1. pathophysiology Colon CA

2. Most colorectal cancers, regardless of etiology, arise from adenomatous polyps. Polyp - a grossly visible protrusion from the mucosal surface – nonneoplastic hamartoma (juvenile polyp) – hyperplastic mucosal proliferation (hyperplastic polyp) – adenomatous polyp – premalignant *only a minority of such lesions becomes cancer

3. Molecular changes mutational activation of an oncogene followed by and coupled with the loss of genes that normally suppress tumorigenesis. – point mutations in the K-ras protooncogene – hypomethylation of DNA, leading to gene activation – loss of DNA (allelic loss) at the site of a tumor-suppressor gene [the adenomatous polyposis coli (APC) gene] on the long arm of chromosome 5 (5q21) – allelic loss at the site of a tumor-suppressor gene located on chromosome 18q [the deleted in colorectal cancer (DCC) gene] – allelic loss at chromosome 17p, associated with mutations in the p53 tumor-suppressor gene

5. Clinically, the probability of an adenomatous polyp becoming a cancer depends on: – gross appearance of the lesion – histologic features – Size Adenomatous polyps: – pedunculated (stalked) – sessile (flat-based) Cancers develop more frequently in sessile polyps

6. Histologically, adenomatous polyps may be – Tubular – villous (i.e., papillary) most are sessile = become malignant more than three times as often as tubular adenomas – tubulovillous

7. Risk Factors for the Development of Colorectal Cancer Diet: Animal fat Hereditary syndromes (autosomal dominant inheritance) Polyposis coli Nonpolyposis syndrome (Lynch syndrome) Inflammatory bowel disease Streptococcus bovis bacteremia Ureterosigmoidostomy Tobacco use

8. Risk Factors for the Development of Colorectal Cancer Diet – more often in upper socioeconomic populations – Colorectal cancer has increased in Japan since that nation has adopted a more "western" diet Animal Fats – animal fats found in red meats and processed meat leads to an increased proportion of anaerobes in the gut microflora resulting in the conversion of normal bile acids into carcinogens Insulin Resistance – "western" diets with physical inactivity has been associated with a higher prevalence of obesity Obese persons – insulin resistance with increased circulating levels of insulin > higher circulating concentrations of insulin-like growth factor type I (IGF-I) > stimulate proliferation of the intestinal mucosa.

9. Hereditary Factors and Syndromes Up to 25% of patients with colorectal cancer have a family history of the disease Hereditable (Autosomal Dominant) Gastrointestinal Polyposis Syndromes SyndromeDistribution of PolypsHistologic TypeMalignant PotentialAssociated Lesions Familial adenomatous polyposis Large intestineAdenomaCommonNone Gardner's syndromeLarge and small intestinesAdenomaCommon Osteomas, fibromas, lipomas, epidermoid cysts, ampullary cancers, congenital hypertrophy of retinal pigment epithelium Turcot's syndromeLarge intestineAdenomaCommonBrain tumors Nonpolyposis syndrome (Lynch syndrome) Large intestine (often proximal) AdenomaCommon Endometrial and ovarian tumors Peutz-Jeghers syndrome Small and large intestines, stomach HamartomaRare Mucocutaneous pigmentation; tumors of the ovary, breast, pancreas, endometrium Juvenile polyposisLarge and small intestines, stomach Hamartoma, rarely progressing to adenoma RareVarious congenital abnormalities