About Hereditary Nonpolyposis Colorectal Cancer

HNPCC is a syndrome that accounts for approximately 5 percent of all colorectal cancer diagnoses. The syndrome is caused by mutations in specific genes, which are described below. Families with HNPCC typically have:

• Three or more closely related family members diagnosed with colorectal cancer
• Affected family members in two or more generations
• At least one person with colorectal cancer diagnosed before the age of 50

The average age of diagnosis of colorectal cancer in families with HNPCC mutations is 45. Though colorectal cancer is the most common malignancy reported in families with HNPCC, the syndrome is also associated with an increased risk for cancers of the uterus, ovaries, stomach, small intestine, biliary system, pancreas, and urinary tract.

There are families with strong histories of colorectal cancer but in whom HNPCC mutations have not been detected. These families may carry mutations in genes yet to be identified or there may not be a mutation at all, the cancer history possibly being explained by ill chance.

Every cell in the human body contains genetic information, or DNA, that directs its growth and development. Genes are the functional units of that genetic information. Each cell contains thousands of genes, each with a specific job to do. Sometimes genes acquire changes that prevent them from working properly. These genetic changes are called mutations.

When a cell divides to create two new cells, its DNA has to be copied. Genetic mutations will sometimes occur during this copying process. Some mutations occur naturally. Other mutations can be caused by exposure to certain foods, chemicals, or radiation. Cells have DNA repair systems that can correct genetic mutations. These DNA repair systems are controlled by a number of genes. If any of these DNA repair genes stop working, cells may no longer be able to correct mutations that occur over the course of their lifetime. Uncorrected mutations in genes that regulate tissue growth can lead to cancer.

HNPCC is a hereditary cancer syndrome caused by mutations in genes that are part of the DNA mismatch repair system. Two genes, called MLH1 and MSH2, are responsible for many cases of HNPCC. Mutations in other mismatch repair genes, MSH6, PMS1, and PMS2, have been detected on rare occasions in families with strong histories of colorectal cancer. A person born with a mutation in either MLH1 or MSH2 has an increased chance of developing colorectal and other HNPCC-associated cancers.

The first step of genetic testing for HNPCC involves looking at tumor tissue from people who have been diagnosed with colorectal cancer. A tissue sample can often be obtained from the hospital where surgery for colorectal cancer took place. The cells of the tumor can be checked for acquired mutations in DNA suggestive of an inherited mutation in one of the DNA mismatch repair genes that causes HNPCC. Tumors that have a lot of these changes are called RER positive or MSI high. RER stands for replication error and MSI stands for microsatellite instability.

A MSI-positive colorectal cancer suggests strongly the DNA mismatch repair system is defective. In the context of a strong family history of colorectal cancer, an MSI-positive tumor most likely occurs because the person was born with a mutation in one of these genes (usually MLH1 or MSH2). It is not an absolute indication of a mutation because MSI-positive tumors arise sporadically (in the absence of family history or germline mutation) in 10 to 15 percent of colorectal cancers.

If an individual tumor tissue tests positive for MSI, then the next step of genetic testing for HNPCC involves analysis of DNA from family members who have had colorectal cancer. The DNA is tested for mutations in the genes known to be associated with this syndrome. Generally, the MLH1 and MSH2 genes are tested because they account for most families with HNPCC. Once we know that a family has a mutation, relatives who have not had cancer can be tested as well.

For individuals who have tested negative for MLH1 and MSH2 gene mutations, new genetic testing for these genes, called Southern blot, has become available. This testing looks for gene changes where large portions of the gene may be missing or rearranged. These changes may be missed or undetectable on more traditional gene sequencing. Genetic testing for mutations in a third gene associated with HNPCC, known as MSH6, has also become available. If you have had negative genetic testing for MLH1 and MSH2 mutations in the past, we encourage you to make an appointment with us in the Clinical Genetics Service at 212-434-5149 to discuss whether further testing makes sense for you.

A MSI-low or indeterminate result means that genetic testing was not informative. A conflicting result means that one family member tested MSI negative while another tested MSI positive. In such cases, further genetic testing of additional relatives may provide more information. It is still possible to have a HNPCC mutation in a family with indeterminate or conflicting results.

It is still possible to have a HNPCC mutation in a family despite a MSI-negative result. Two or more MSI-negative results in a family suggest that a HNPCC mutation is not likely to be present in the family. Also, a MSI-negative result does not rule out another type of hereditary colon cancer predisposition. The level of risk depends on the family history (see Table 1 below). Moreover, individuals in a family may be at increased risk for colorectal cancer due to other factors (e.g., shared environment, lifestyle).

Individuals in families with MSI-negative results should continue to perform colonoscopies at least every 5 years. However, depending on your family history, additional screening may be recommended. We advise you to consult a genetic counselor or a knowledgeable physician to obtain recommendations pertinent to your risk.

