Genetic Risk Factors for Colorectal Cancer

Like many cancers, colorectal cancer (CRC) can develop due to certain genetic risk factors. Genetic risk factors are certain gene changes that are passed down through your family. These inherited gene changes – also known as genetic mutations – account for about 5 percent of colorectal cancer cases.¹

If you have a family history of CRC, it is important to understand these genetic risk factors and how they can affect you.

Genetic mutations linked to CRC

Several genetic mutations can make someone more likely to develop colorectal cancer.¹

Lynch syndrome

The most common genetic cause of colorectal cancer is Lynch syndrome. Lynch syndrome is also known as hereditary nonpolyposis colorectal cancer (HNPCC). About 2 to 4 percent of all people with CRC have Lynch syndrome.^1,2

People with Lynch syndrome have a higher risk of developing CRC and other types of cancer, such as endometrial and breast cancer. They are also at a higher risk of developing CRC at a younger age than the general population.^1,2

Lynch syndrome happens because of mutations in the genes that help repair DNA. The affected genes are called mismatch repair genes. They include:^1,2

• MLH1
• MSH2
• MSH6
• PMS2
• EPCAM

Normally, these genes fix mistakes in the DNA that occur when cells divide. But if the genes are not working properly, DNA mistakes build up. This can lead to cancer.^1,2

Familial adenomatous polyposis (FAP)

Familial adenomatous polyposis (FAP) is another inherited condition that increases the risk of CRC. FAP occurs in about 1 percent of CRC cases.1,2

People with FAP develop hundreds or even thousands of polyps in their colon and rectum, starting at a young age (usually 10 to 12). If these polyps are not removed, they will almost always turn into cancer by the time a person is in their 40s.1,2

FAP is caused by a mutation in the APC gene, which normally helps control how cells grow. When this gene is mutated, polyps form in large numbers.^1,2

Attenuated FAP (AFAP)

Attenuated FAP (AFAP) is a milder form of FAP. People with AFAP develop fewer polyps, often between 10 and 100. In this subtype, CRC typically occurs at a later age – in a person’s 40s and 50s. The risk of colorectal cancer is still high, but it is not as extreme as in classic FAP. AFAP is also linked to mutations in the APC gene.^1,2

Gardner syndrome

Gardner syndrome is a type of FAP in which polyps in the colon and rectum come with extra complications. People with Gardner syndrome may develop noncancerous growths in other areas of the body, such as the skin, bones, and soft tissue.^1,2

Turcot syndrome

Turcot syndrome is linked with mutations in the APC or MLH1 genes. People with Turcot syndrome may develop multiple polyps in the colon, increasing their risk of CRC. They also face a higher risk of brain tumors like medulloblastomas or gliomas.^1,2

Genetic mutations linked to metastatic CRC

In some cases, colorectal cancer can spread to other parts of the body. This is called metastatic CRC. Certain genetic mutations make this more likely to happen.³

BRAF V600E

One key mutation linked to metastatic colorectal cancer is called BRAF V600E. This mutation occurs in the BRAF gene, which helps regulate cell growth. When this gene is mutated, cells grow uncontrollably. This leads to cancer that is much more aggressive and more likely to spread to other areas of the body.³

The BRAF V600E mutation occurs in roughly 8 to 12 percent of people who have genetic mutations linked to metastatic CRC. The mutation is more likely to affect:³

• Women
• People over the age of 60
• People with right-sided colon cancer
• White people

If someone is diagnosed with metastatic CRC, doctors may test them for the BRAF V600E mutation. Knowing whether the mutation is present can help guide treatment decisions.³

Rare genetic mutations that may lead to CRC

While they are less common, certain rare inherited conditions can also be risk factors for colorectal cancer.^1,2

Peutz-Jeghers syndrome (PJS)

Peutz-Jeghers syndrome (PJS) is a rare genetic condition that leads to the development of polyps in the digestive tract and dark spots on the skin. Most commonly, these spots show up around the mouth, hands, and feet.^1,2

Mutations in the STK11 gene cause PJS. This gene helps regulate cell growth. People with PJS have a higher risk of developing CRC, along with other types of cancer such as breast, ovarian, and pancreatic cancer.^1,2

Serrated polyposis syndrome (SPS)

Serrated polyposis syndrome (SPS) is a rare condition where multiple serrated polyps – growths that look saw-toothed or serrated under a microscope – develop throughout the colon. These polyps are generally benign (noncancerous), but they can turn into cancer over time. People with SPS have a greater risk of developing CRC.⁴

MUTYH-associated polyposis (MAP)

MUTYH-associated polyposis (MAP) is another rare condition that increases the risk of CRC. It is caused by mutations in the MUTYH gene, which helps repair DNA damage.^1,2

Unlike FAP, MAP usually leads to fewer polyps in the colon and rectum. But the risk of cancer is still elevated. MAP is inherited in a recessive pattern. This means that a person must inherit 2 copies of the mutated gene (1 from each parent) in order to develop the condition. It also raises the risk of other cancers, such as breast, bladder, and thyroid cancer.^1,2

Cystic fibrosis (CF)

People with cystic fibrosis (CF) also have a higher risk of developing gastrointestinal cancers, including CRC. This is especially true for those who have had a lung transplant. People with CF now live longer due to treatment advancements. They should be monitored closely for colorectal cancer.¹

The importance of genetic testing and screening

If you have a family history of colorectal cancer or any genetic condition mentioned above, genetic testing can provide valuable information. Genetic testing is done through a blood sample. Knowing whether you have a genetic risk can help you and your doctors make decisions about screenings and preventive treatments.⁵

Regular colonoscopies can catch polyps early, before they turn into cancer. Other screenings may be recommended as well, depending on your family history. Talk to your doctor about which genetic screening tests are right for you.⁵