Inherited Risk for Colorectal Cancer

About 5 to 10 percent of all colorectal cancers are caused by a heritable mutation – a genetic change that can be passed on from parent to child.

The two major subtypes of hereditary colon cancer are called familial adenomatous polyposis (FAP) and Lynch syndrome, also known as hereditary nonpolyposis colorectal cancer (HNPCC). In addition, some rare conditions – including attenuated familial adenomatous polyposis (AFAP) and MUTYH-associated polyposis (MAP) – have been associated with an inherited risk for colorectal cancer.

There are additional, unusual causes of hereditary colorectal cancer that will be discussed with you if your personal or family history suggests that one of these syndromes might be present.

In some families, there is a strong history of colorectal cancer although no known mutations have been detected. It is not known whether the disease susceptibility of these families occurs randomly or by hereditary mutations that have not yet been identified.

Types of Hereditary Colon Cancer

Lynch syndrome, or HNPCC, accounts for 2 to 3 percent of all colorectal cancer diagnoses. People with this condition have an 80 percent lifetime risk of developing colorectal cancer, as well as an increased risk for certain other cancers, including tumors of the uterus, ovary, stomach, small intestine, biliary system, pancreas, and urinary tract.

Families with Lynch syndrome 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 mutations that cause Lynch syndrome occur in genes that play a role in DNA mismatch repair, a process that allows a cell to repair errors in its genetic code. Such errors may arise when the DNA is damaged or may occur randomly when a cell divides. Inherited mutations in genes that are important for DNA mismatch repair may lead to the accumulation of DNA errors in cells, increasing the risk for cancer.

Mutations in two genes called MLH1 and MSH2 are responsible for most cases of Lynch syndrome, but in a few cases the disease has been linked to mutations in other DNA repair genes, including MSH6, PMS1, and PMS2.

Familial adenomatous polyposis (FAP) is a rare condition associated with less than 1 percent of colorectal cancers. It is characterized by polyposis, the development of thousands of polyps in the colon, often at a young age.

Most people with FAP that is left untreated eventually develop colorectal cancer, often around age 40. In rare cases, FAP can lead to the development of polyps or stomach cancer of the upper gastrointestinal tract.

People who have been diagnosed with FAP are strongly encouraged to seek medical help at a specialized treatment center such as Memorial Sloan Kettering.

FAP is caused by mutations in a gene called APC. These gene changes usually run in families, but about 25 percent of people with APC mutations do not have a family history of FAP. In those people, an APC mutation is likely to have developed by chance (known as a de novo mutation).

People who carry an APC mutation have a 50 percent chance of passing that mutation on to a child. This also means that if one of your parents has a FAP-associated mutation, your risk of carrying the same mutation is 50 percent.

Gene sequencing tests can be used to determine if a person with a family history of colorectal cancer has FAP.

Attenuated familial adenomatous polyposis (AFAP) is a milder form of FAP. While people with the classic form of FAP often have hundreds or thousands of polyps in the colon, AFAP tends to cause fewer polyps, typically around 30 and rarely more than 100.

If AFAP is left untreated, it can lead to colorectal cancer, typically around age 55. In some cases, it can also lead to polyps or stomach cancer of the upper gastrointestinal tract.

As with the classic form of FAP, AFAP is due to mutations in the APC gene, which can be detected by a gene sequencing test.

In recent years, researchers have found that mutations in a gene called MUTYH may lead to the development of polyps resembling those seen in AFAP. The condition is known as MUTYH-associated polyposis (MAP).

MAP is passed down in families in an autosomal recessive manner, which means that a person needs to inherit two copies of a mutated MUTYH gene – one copy from each parent – to be predisposed to cancer.

In contrast, other types of hereditary colon cancer are autosomal dominant, meaning that it only takes one copy of a mutated gene, inherited from either the father or the mother, to have an increased risk for colorectal cancer.

Genetic Testing for Colorectal Cancer

A number of genetic tests are available to determine whether a person has a genetic change that predisposes him or her to colorectal cancer, including tests for MLH1, MSH2, APC, MSH6, PMS2, and MUTYH mutations. Genetic counselors and physicians can help you understand your individual cancer risk and which type of genetic tests, if any, may be useful for you or for other members of your family.

If you have a family history of colorectal cancer, we encourage you to speak to a genetic counselor – regardless of whether you would like to undergo genetic testing. We can help you understand and manage your cancer risk with or without the use of genetic tests.

Important Information for Those Who Have Had Colon Cancer Testing prior to November 2004

If you underwent genetic testing for colorectal cancer prior to November 2004, and the results were negative, you may wish to consider undergoing new tests that have become available since then.

For genetic testing of the MLH1, MSH2, and APC genes, a test called Southern blot is now available that looks for gene changes in which large portions of a gene may be missing or rearranged. There is a possibility that your previous genetic tests may not have detected such mutations, if they are present.

In addition, three genes that predispose to colorectal cancer – PMS2, MSH6, and MUTYH – have been identified in recent years, and new genetic tests are available to test for mutations in these genes.

We encourage you to call the Clinical Genetics Service at 212-434-5149 to make an appointment for further testing.

Colorectal Cancer Screening

A number of screening tests are available to find abnormal growths in the colon, called precancerous polyps, which potentially might cause colorectal cancer.

Learn more about these tests and Memorial Sloan Kettering’s guidelines for colorectal cancer screening.

Colorectal Cancer Risk Management

Each type of hereditary colorectal cancer calls for a different management strategy, but frequent monitoring is often the primary approach.

For some people at risk, surgical removal of the colon may be recommended to prevent the cancer from occurring. In some cases, doctors may recommend medications to reduce a person’s cancer risk while monitoring for signs of cancer.