Hereditary nonpolyposis colorectal cancer

Hereditary nonpolyposis colorectal cancer (HNPCC), also known as Lynch syndrome, is characterized by an increased risk of colorectal cancer and other cancers of the endometrium, ovary, stomach, small intestine, hepatobiliary tract, upper urinary tract, brain, and skin. HNPCC is subdivided into Lynch Syndrome I (familial colon cancer) and Lynch Syndrome II (other cancer of the gastrointestinal system or the reproductive system). The increased risk for these cancers is due to inherited mutations that degrade the self-repair capability of DNA.

Lynch syndrome was named in honor of Dr. Henry T. Lynch, professor of medicine at Creighton University Medical Center.^[1]

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Characteristics of HNPCC-associated colon cancers

In the United States, about 160,000 new cases of colorectal cancer are diagnosed each year. Hereditary nonpolyposis colorectal cancer is responsible for approximately 2 percent to 7 percent of all diagnosed cases of colorectal cancer. The average age of diagnosis of cancer in patients with this syndrome is 44 years old, as compared to 64 years old in people without the syndrome. ^[2]

HNPCC defects in DNA mismatch repair lead to microsatellite instability, also known as MSI-H, which is a hallmark of HNPCC. Three major groups of MSI-H cancers can be recognized by histopathological criteria:

• (1) right-sided poorly differentiated cancers
• (2) right-sided mucinous cancers
• (3) adenocarcinomas in any location showing any measurable level of intraepithelial lymphocyte (TIL)

MSI is identifiable in cancer specimens in the pathology laboratory. ^[3]

Malignant consequences of the Lynch syndrome

Individuals with HNPCC have about an 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 for members of families that meet the Amsterdam criteria. 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.

Genetic basis of Lynch syndrome

HNPCC is known to be associated with mutations in genes involved in the DNA mismatch repair pathway

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. This also means that the Amsterdam criteria fail to identify many patients at risk for Lynch syndrome. Improving the criteria for screening is an active area of research, as detailed in the Screening Strategies section of this article.

  HNPCC is inherited in an autosomal dominant manner. Most 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 patients with an HNPCC gene mutation have a parent who had cancer. Some patients develop HNPCC de-novo in a new generation, without inheriting the gene. These patients are often only identified after developing an early-life colon cancer. Parents with HNPCC have a 50% chance to pass the gene on to each child.

Screening strategy for colon cancer patients

Genetic testing for mutations in DNA mismatch repair genes is expensive and time-consuming, so researchers have proposed techniques for identifying cancer patients who are most likely to be HNPCC carriers as ideal candidates for genetic testing. The Amsterdam Criteria (see below) are useful, but do not identify up to 30% of potential Lynch syndrome carriers^{[citation needed]}. In colon cancer patients, pathologists can measure microsatellite instability in colon tumor specimens, which is a surrogate marker for DNA mismatch repair gene dysfunction. If there is microsatellite instability identified, there is a higher likelihood for a Lynch syndrome diagnosis. Recently, researchers combined microsatellite instability (MSI) profiling and immunohistochemistry testing for DNA mismatch repair gene expression and identified an extra 32% of Lynch syndrome carriers who would have been missed on MSI profiling alone.^{[citation needed]} Currently, this combined immunohistochemistry and MSI profiling strategy is the most advanced way of identifying candidates for genetic testing for the Lynch syndrome.

Genetic counseling and genetic testing are recommended for families that meet the Amsterdam criteria, preferably before the onset of colon cancer.

Amsterdam criteria

The following are the Amsterdam criteria in identifying high-risk candidates for molecular genetic testing:^[6]

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
• Familial adenomatous polyposis (FAP) has been excluded

Diagnosis

The Amsterdam clinical criteria identifies candidates for genetic testing, and genetic testing can make a diagnosis of Lynch syndrome. Genetic testing is commercially available through Myriad Genetics, and consists of a blood test.

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