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Hereditary nonpolypsis colorectal cancer (HNPCC) is characterized by an increased risk of colon cancer and other cancers such as endometrium, ovary, stomach, small intestine, hepatobiliary tract, upper urinary tract, brain, and skin. Individuals with HNPCC have about a 80% lifetime risk for colon cancer. Two-thirds of these cancers occur in the proximal colon. The mean age of colorectal cancer diagnosis is 44. Also, women with HNPCC have a 30-50% lifetime risk of endometrial cancer. The average age of diagnosis of endometrial cancer is about 46 years. Among women with HNPCC who have both colon and endometrial cancer, about half present first with endometrial cancer. In HNPCC, the mean age of diagnosis of gastric cancer is 56 years of age with intestinal-type adenocarcinoma being the most commonly reported pathology. HNPCC-associated ovarian cancers have an average age of diagnosis of 42.5 years-old; approximately 30% are diagnosed before age 40 years. Other HNPCC-related cancers have been reported with specific features: the urinary tract cancers are transitional carcinoma of the ureter and renal pelvis; small bowel cancers occur most commonly in the duodenum and jejunum; the central nervous system tumor most often seen is glioblastoma.
Diagnosis
The Amsterdam clinical criteria or genetic testing can make a diagnosis. The HNPCC is known to be associated with mutations in four genes involved in the mismatch repair pathway (MLH1, MSH2, MSH6, and PMS2). Mutations in MLH1 and MSH2 account for approximately 90% of detected mutations in families with HNPCC. Mutations in the MSH6 gene are seen in about 7-10% of families with HNPCC. Mutations in the PMS2 gene account for less than 5% of mutations in families with HNPCC. Up to 39% of families with mutations in an HNPCC gene do not meet the Amsterdam criteria. Therefore, families found to have a deleterious mutation in an HNPCC gene should be considered to have HNPCC regardless of the extent of the family history.
Amsterdam Criteria
- Three or more family members with a confirmed diagnosis of colorectal cancer, one of whom is a first degree (parent, child, sibling) relative of the other two
- Two successive affected generations
- One or more colon cancers diagnosed under age 50 years
- Familial adenomatous polyposis (FAP) has been excluded
Amsterdam Criteria II
- Three or more family members with HNPCC-related cancers 3 , one of whom is a first degree relative of the other two
- Two successive affected generations
- One or more of the HNPCC-related cancers diagnosed under age 50 years
(From Vasen HF, Watson P, Mecklin JP, Lynch HT (1999) New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative group on HNPCC. Gastroenterology 116:1453-6)
Genetics
HNPCC is inherited in an autosomal dominant manner. TMost people with HNPCC inherit the condition from a parent. However, due to incomplete penetrance, variable age of cancer diagnosis, cancer risk reduction, or early death, not all with an HNPCC gene mutation have a parent who had cancer. Parents with HNPCC have a 50% chance to pass the gene on to each child. Genetic counseling and genetic testing is recommended for families that meets the Amsterdam criteria or may have a high risk for HNPCC.
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