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IBD and the risk of Colorectal Cancer.
One of the more troubling consequences of having inflammatory bowel disease (IBD), ie Crohn's disease or ulcerative colitis, is an increased risk of developing colorectal cancer.
3.7% of patients with ulcerative colitis have colorectal cancer which is about five-fold higher than the risk for the general population. The possibility increases the longer a person lives with the disease. Until recently, it was thought that the increased cancer risk was linked to ulcerative colitis but not to Crohn's disease. However, more recent studies have shown that people with Crohn's disease that affects the colon have similar risk for developing colorectal cancer as those with ulcerative colitis. The increased risk has prompted researchers to investigate whether there may be ways to detect which patients are most likely to develop this condition.
Some risk factors are known. The three main factors are:
Colorectal cancer rarely occurs until IBD has been present for at least eight years. Ulcerative colitis patients who have a first-degree relative (parent, sibling, or child) with colorectal cancer have 2.5 times greater risk of colorectal cancer; with Crohn's disease, the increased risk is 3.7 times. People in whom the entire colon is involved are at the greatest risk, those with only part of the colon having colitis are at intermediate risk, and those with inflammation only of the rectum are at lower risk. This applies to patients with both active and inactive disease.
Currently, the main method for early detection of colorectal cancer or pre-cancerous lesions in people with IBD is colonoscopy. Colonoscopy is not 100% accurate in finding cancer in people with IBD. This is partly because the signs of colorectal cancer may be different in people with IBD. In most cases, this form of cancer starts as a polyp (a small protrusion, or lump, growing from the wall of the intestine). Polyps can start out benign and become malignant, and they are usually easily detected during a colonoscopy. People with IBD, however, do not always form polyps as the pre-cancerous lesion. Instead, abnormal and potentially pre-cancerous tissue (changes in the cells, called dysplasia) may lay flat against the wall of the intestine. Also, in IBD patients, abnormal, pre-cancerous cells can be present in an area of the intestinal wall that visually appears normal. Because detection of colorectal cancer is more difficult in people with IBD, standard colonoscopy is usually accompanied by a series of biopsies. Small tissue samples from 40 to 50 areas in the wall of the colon will be taken for microscopic examination.
Chromo-endoscopy is a newer procedure that may be a more efficient method than biopsy of the colon. Specialized dyes are sprayed on the surface of the inside lining of the colon. The pattern of staining that these dyes produce allows the physician to differentiate normal from dysplastic tissue. This method appears to improve early diagnosis of pre-cancerous and cancerous tumors.
In colorectal cancer, benign pre-cancerous lesions turn malignant due to certain changes in DNA. For example, in about 85 % of all cases, changes take place that cause the loss of function of two tumor suppressor genes: APC and p53. The remaining 15 % of colorectal cancers result from the body's inability to repair its DNA. The process of DNA repair allows the body to fix damage to genes caused by environmental factors. Abnormalities in these processes can lead to cancer.
These cancer-initiating processes are similar for both IBD and non-IBD patients. However, the timing tends to be different. In ulcerative colitis patients, loss of function of the p53 gene (which causes malignancy) tends to happen earlier than loss of function of the APC gene (responsible for the formation of the tumor). It's not yet known whether this is also true in Crohn's patients who develop colorectal cancer.
In one study of 95 ulcerative colitis patients, the 37 patients with the abnormal p53 gene were more likely than those without it to develop dysplasia or cancer. Therefore, if confirmed in more studies, the p53 mutation may prove to be a useful marker of cancer risk. Other genes are also being studied as possible markers of cancer risk, including the HPP1 gene and the CDH1 promoter gene.
Another potential new approach may allow for a much simpler biopsy procedure. The genetic abnormalities associated with the development of dysplasia and cancer seem to occur within all the tissue of the lining of the colon (not just the areas in which dysplasia is found). In one study, abnormalities were present throughout the colon, but not in other areas of the gastrointestinal tract. If this finding is confirmed, it could mean that a simple biopsy can be done to determine which patients with ulcerative colitis are likely to have dysplasia..
During Digestive Disease Week, a professional gastro-enterology conference held in May, many new studies on colorectal cancer were presented. These studies focused primarily on prevention and treatment. Researchers now believe that chronic inflammation is the cause of one or more genetic mutations that may result in the development of cancer or dysplasia in people with ulcerative colitis.
One study showed that ulcerative colitis patients have extensive genomic instability-an early marker for cancer. Genomic instability is an important concept that refers to how quickly mutations occur to the genetic material in cells. The cells in our body engage in a natural process of death and renewal. It is possible for the cells to continually carry a particular mutation through several cycles, or generations, of this death and renewal, as well as develop new mutations that also carry through. The rate of these mutations is known as, genomic instability.
Marked genomic instability was detected in 33% of patients with ulcerative colitis with dysplasia, in 10% of ulcerative colitis patients without dysplasia, and in no patients in the control group, or group of people without colitis. In addition, common mutations occurred in several genes associated with sporadic colorectal cancer (cancer that is not found continuously throughout the colon, like it is in those with IBD). Researchers concluded that genomic instability is widespread in ulcerative colitis patients with dysplasia or cancer. Early discovery of the particular mutation as a possible early indicator of cancer can affect the timing and type of treatment offered.
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