Hereditary Colorectal Cancer and Your Genetic Risk

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

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

What genetic conditions increase colorectal cancer risk?

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, 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 genetic risk of developing CRC and other types of cancer, such as endometrial and breast cancer. They're 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. These are called mismatch repair genes, and they include:^1,2

• MLH1
• MSH2
• MSH6
• PMS2
• EPCAM

These genes normally fix mistakes in the DNA that happen when cells divide. But when the genes aren't working properly, DNA mistakes build up. Over time, 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 aren't removed, they will almost always turn into cancer by the time a person reaches 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 this subtype develop fewer polyps, often between 10 and 100. CRC linked to AFAP typically shows up later, in a person’s 40s and 50s. The risk of colorectal cancer is still high, but it's 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 where 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

What genetic mutations are 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 normally helps regulate cell growth. When this gene is mutated, cells grow uncontrollably. This leads to a more aggressive cancer that's 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. This 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 genetic risk factors for colorectal cancer.^1,2

Peutz-Jeghers syndrome (PJS)

Peutz-Jeghers syndrome (PJS) is a rare genetic condition that causes polyps in the digestive tract and dark spots on the skin. These spots most commonly show up around the mouth, hands, and feet.^1,2

Mutations in the STK11 gene cause PJS. This gene normally 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, or 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 what's called a recessive pattern, meaning a person must inherit 2 copies of the mutated gene - 1 from each parent - 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, so they should be monitored closely for colorectal cancer.¹

Why does genetic testing and screening matter?

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 carry 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