signs and symptoms 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, 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. cause 75–95% of colorectal cancer cases occur in people with little or no genetic risk. risk factors include older age, male sex, high intake of fat, sugar, alcohol, red meat, processed meats, obesity, smoking, and a lack of physical exercise. approximately 10% of cases are linked to insufficient activity. the risk from alcohol appears to increase at greater than one drink per day. drinking five glasses of water a day is linked to a decrease in the risk of colorectal cancer and adenomatous polyps. 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. it has been suggested that the presence of antibodies to streptococcus bovis/gallolyticus antigens or the antigens themselves in the bloodstream may act as markers for the carcinogenesis in the colon. pathogenic escherichia coli may increase the risk of colorectal cancer by producing the genotoxic metabolite, colibactin. 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. people with inflammatory bowel disease account for less than 2% of colon cancer cases yearly. in those with crohn's disease, 2% get colorectal cancer after 10 years, 8% after 20 years, and 18% after 30 years. in people who have ulcerative colitis, approximately 16% develop either a cancer precursor or cancer of the colon over 30 years. genetics those with a family history in two or more first-degree relatives (such as a parent or sibling) have a two to threefold greater risk of disease, and this group accounts for about 20% of all cases. a number of genetic syndromes are also associated with higher rates of colorectal cancer. the most common of these is hereditary nonpolyposis colorectal cancer (hnpcc, or lynch syndrome) which is present in about 3% of people with colorectal cancer. other syndromes that are strongly associated with colorectal cancer include gardner syndrome and familial adenomatous polyposis (fap). 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, 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 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 potential for 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. 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. the apc protein prevents the accumulation of β-catenin protein. without apc, β-catenin accumulates to high levels and translocates (moves) into the nucleus, binds to dna, and activates the transcription of proto-oncogenes. these genes are normally important for stem cell renewal and differentiation, but when inappropriately expressed at high levels, they can cause cancer. while apc is mutated in most colon cancers, some cancers have increased β-catenin because of mutations in β-catenin (ctnnb1) that block its own breakdown, or have mutations in other genes with function similar to apc such as axin1, axin2, tcf7l2, or nkd1. 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 their programmed death if they have wnt pathway defects. 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. other proteins responsible for programmed cell death that are commonly deactivated in colorectal cancers are tgf-β and dcc (deleted in colorectal cancer). tgf-β has a deactivating mutation in at least half of colorectal cancers. sometimes tgf-β is not deactivated, but a downstream protein named smad is deactivated. dcc commonly has a deleted segment of a chromosome in colorectal cancer. approximately 70% of all human genes are expressed in colorectal cancer, with just over 1% of having increased expression in colorectal cancer compared to other forms of cancer. some genes are oncogenes: they are overexpressed in colorectal cancer. for example, genes encoding the proteins kras, raf, and pi3k, which normally stimulate the cell to divide in response to growth factors, can acquire mutations that result in over-activation of cell proliferation. the chronological order of mutations is sometimes important. if a previous apc mutation occurred, a primary kras mutation often progresses to cancer rather than a self-limiting hyperplastic or borderline lesion. pten, a tumor suppressor, normally inhibits pi3k, but can sometimes become mutated and deactivated. comprehensive, genome-scale analysis has revealed that colorectal carcinomas can be categorized into hypermutated and non-hypermutated tumor types. 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 activity of myc, a central player in colorectal cancer. mismatch repair (mmr) deficient tumours are characterized by a relatively high amount of poly-nucleotide tandem repeats. 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). consequently, a deficiency in mmr proteins may lead to an inability to detect and repair genetic damage, allowing for further cancer-causing mutations to occur and colorectal cancer to progress. the polyp to cancer progression sequence is the classical model of colorectal cancer pathogenesis. the polyp to cancer sequence describes the phases of transition from benign tumours into colorectal cancer over many years. central to the polyp to crc sequence are gene mutations, epigenetic alterations, and local inflammatory changes. the polyp to crc sequence can be used as an underlying framework to illustrate how specific molecular changes lead to various cancer subtypes. field defects longitudinally opened freshly resected colon segment showing a cancer and four polyps. plus a schematic diagram indicating a likely field defect (a region of tissue that precedes and predisposes to the development of