Fall 2003 Issue: Inhereditary Colorectal Cancer Syndromes


Fall 2003
INHEREDITARY COLORECTAL CANCER SYNDROMES The polyp-cancer sequence understanding of colorectal cancer is thought to explain up to 90% of colorectal cancer. A benign polyp starts with an initial acquired genetic mutation in a colonocyte. As the polyp slowly grows it accumulates further genetic mutations and becomes sequentially more abnormal until it becomes an invasive cancer. In patients with inherited genetic abnormalities (5-10 % of colorectal cancers) every cell in the body, including ALL the colonocytes, has an initial genetic abnormality to start with. In the Familial Adenomatous Polyposis syndrome, all the cells in the body have the Adenomatous Polyposis Coli (APC) gene, usually the first acquired abnormality in the sporadic polyp-cancer sequence. Patients with FAP typically present with rectal bleeding in the late teens to early twentys and when examined endoscopicly have hundreds to thousands of adenomatous polyps. Left untreated nearly 100% will have colorectal cancer by 40. FAP is an autosomal dominant genetic disorder with nearly 100% penetrance. There is a 50% chance that each child will inherit the genetic abnormality and nearly all patients with the abnormality will get the syndrome. These patients can also get benign and malignant tumors of the stomach, duodenum, small bowel, brain, thyroid and pancreas. Some will also get desmoid tumors, osteomas, epidermoid cysts and dental abnormalities (Gardner’s syndrome). Patients at risk should start sigmoidoscopic testing at 12-15. If polyps are identified, then proctocolectomy with ileostomy or ileo-anal pouch can eliminate the risk of colorectal cancer. Subtotal colectomy with ileorectal anastomosis will reduce the risk but careful ongoing surveillance of the rectum is needed. Genetic testing of an index patient can help determine the risk for first-degree relatives. If the index patient tests positive then at risk relatives can have focused testing for the specific abnormality found in the index patient. A negative test indicates risk for colorectal cancer equal to the general population and usual screening criteria apply. A positive test indicates presence of the genetic disposition and increased risk for polyps and cancer. Early endoscopic surveillance and surgery are indicated. Hereditary Non-Polyposis Colon Cancer (HNPCC) is a somewhat less severe but less obvious genetic abnormality in “mismatch repair genes: genes that code for repair of mistakes in DNA replication. Currently 5 such genes have been identified: MLH1, MSH2, MSH6, PMS1 and PMS2.		Abnormality in one of these genes will increase the risk of colorectal cancer to nearly 80% by age 70 with increased risk of second colorectal cancer, multiple colorectal cancers or a cancer proximal to the splenic flexure, out of reach of diagnostic sigmoidoscopy. Some families also have increased risk of cancers in the uterus (endometrial), ovaries, stomach, small bowel, hepatobiliary tract, brain and GU tract. Clinical diagnostic criteria for HNPCC include: (Amsterdam criteria) 1) 3 or more relatives with colorectal cancer, with one being a first-degree relative of the other two. 2) Colorectal cancer in at least 2 generations. 3) One or more colorectal cancers before the age of 50. Some authors suggest these criteria are too strict and miss too many inherited colorectal cancers. Bethesda criteria include everyone meeting the criteria above plus all patients who might have 1) two HNPCC related tumors: (two or more colorectal cancers, endometrial, ovarian, gastric, hepatobiliary, small bowel or transitional cell GU cancers.) 2) Colorectal cancer and any first-degree relative with a cancer listed above and one of the cancers occurred at younger than 50 and colonic adenoma at younger than 40. Because patients with HNPCC are at increased risk for second colorectal cancers subtotal colectomy is usually recommended as the definitive operation for the index colorectal cancer. This reduces the risk of second and subsequent colorectal cancers. In women with HNPCC and colorectal cancer, hysterectomy should also be discussed due to the significantly increased risk of endometrial cancer. Genetic tests are available for FAP, AFAP and HNPCC. Testing can be a general test of the entire gene sequence or focused testing for a known familial abnormality. The former is much more expensive. Results can be: positive-the suspected abnormality is present; negative-the suspected abnormality is absent; or indeterminate-an abnormality is found but it is one of uncertain clinical significance. “Positive” patients have the syndrome and should undergo close surveillance or prophylactic surgery. “Negative” patients are at the same risk as the general population and the usual screening recommendations apply for colonoscopy starting at age 50. Indeterminate results may indicate a new genetic abnormality that needs further study. Surveillance as for “positive” patients is usually recommended depending on the cancers actually seen in the family. REMEMBER: COLORECTAL CANCER IS PREVENTABLE!!!
Kitsap ColoRectal Surgery, Johnny B. Green, MD, FACS, FASCRS Eastwood Building, 2528 Wheaton Way, #103, Bremerton, WA 98310 Voice: (360) 377-4717 -- Fax: (360) 377-4134 www.kitsapcolorectal.com

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