Table 1. Summary of Familial Risk of Colon Cancer

Approximate Lifetime Risk of Colon Cancer

• General Population Risk in the US ~ 6 Percent
• One First-Degree Relative with Colon Cancer ~ 2 to 3-Fold Increased
• Two First-Degree Relatives with Colon Cancer ~ 3 to 4-Fold Increased
• First-Degree Relative with Colon Cancer Diagnosed at 50 years ~ 3 to 4-Fold Increased
• One Second- or Third-Degree Relative with Colon Cancer ~ 1.5-Fold Increased
• Two Second-Degree Relatives with Colon Cancer ~ 2 to 3-Fold Increased
• One First-Degree Relative with an Adenomatous Polyp ~ 2-Fold Increased

NOTE. First-degree relatives include parents, siblings, and children; second-degree relatives include grandparents, aunts, and uncles; and third-degree relatives include great-grandparents and cousins. Data from Burt RW. Colon cancer screening. Gastroenterology, 2000;119:837-853.

People who inherit a HNPCC gene mutation have up to a 75 percent chance of developing colorectal cancer by the age of 65. Mutation carriers who have already been diagnosed with colorectal cancer have an increased risk of developing a second colorectal cancer. This risk could be as high as 50 percent.

Women who inherit a HNPCC gene mutation also have:

• Up to a 40 to 60 percent lifetime risk of developing uterine (endometrial) cancer. This is in contrast to the general population's risk for uterine cancer, which is approximately 3 percent.

• A 5 to 15 percent lifetime chance of developing ovarian cancer. The general population's risk for ovarian cancer is 1 to 2 percent.

Colorectal and endometrial cancers are the most common malignancies reported in HNPCC families, but other cancers are associated with HNPCC mutations as well. These cancers can affect both men and women. They include cancers of the:

• Stomach
• Small intestine
• Biliary system
• Pancreas
• Upper urinary (kidney and ureter) tract

People with an HNPCC gene mutation may develop one or more of these cancers. There is also the possibility that they may never develop cancer at all.

Screening tests can help to detect cancer at an early stage when it is more likely to be curable.

These tests include:

• A colonoscopy every year beginning by the age of 20 to 25 or 5 to 10 years before the earliest diagnosis in family, whichever comes first. During a colonoscopy, the doctor passes a thin flexible tube through the anus to look inside the colon. Colorectal cancer usually begins as a benign, precancerous polyp. If a polyp is found during the colonoscopy, it can usually be removed right away. Having routine colonoscopies increases the chance of detecting colorectal cancer early.

• Urine cytology and renal ultrasounds every 1 to 2 years beginning by the age of 30 to 35 for anyone who has a family history of cancers of the urinary tract.

• Upper endoscopy, including duodenoscopy at least every 4 years beginning at the age of 30 to 35. If adenomas are found, upper endoscopy, including duodenoscopy, should be directed by the individual physician.

For women:

• A pelvic examination every 6 months beginning by the age of 30.

• A transvaginal ultrasound every 6 months beginning by the age of 30. This ultrasound scan is called transvaginal because the ultrasound probe must be inserted into the vagina. With the ultrasound, the doctor uses sound waves to take pictures of the uterus and the ovaries.

• Annual endometrial biopsies beginning at the age of 30.

• A blood test (CA125) every 6 months to assist in screening for ovarian cancer, beginning at age 30.

• Other modalities may be considered depending on family history.

Having an operation to remove an organ at-risk should reduce one's risk of cancer, but it is not yet known if surgery can prevent cancer for people with HNPCC gene mutations. Your doctor and genetic counselor can provide you with more information about risk-reducing surgery.

There is evidence to suggest that certain dietary supplements (e.g., folate, calcium, aspirin) may decrease the risk of colorectal cancer. Certain dietary choices are known to increase one's risk of developing colorectal cancer (e.g., regular ingestion of red meats), and others may decrease one's risk (e.g., a high-fiber/low-fat diet). Researchers are also trying to determine if certain "preventive" drugs may help to decrease the risk of cancer. It is not yet known whether these agents decrease the risk in individuals with HNPCC.

If a HNPCC gene mutation has already been found in your family but is "negative" in your blood sample, this tells us that you have not inherited that mutation, unless you have certain risk factors or an "unexplained" family history of cancer. Your risk to develop cancer would be no greater than that of the general population.

If a HNPCC gene mutation has not been found in your family, a "negative" test result for you has limited value. It is possible that a different gene, known or unknown, is responsible for the cancers in your family. For example, there are less common hereditary colon cancer and colon polyp syndromes such as classic and attenuated familial adenomatous polyposis (FAP and AFAP) and MYH. A "negative" test result may also mean that you have a mutation in a HNPCC gene but that it has gone undetected. Genetic tests do not necessarily detect all mutations. A third possibility is that the cancers in your family are not hereditary.

Colorectal cancer is a relatively common disease. More than one person in a family may have developed colorectal cancer purely by chance alone. Given the uncertainty of a negative test result in this setting, one must continue screening according to one's family history. This means that frequent colonoscopies may still be recommended if you have a family history of colon cancer regardless of genetic test results. Depending on your family history, screening for gynecologic cancers may still be advised. This should be discussed with your doctor and a genetic counselor on an individual basis.