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Colorectal cancer is a major cause of cancer-related mortality in the world. It is currently the third-most-common cancer in incidence in the United States and accounts for about 8.5% of all cancer-related mortality (nearly 136,000 new cases and 50,000 deaths each year) (1). This chapter reviews our current understanding of colorectal cancer, describes the known genetic mutations and risk factors, and outlines emerging screening, prevention, and therapeutic strategies, with particular emphasis on the approach taken at MD Anderson Cancer Center (MDACC).


Carcinogenesis: The Adenoma–Adenocarcinoma Sequence

Colorectal neoplasia results from accumulation of alterations over years, ultimately transforming normal epithelium to intraepithelial neoplasia (dysplasia) and then malignant epithelium. Three different pathways driving carcinogenesis include chromosomal instability, microsatellite instability (MSI), and CpG island methylation. The chromosomal instability pathway identifies early mutations in genes such as the tumor suppressor APC and the K-ras proto-oncogene and later genetic events, including mutations in the deleted in colon cancer (DCC) gene and the tumor suppressor gene p53.

Risk Factors

Genetic predisposition and acquired risk factors progress stepwise from normal colonic mucosa to adenomatous polyps to invasive adenocarcinoma in individuals with acquired (somatic) or inherited genetic (germline) mutations, with further environmental, dietary, or other less-well-understood factors. Personal or family histories of colorectal cancer or polyps, older age, and inflammatory bowel disease (IBD) have all been associated with an increased risk of colorectal cancer (Table 24-1).

Table 24-1Lifetime Risks of Colorectal Cancer


A “Western” diet rich in saturated fat has been associated with an increased risk of colon cancer. Fiber may decrease the fecal carcinogen concentration and transit time, thus reducing the period of exposure to colonic mucosa. However, the prospective Nurses Health Study of 88,757 women aged 34 to 59 years found no association between fiber intake and the risk of colorectal cancer after a median follow-up of 16 years (2).


Increased body mass index (BMI), and central obesity are emerging as risk factors for colorectal cancer. The Framingham Study found that a BMI >30 increased the risk of colon cancer by 50% among middle-aged (30-54 years) individuals and by 2.4-fold for those aged 55 to 79 years, and waist circumference was a stronger predictor than BMI (3).

Adenomatous Polyps

Carcinoma is present in 5% of adenomas, where the potential for malignant transformation is 8 ...

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