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Key Points

  • Disease summary:

    • Colorectal cancer remains the second leading cause of cancer deaths in the United States, with an estimated 143,000 new diagnoses anticipated in 2012. The lifetime risk of any individual developing colon cancer is 5.1%. Often, the disease has no presenting symptoms, but can manifest through changes in bowel habits or appetite, vague abdominal pain, overt bleeding, occult blood loss, iron deficiency anemia, weight loss, or obstructive bowel symptoms. A significant number of afflicted individuals demonstrate a family history of colon cancer. Moreover, a small subset of these individuals will present with features of an established familial cancer syndrome. Careful integration of the family and personal history, physical examination findings, and endoscopic findings play a critical role in recognition and management of these high-risk individuals. Small bowel cancers remain rare, and account for less than 0.5% of all new cancers diagnosed. Malignancies of the small bowel include adenocarcinoma, lymphomas, carcinoids, and mesenchymal tumors. On occasion, cancers of the small bowel may also represent as a manifestation of a familial cancer syndrome.

  • Differential diagnosis:

    • In the evaluation of an individual with a familial cancer syndrome, the first consideration should be an assessment of polyp burden. Lynch syndrome is the only defined nonpolyposis syndrome with colon and/or extracolonic cancers. Among those patients with polyposis, the main consideration is whether the polyps are adenomatous or hamartomatous. For those patients with large numbers of tubular adenomas, familial adenomatous polyposis (FAP) and MUTYH-associated polyposis (MAP) are in the differential diagnosis. Peutz-Jeghers syndrome (PJS), juvenile polyposis syndrome (JPS), and PTEN hamartomatous tumor syndromes (PHTS) are considered for those with hamartomatous polyposis.

  • Monogenic forms:

    • Approximately 5% of colon cancer cases are linked to known familial colon cancer syndromes. Generally, these syndromes are broadly classified into polyposis or nonpolyposis syndromes. The most common nonpolyposis syndrome is Lynch syndrome (hereditary nonpolyposis colon cancer [HNPCC]), which accounts for 3% of all colon cancers. Polyposis syndromes include FAP, MAP, JPS, PJS, and PHTS. Of these polyposis syndromes, the first two are adenomatous polyposis syndromes and the latter three are rare hamartomatous polyposis syndromes. Many of these syndromes may also present with cancers outside of the colon including those of the small bowel, stomach, soft tissues, hepatobiliary system, uterus, ovary, urogenital tissues, skin, and central nervous system.

  • Family history:

    • While only 5% of colon cancers are currently estimated to be linked to established colon cancer syndromes, over 25% of afflicted individuals may demonstrate a family history of colon cancer.

  • Twin studies:

    • Analysis of Nordic twins demonstrates that the average genetic contribution to the risk of developing colon cancer is approximately one-third.

  • Environmental factors:

    • Smoking, diet (red meat consumption), obesity (risk greater for men than women)

  • Genome-wide associations:

    • While several loci have been identified, novel mechanisms and drug targets have yet to be elucidated from genome-wide association studies (GWAS).

  • Pharmacogenomics:...

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