The 2nd largest cause of cancer mortality

Colorectal cancer also known as colon cancer or bowel cancer is the fourth most prevalent cancer and the second largest cause of cancer mortality in the western world. It is also one of the most curable cancers when identified early1. In the USA only 39% of colorectal cancers are detected early, at a localised and often symptomless stage when the five year survival rate is 90%2.  This highlights the importance of colorectal cancer screening.

Most colon cancers develop from benign polyps on the surface of the colon.  Risk factors include:

• Diet – The incidence rate is much higher in western society and countries that have adopted a western diet.
• Obesity - There is an increased risk of developing colorectal cancer if overweight
• Family History – A small number of colon cancers are linked to a dominantly inherited predisposition however the risk or developing colon cancer is twice as high if one or immediate family members have been affected. 
• Familial adenomatous polyposis (FAP) – FAP is a genetic condition resulting in the presence of multiple adenomas in the large intestine.  Mutations on the APC tumour suppressor gene are responsible for the development of FAP.   Individuals with FAP are at an increased risk of developing colorectal cancer.
• Hereditary non-polyposis colorectal cancer (HNPCC) – HNPCC is another genetic condition resulting from mutations in the mismatch repair genes hMSH2 and hMLH1.

With many of the risk factors being hereditary genetic screening for predisposed mutations can enable the early detection and therefore treatment of colorectal cancers.

Many colorectal cancers are the result of several mutations in the tumour suppressor genes and proto-oncogenes over a period of years. Some of the main genes involved are listed below:

APC Tumour Suppressor Gene - Mutation of the APC tumour suppressor gene is often the earliest identifiable event in colorectal carcinogenesis. Loss of function of the APC protein deregulates ß-catenin resulting in the stimulation of cell proliferation.  All daughter cells carry the APC mutation. 

K-ras and BRAF - Point mutations in the oncogenes K-ras or BRAF permanently activate the proteins involved in the transduction of extracellular growth signals.  Continuous signals from cell surface receptors to the nucleus allow progression to adenoma. 

TP53 Tumour suppressor gene- Inactivating mutations of the TP53 tumour suppressor gene can trigger the transition to malignant cancer by preventing cell cycle arrest or apoptosis in response to DNA damage.

Screening is important to detect cancer before the onset of symptoms increasing the chances of survival.  At present current screening methods include;

• Colonoscopy and Sigmoidoscopy – are invasive methods involving the use of a camera to examine the inside of the bowel allowing the identification of cancerous and pre cancerous cells. Although these are sensitive and specific there is poor patient compliance. 
• Fecal occult blood test (FOBT) – This is a non invasive, indirect method of checking for heme and haemoglobin in stool samples. Although in expensive and non invasive FOBT is neither specific nor sensitive. 
• Virtual colonoscopy – non invasive method involving the use of x-rays to produce 3D images of the colon, can identify polyps on the inside of the colon.

Faecal DNA testing is a non invasive method allowing the identification of the mutations associated with colorectal cancer resulting in earlier detection and better patient prognosis. The Ranplex CRC assay utilises this method and is suitable for detecting mutation in the genes listed above.

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References:
1.Toribara NW and Sleisenger MH. (1995) Screening for colorectal cancer. N Engl Med 332(13):861-7
2. Fearon ER and Vogelstein B. (1990) A genetic model for colorectal tumorigenesis. Cell 61(5):759-67.