Colon cancer causes

Though still the second leading cause of cancer death, mortality rates for colon cancer have declined over the last 30 years as a result of better and increasingly used screening programs and more effective and better tolerated treatments. 

Besides age, the development of colorectal cancer appears to be caused by variety of dietary or environmental factors, comor-bid disease states, and genetic susceptibility to the disease. Table 88-1 lists well-known risk factors for developing colon cancer. Epidemiologic studies of worldwide incidence of colorectal... 

In addition to their beneficial effects, some medications may actually cause cellular injury and disease. An example of this phenomenon involves nonsteroidal anti-inflammatory drugs (NSAIDS). These drugs include aspirin (a derivative of salicylic acid), ibuprofen (arylpropionic acid, Advil ), and acetaminophen (para-aminophenol derivative, Tylenol ). Because of their beneficial pharmacological effects, consumption of these agents has increased significantly in recent years. NSAIDS have the ability to treat fever, pain, acute inflammation, and chronic inflammatory diseases such as arthritis. They are also used prophylactically to prevent heart disease, stroke, and colon cancer. 

McCullough ML, Robertson AS, Chao A, Jacobs EJ, Stampfer MJ, Jacobs DR, Diver WR, Calle EE and Thun MJ. 2003. A prospective study of whole grains, fruits, vegetables and colon cancer risk. Cancer Causes Control 14(10) 959-970. 

Am ino-1-methy 1-6-phenyl irnidazo 4,5-b]pyridine (29 PhIP), usually the most abundant product of food-derived mutagens, is formed by heating creatine and phenylalanine at 200 °C200. This compound is modestly mutagenic in the Ames test, but is a potent carcinogen in rats and mice, causing breast and colon cancers. 

A second group of inherited colon cancers are termed hereditary nonpolyposis colorectal cancer (HNPCC). HNPCC may account for 5% of all colon cancer cases and can be caused by mutations in any of five different genes. All of these genes encode proteins involved in DNA mismatch repair (Fig II-5-3). As with inherited breast cancer, fiiulty DNA repair leads to mutated cells capable of producing tumors. 

There is a striking relationship between the levels of meat consumption in different countries and the rates of colon cancers in those countries. But does that observation alone establish that meat consumption is causative Is this type of information, of itself, a sufficient basis for public health authorities to recommend that the citizens of high risk countries such as New Zealand and the United States, for example. 

Choi PM, Tchou-Wong KM, Weinstein IB (1990) Overexpression of protein kinase C in HT29 colon cancer cells causes growth inhibition and tumor suppression. Mol Cell Biol 10 4650-4657... 

Goldstein DR, Cacace AM, Weinstein IB (1995) Overexpression of protein kinase C pi in the SW480 colon cancer cell line causes growth suppression. Carcinogenesis 16 1121-1126... 

Lawrence TS, Davis M, Tang HY, et al. Fluorodeoxyuridine-mediated radiosensitization of human colon cancer cells is not caused by cell cycle redistribution. ProcAACR 1992 33 502, (abstr 3002). 

Figure 15.1 Hazard ratios and 95 per cent confidence intervals for death from any cause (panel (a)) and recurrence (panel (b)) by treatment group (Sargent DJ, Goldberg RM, Jacobson SD, MacDonald JS et al., A pooled analysis of adjuvant chemotherapy for resected colon cancer in elderly patients. New England Journal of Medicine, 345, 1091-1097. (2001) Massachusetts Medical Society.)...

Microsatellite instability (MSI) in the tumor caused by defeetive DNA mismateh repair has been associated with outeome to ehemotherapy (34). For example, a study of 320 Dukes B2 and C colon cancers treated with 5-FU therapy showed that MSI status was eorrelated with improved survival (p = O.OI) (35). MSI is also associated with a mutator phenotype that may lead to mutations in pharmaeogenetic markers, which would not be pieked up by screening the germline genome. 

With aromatic amines such as benzidine, 4-aminobiphenyl and 2-aminonaphthalene, which cause bladder cancer, epidemiological evidence suggests that those with the slow acetylator phenotype who have occupational exposure are more at risk. In contrast, with the heterocyclic amines produced in food by cooking, such as PhIP, which cause colon cancer, it seems from similar evidence that fast acetylators are more at risk. 

Repair of damaged DNA When the new strand containing the mismatch is identified, an endonuclease nicks the mismatched strand, and the mismatched base(s) is/are removed. The gap left by removal of the mismatched nucleotide(s) is filled, using the sister strand as a template, by a 5 —>3 DNA polymerase (DNA polymerase I in E. coli)- The 3-hydroxyl of the newly synthesized DNA is spliced to the 5-phosphate of the remaining stretch of the original DNA strand by DNA ligase (see p. 403). [Note A defect in mismatch repair in humans has been shown to cause hereditaiy nonpolyposis colon cancer (HNPCC), one of the most common inherited cancers.]... 

There are two major forms of hereditary susceptibility to colon cancer.00 Familial adenomatous polyposis is caused by defects in the APC gene (see Chapter 32). The more common hereditary nonpolyposis colorectal cancer (HNPCC), which includes many endometrial, stomach, and urinary tract tumors, results from defects in DNA mismatch repair. -)) The proteins hMSH2 and hMSLl are homologs of the E.coli MutS and MutL (main text). 

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