The Genetics of Colon Cancer

In last month's column we explained why cancer is always genetic in causation. Changes leading to the malignant state occur in a stepwise fashion within our genes. Although only rarely (10% of cases) is cancer a hereditary condition, the study of cancer families has helped us to better understand the process of how cancer develops. Members of cancer families can inherit a change in their genetic material that increases their susceptibility to developing cancer. They do not inherit the cancer itself. Rather, they have inherited the first 'hit' in a cancer predisposition gene. Further environmental exposures (smoking, chemicals, radiation) may then trigger the accumulation of other mutations within their genes to directly influence the onset, variability and progression of the cancer.

One classic example of this stepwise mutation process in cancer is seen in a condition called Familial Adenomatous Polyposis (FAP). FAP accounts for about 1% of colon cancer cases. Unlike most forms of colon cancer, all cases of FAP are inherited. To date, at least 5 stepwise genetic events take place in FAP to cause cancer.

FAP is common, occurring in approximately 1 out of every 5,000 individuals. Males and females are equally affected. Age of onset of signs and symptoms usually begin by the second or third decade. Internal examination of the colon (large intestine) allows the physician to identify the presence of numerous small, non-cancerous polyps (pol-lips) that form on the lining of the colon. In FAP, the complete lining of the large intestine may be covered with these tissue overgrowths. Complete surgical removal of these growths is essential, for over a period of several years many of these polyps can grow larger and eventually become cancerous. In FAP, the lifetime risk of developing colon cancer is 100% by age 40. Complete removal of the intestine may be necessary to prevent colon cancer.

Polyp development into cancerous tissue of the colon occurs through stepwise mutation of several genes. These genes act at various stages of the cancer. APC, the first gene identified for colon cancer, may start the process. Individuals with FAP inherit a non-working copy of this gene. Loss of APC in the colon cells allow the formation of polyps. The next step occurs when a single cell in these small benign polyps acquires an additional mutation, often in a gene called K-ras. 'Knock-out' of this second gene causes loss of normal cell cycle control. This cell becomes further changed, and soon overgrows its sister cells. Additional 'hits' in other genes (p53, DCC and nm23) result. When a colon cell has acquired mutations in each of these five genes, it becomes cancerous and invades neighboring tissues. The whole process in FAP, from the initial growth of the small polyps to full blown colon cancer, takes around 20-40 years. Much of what we now understand in FAP may apply to the more common and later onset forms of non-inherited colon cancer as well.

By understanding how genes interact to gradually transform colon cells into an invasive cancer, researchers can devise better ways of earlier diagnosis, treatment and prevention. It will also lead to a better understanding of the environmental triggers that are part of the cancer process. Please look for our November column when we will discuss breast cancer.