Hereditary nonpolyposis colorectal cancer

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Hereditary nonpolyposis colorectal cancer (HNPCC) is a colon cancer, characterised by a risk of other cancers of the endometrium, ovary, stomach, small intestine, hepatobiliary tract, upper urinary tract, brain, and skin. The increased risk for these cancers is due to inherited mutations that impair DNA mismatch repair.

Terminology

According to some sources, HNPCC is also called Lynch syndrome, after Henry T. Lynch (professor of medicine at Creighton University Medical Center),^[1] who characterized it in 1966.^[2] It is divided into Lynch syndrome I (familial colon cancer) and Lynch syndrome II (colorectal cancer and another type of cancer, usually, but not limited to, the gastrointestinal system or the reproductive system).

Other sources reserve the term "Lynch syndrome" when there is a known DNA mismatch repair defect, and use the term "Familial colorectal cancer type X" when the Amsterdam criteria are met but there is no known DNA mismatch repair defect.^[3] The latter type has a lower incidence of cancer.^[4] About 35% of patients meeting Amsterdam criteria do not have a DNA-mismatch-repair gene mutation.^[5]

Complicating matters is the presence of an alternative set of criteria, known as the "Bethesda Guidelines".^[6][7][8]

Epidemiology

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. ^[9]

Cause

HNPCC defects in DNA mismatch repair lead to microsatellite instability, also known as MSI-H, which is a hallmark of HNPCC. MSI is identifiable in cancer specimens in the pathology laboratory. ^[10]

Genetics

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

Patients with MSH6 mutations are more likely to be Amsterdam criteria II-negative.^[17] The presentation with MSH6 is slightly different than with MLH1 and MSH2, and the term "MSH6 syndrome" has been used to describe this condition.^[18] In one study, the Bethesda guidelines were more sensitive than the Amsterdam Criteria in detecting it.^[19]

Up to 39% of families with mutations in an HNPCC gene do not meet the Amsterdam criteria.^{[citation needed]} 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 fashion.

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.

Classification

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)

Risk of colon cancer

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.

Screening

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:^[20]

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, 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 and consists of a blood test.

Therapy

Surgery remains the front-line therapy for HNPCC. There is an ongoing controversy over the benefit of 5-fluorouracil-based adjuvant therapies for HNPCC-related colorectal tumours, particularly those in stages I and II.^[21]

After reporting a null finding from their randomized controlled trial of aspirin (ASA) to prevent against the colorectal neoplasia of Lynch Syndrome,^[22] Burn and colleagues have recently reported new data, representing a longer follow-up period than reported in the initial NEJM paper. These new data demonstrates a reduced incidence in Lynch Syndrome patients who were exposed to at least four years of high-dose aspirin, with a satisfactory risk profile.^[23] These results have been widely covered in the media; future studies will look at modifying (lowering) the dose (to reduce risk associated with the high dosage of ASA. Individuals with Lynch Syndrome may wish to discuss the application of these results with their medical care team.

References

External links

• FAQs on HNPCC from the National Institute of Health
• hnpcc at NIH/UW GeneTests
• Lynch Syndrome Reading List by Dr. Kubin
• Lynch Syndrome Awareness/Fundraising by Selena Martinez
• National Cancer Institute: Genetics of Colorectal Cancer information summary