A SYSTEMATIC REVIEW OF COLORECTAL CANCER
Colorectal cancer (CRC) is a common and lethal disease. The risk of developing CRC is influenced by both environmental and genetic factors. Colorectal cancer (also known as colon cancer, rectal cancer, or bowel cancer) is the development of cancer in the colon or rectum (parts of the large intestine). It is due to the abnormal growth of cells that have the ability to invade or spread to other parts of the body. Signs and symptoms may include blood in the stool, a change in bowel movements, weight loss, and feeling tired all the time.
Risk factors for colorectal cancer include lifestyle, older age, and inherited genetic disorders. Other risk factors include diet, smoking, alcohol, lack of physical activity, family history of colon cancer and colon polyps, presence of colon polyps, race, exposure to radiation, and even other diseases such as diabetes and obesity. Genetic disorders only occur in a small fraction of the population. A diet high in red, processed meat, while low in fiber increases the risk of colorectal cancer. Other diseases such as inflammatory bowel disease, which includes Crohn’s disease and ulcerative colitis, can increase the risk of colorectal cancer. 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.
Bowel 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 if the disease has spread. Screening is effective for preventing and decreasing deaths from colorectal cancer. Screening is recommended starting from the age of 50 to 75. 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. Their general use is not recommended for this purpose, however, due to side effects.
REVIEW OF COLORECTAL CANCER
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 mutations in the Wnt signaling pathway that increase signaling activity. The 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 kills cells if they have Wnt pathway defects. Eventually, a cell line acquires a mutation in the TP53 gene and transforms the tissue from an 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.
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
Diagnosis of colorectal cancer is via sampling of areas of the colon suspicious for possible tumor development typically done during colonoscopy or sigmoidoscopy, depending on the location of the lesion. The extent of the disease is then usually determined by a CT scan of the chest, abdomen and pelvis. There are other potential imaging test such as PET and MRI which may be used in certain cases. Colon cancer staging is done next and based on the TNM system which is determined by how much the initial tumor has spread, if and where lymph nodes are involved, and the extent of metastatic disease.
The microscopic cellular characteristics of the tumor are usually reported from the analysis of tissue taken from a biopsy or surgery. A pathology report will usually contain a description of cell type and grade. The most common colon cancer cell type is adenocarcinoma which accounts for 98% of cases. Other, rarer types include lymphoma and squamous cell carcinoma.
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 are usually not curable, with management focusing on improving quality of life and symptoms. Five year survival rates in the United States are around 65%. This, however, 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 2012 there were 1.4 million new cases and 694,000 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
Location and appearance of two example colorectal tumors
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. While rectal bleeding or anemia are high-risk features in those over the age of 50, other commonly-described symptoms including weight loss and change in bowel habit are typically only concerning if associated with bleeding.
Greater than 75–95% of colon cancer occurs in people with little or no genetic risk. Other risk factors include older age, male gender, high intake of fat, alcohol or red meat, obesity, smoking, and a lack of physical exercise. Approximately 10% of cases are linked to insufficient activity. The risk for alcohol appears to increase at greater than one drink per day. Drinking 5 glasses of water a day is linked to a decrease in the risk of colorectal cancer and adenomatous polyps.
CRC incidence and mortality rates vary markedly around the world. Globally, CRC is the third most commonly diagnosed cancer in males and the second in females, with 1.4 million new cases and almost 694,000 deaths estimated to have occurred in 2012. Rates are substantially higher in males than in females. Global, country-specific incidence and mortality rates are available in the World Health Organization GLOBOCAN database.
In the United States, both the incidence and mortality have been slowly but steadily decreasing. Annually, approximately 132,700 new cases of large bowel cancer are diagnosed, of which 93,090 are colon and the remainder rectal cancers. Annually, approximately 49,700 Americans die of CRC, accounting for approximately 8 percent of all cancer deaths.
Incidence — Globally, the incidence of CRC varies over 10-fold. The highest incidence rates are in Australia and New Zealand, Europe, and North America, and the lowest rates are found in Africa and South-Central Asia (CRC incidence by world area). These geographic differences appear to be attributable to differences in dietary and environmental exposures that are imposed upon a background of genetically determined susceptibility.
Low socioeconomic status (SES) is also associated with an increased risk for the development of colorectal cancer; one study estimated the CRC risk to be about 30 percent increased in the lowest as compared with the highest SES quintile. Potentially modifiable behaviors such as physical inactivity, unhealthy diet, smoking, and obesity are thought to account for a substantial proportion (estimates of one-third to one-half) of the socioeconomic disparity in risk of new onset colorectal cancer. Other factors, particularly lower rates of CRC screening, also contribute substantively to SES differences in CRC risk.
Globally more than 1 million people get colorectal cancer every year resulting in about 715,000 deaths as of 2010 up from 490,000 in 1990. As of 2012, it is the second most common cause of cancer in women (9.2% of diagnoses) and the third most common in men (10.0%) with it being the fourth most common cause of cancer death after lung, stomach, and liver cancer. It is more common in developed than developing countries. Globally incidences vary 10-fold with highest rates in Australia, New Zealand, Europe and the US and lowest rates in Africa and South-Central Asia.
Worldwide, colorectal cancer represents 9.4% of all incident cancer in men and 10.1% in women. Colorectal cancer, however, is not uniformly common throughout the world.3 There is a large geographic difference in the global distribution of colorectal cancer. Colorectal cancer is mainly a disease of developed countries with a Western culture.3 In fact, the developed world accounts for over 63% of all cases. The incidence rate varies up to 10-fold between countries with the highest rates and those with the lowest rates. It ranges from more than 40 per 100,000 people in the United States, Australia, New Zealand, and Western Europe to less than 5 per 100,000 in Africa and some parts of Asia. However, these incidence rates may be susceptible to ascertainment bias; there may be a high degree of underreporting in developing countries.
Colorectal cancer is a major cause of morbidity and mortality throughout the world. It accounts for over 9% of all cancer incidence. It is the third most common cancer worldwide and the fourth most common cause of death. It affects men and women almost equally, with just over 1 million new cases recorded in 2002, the most recent year for which international estimates are available. Countries with the highest incidence rates include Australia, New Zealand, Canada, the United States, and parts of Europe. The countries with the lowest risk include China, India, and parts of Africa and South America.
Lastly, Colorectal cancer survival is highly dependent upon stage of disease at diagnosis, and typically ranges from a 90% 5-year survival rate for cancers detected at the localized stage; 70% for regional; to 10% for people diagnosed for distant metastatic cancer. In general, the earlier the stage at diagnosis, the higher the chance of survival.
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