Causes of colon and rectal cancer

There are environmental and genetic factors to be considered when discussing the occurrence of this disease. The study of migrants from one country to another demonstrates that the second generation after migration acquires an incidence of colorectal cancer more nearly approximating that of the new home country, whether high or low in incidence. This argues strongly for environmental factors and diet seems to be the most likely contributor to the change in risk. Dietary foodstuffs, passing through the bowel and progressively accumulating biodegraded, non-absorbed yet potentially carcinogenic end-products, lead to exposure of the lining of the bowel (this lining being the site of origin of all bowel carcinomas) to dietary derived carcinogens. However, where there is a lot of fibre in the diet, then these carcinogens are first diluted in concentration and, due to the faster transit time of digested food in the colon before excretion, the bowel lining is exposed to these substances for a shorter time than in people whose diet is low in fibre and whose colonic contents have a longer transit time. As Western diets tend to be low in fibre, one of the health measures aimed at lowering colorectal disease is the increase in the fibre content of diets; it should be said here that such an increase in fibre is expected to lower other colonic disease of Western society such as diverticulosis.

 

Approximately 10-15% of all colorectal cancer has a familial or genetic basis; these cancers tend to occur at a younger age and below the age of fifty years. The best known familial syndrome is called familial polyposis coli, which runs strongly in families and the patients exhibit multiple polyps throughout the large bowel (a term which includes the colon and rectum) from an early age. So great is the risk that these will develop into cancers that the patients are recommended to have a prophylactic proctocolectomy in early adult life to forestall this eventuality; put another way, these patients are recommended to have their colon and rectum surgically removed before the polyps have a chance to turn into cancers and spread. Following proctocolectomy the ileum (the final section of the small bowel) is connected to the rectal stump such that the patient does not have an ‘-ostomy’. Hereditary non-polyposis colonic cancer (HNPCC) is another familial predisposing condition to cancer of the large bowel and accounts for approximately 10% of all large bowel cancers; the genetic defect has been tied down to a mutation in genes that normally control DNA mismatch repair. When defective, as in HNPCC, these genes fail to detect (naturally occuring) DNA damage and progressive accumulation of damaged DNA will inevitably lead to carcinogenic mutations in due course and thence to cancer.

 

Sporadically (i.e. not related to genetic predisposition syndromes) colonic polyps are precancerous when they grow above a certain size (say 2 cm. diameter).

 

Inflammatory bowel disease, specifically ulcerative colitis, that has persisted over many years, is a precancerous condition predisposing to cancers of both the colon and rectum.

 

Hereditary syndromes in detail: Where colon cancer develops before the age of 45 years, at least 15% of relatives will develop this disease; genetic counselling has become more important in recent years, particularly as the understanding of the genetics has improved also. Familial adenomatous polyposis (FAP), a disease mentioned above, is inherited as an autosomal dominant trait, patients developing pan-colonic and rectal adenomatous polyps (50% by the age of fifteen and 95% by the age of 35 years. Untreated, 100% of patients will develop colorectal cancer. The treatment of choice is Prophylactic ('insurance policy') total removal of rectum and colon (procoto-colectomy), usually advised in the late teens - a dfficult choice but necessary. Occasionally, as total procto-colectomy necessitates the patient to have the bowel emptying through a stoma on the anterior abdominal wall (an 'ileostomy'), the specialist may feel it safe to join the ileum to a small rectal 'stump' that he leaves behind to allow normal passage of faeces through the anus. He can then monitor to ensure that this residual rectum does not develop the disease - thus allowing the patient to avoid a stoma on the anterior abdominal wall. The familial adenomatous polyposis (APC) gene has been localised to chromosome 5q21 and currently it is possible to detect mutations in the APC gene in up to 83% of families with FAP. HNPCC is transmitted also as an autosomal dominant trait. It is associated with germline mutations in one of five DNA mis-match repair genes (MSH2,MSH1, PMS1,PMS2 and MSH6). The incidence of a mutated mis-match gene is approximately 1 in 1000 paeople. The Amsterdam criteria help to idetify those at risk: Where colorectal cancer occurs in at least two generations, particularly where one or more colorectal cancers occur before the age of 50, and where three or more relatives have the cancer or an associated cancer (endometrial, ovary, small bowel, hepatobiliary tree,ureter or renal pelvis)- such patients are at risk of having this genetic predisposition. The later Bethesda criteria are more all-embracing and formulated because some people with the genetic mutations of HNPCC (and therefore at risk)did not fit within the Amsterdam criteria. The people who are now perceived to benefit from further clinical genetic advice are: Individuals who fit the Amsterdam criteria. Individuals with two HNPCC associated cancers. Individuals with colo-rectal cancer and a first degree relative with the disease or HNPCC associated cancer, especially at less than 45 years, (or an adenoma of the colo-rectum diagnosed at less than 40 years).Individuals with an undifferentiated right sided colon cancer or a colon cancer of signet-ring type (histology finding) at less than 45 years of age. Individuals with an adenoma of colon or rectum at less than 40 years. All these patients should be considered for further clinical genetic advice and at least 40% will have the characteristic genetic mutations in the five genes that are listed above - based on current genetic 'fingerprinting'. Where HNPCC is suspected based on the above criteria, but the genetic testing is negative,then tests for micro-satellite instability (MSI) are considered and MSI will be identified identified in 90% of those with some HNPCC predisposition. MSI testing may also be prognostic.