Pathophysiology Colorectal cancers arise from dysplastic adenomatous polyps in the majority of cases.

There is a multistep process involving the inactivation of a variety of tumour-suppressor and DNA repair genes, along with simultaneous activation of oncogenes. This confers a selective growth advantage to the colonic epithelial cell and drives the transformation from normal colonic epithelium to adenomatous polyp to invasive colorectal cancer. Germline mutations underlie the well-described inherited colon cancer syndromes, whereas sporadic cancers arise from a step-wise accumulation of somatic genetic mutations. A single germline mutation in the adenomatous polyposis coli (APC) tumour suppressor gene is responsible for the dominantly inherited syndrome that bears the same name. Clinical expression of the disease is seen when the inherited mutation of one APC allele is followed by a second hit mutation or deletion of the second allele. Ulcerative colitis and Crohn's colitis are associated with an increased risk of colorectal cancer with an interim step of dysplastic epithelium. Spread of colorectal cancer is to local lymph nodes and via the vasculature to liver and lungs and, less commonly, to bone and brain. However, as survival improves with systemic chemotherapy, bone and brain metastases have been increasingly reported. [19]

Colon Cancer Colon cancer:

begins with the development of polyps in the epithelium of the colon. Polyps are benign growths. As time passes, the polyps may get bigger. At some point, nests of malignant cells may appear within the polyps If the polyp is not removed, some of these malignant cells will escape from the primary tumor and metastasize throughout the body.

Examination of the cells at the earliest, polyp, stage, reveals that they contain one or two mutations associated with cancer. Frequently these include

the deletion of a healthy copy of the APC (adenomatous polyposis coli) gene on chromosome 5 leaving behind a mutant copy of this tumor suppressor gene Two results: 1. One of the functions of the APC gene product is to destroy the transcription factor -catenin thus preventing it from turning on genes that cause the cell to divide. With no, or a defective, APC protein, the normal brakes on cell division are lifted. 2. Another function of the APC protein is to help attach the microtubules of the mitotic spindle to the kinetochores of the chromosomes. With no, or a defective, APC product available, chromosomes are lost from the spindle producing aneuploid progeny. a mutant proto-oncogene (often RAS).

deletion and/or mutation of the tumor suppressor gene p53

Note that each of the mutations shown probably occurs in one cell of the type affected. This cell then develops into the next stage of the progression. The mutations do not necessarily occur in the order shown, although they often do. The cells in the later stages of the disease show a wide variety of additional mutations including point mutations, deletions, translocations, and duplications. A dozen or more of these are "driver" mutations playing significant roles in the malignancy. The others are probably "passenger" mutations that play no role in the process. A similar stepwise genetic progression occurs in

lung cancer [Link] breast cancer cancer of the mouth and pharynx.

It is becoming clear that this is what one should expect. What distinguishes one cancer from another is not the tissue of origin, but the particular accumulation of mutations that drive its growth. Once these are identified, it will eventually be possible to choose chemotherapeutic agents that target the particular pathways in a given cancer personalized therapy. [Link to an example.] Cancers become more common as one gets older. The graph shows the death rate from cancer in the United States as a function of age. The graph can best be explained by the need for an accumulation of several "hits" to genes that control the cell cycle before a cell can become cancerous. The graph also explains why cancer has become such a common cause of death during the twentieth century. It probably has very little to do with exposure to the chemicals of modern living and everything to do with the increased longevity that has been such a remarkable feature of this century. A population whose members increasingly survive accidents and infectious disease is a population increasingly condemned to death from such "organic" diseases as cancer. Causes of Cancer Cancers are caused by

anything that damages DNA; that is anything that is mutagenic o radiation that can penetrate to the nucleus and interact with DNA o chemicals that can penetrate to the nucleus and damage DNA. Chemicals that cause cancer are called carcinogens. anything that stimulates the rate of mitosis. This is because a cell is most susceptible to mutations when it is replicating its DNA during the S phase of the cell cycle. o certain hormones (e.g., hormones that stimulate mitosis in tissues like the breast and the prostate gland) o chronic tissue injury (which increases mitosis in the stem cells needed to repair the damage) o agents that cause inflammation (which generates DNA-damaging oxidizing agents in the cell) o certain other chemicals; some the products of technology [example] o certain viruses