What Causes Colorectal Cancer?

Researchers have found several factors that can increase a person’s risk of colorectal cancer, but it’s not yet clear exactly how all of these factors might cause this cancer.

Gene changes that may lead to colorectal cancer

Cancer is caused by changes in the DNA inside our cells. DNA is the substance in our cells that makes up our genes, which control how our cells function. We usually look like our parents because they are the source of our DNA. But DNA affects more than just how we look.

Some genes help control when our cells grow, divide into new cells, and die:

• Certain genes that help cells grow, divide, and stay alive are called oncogenes.
• Genes that help keep cell division under control or instruct cells to die at the right time are called tumor suppressor genes.

Cancers can be caused by DNA mutations (changes) that turn on oncogenes or turn off tumor suppressor genes. This leads to cells growing out of control. Changes in many different genes are usually needed to cause colorectal cancer.

For more about how genes changes can lead to cancer, see Genes and Cancer.

Inherited (germline) gene mutations

Some DNA mutations can be passed on in families and are found in all of a person’s cells. These are called inherited mutations. A very small portion of colorectal cancers are caused by inherited gene mutations. Many of these DNA changes and their effects on the growth of cells are now known. For example:

• Familial adenomatous polyposis (FAP), attenuated FAP (AFAP), and Gardner syndrome are caused by inherited changes in the APC gene. The APC gene is a tumor suppressor gene; it normally helps keep cell growth in check. In people with inherited changes in the APC gene, this “brake” on cell growth is turned off, causing hundreds of polyps to form in the colon. Over time, cancer will nearly always develop in one or more of these polyps.
• Lynch syndrome (hereditary non-polyposis colon cancer, or HNPCC) is caused by changes in genes that normally help a cell repair damaged DNA. A mutation in one of the DNA repair genes like MLH1, MSH2, MSH6, PMS2, and EPCAM can allow DNA errors to go unfixed. These errors will sometimes affect growth-regulating genes, which may lead to the development of cancer.
• Peutz-Jeghers syndrome is caused by inherited changes in the STK11 (LKB1) gene, a tumor suppressor gene.
• MUTYH-associated polyposis (MAP) is caused by mutations in the MUTYH gene, which impacts how the cell “proofreads” or checks the DNA and fixes errors when cells divide.
• Cystic fibrosis (CF) is caused by inherited mutations in the CFTR gene. Exactly how changes in this gene increase colorectal cancer risk isn’t yet clear.

Special genetic tests can find gene mutations linked to these inherited conditions. If you have a family history of colorectal polyps or cancer or other symptoms linked to one of these conditions, you may want to ask your doctor about genetic counseling and genetic testing.

The American Cancer Society recommends discussing genetic testing with a qualified cancer genetics professional before any genetic testing is done. For more on this, see Understanding Genetic Testing for Cancer Risk and What Happens During Genetic Testing for Cancer Risk? 

Acquired (somatic) gene mutations

Most gene mutations that lead to cancer are acquiredorsomatic mutations. They happen during a person’s lifetime and are not passed on to their children. These DNA changes only affect cells that come from the original mutated cell.

In most cases of colorectal cancer, the DNA mutations that lead to cancer are acquired during a person’s life rather than having been inherited. Certain risk factors probably play a role in causing these acquired mutations, but so far it’s not known what causes most of them.

There doesn’t seem to be a single genetic pathway to colorectal cancer that’s the same in all cases. In many cases, the first mutation occurs in the APC gene. This leads to an increased growth of colorectal cells because of the loss of this “brake” on cell growth. Further mutations may then occur in other genes, which can lead the cells to grow and spread uncontrollably. Other genes that aren’t known yet are probably involved as well.