The Genetics of Colon and Rectal Cancers

The majority of colorectal cancers are sporadic, meaning that a non-inherited gene mutation develops during a person’s lifetime that causes cancer to develop. These are called acquired genetic mutations. 

About 5% of all colorectal cancers develop from an inherited gene mutation passed down from at least one parent. Individuals with hereditary gene mutations related to colon cancer have a higher chance of receiving a diagnosis than the average person. They also tend to occur at an earlier age than non-inherited cases of colorectal cancer. 

Inherited Gene Mutations Related to Colorectal Cancer

Some mutations, called inherited mutations, are passed from generation to generation. These inherited mutations are present throughout a person’s life in nearly every cell of the body. Common genetic syndromes, which are disorders caused by one or more abnormalities in the genome, have been linked to colorectal cancer.

The most common genetic syndromes may include:

• Familial adenomatous polyposis (FAP) is caused by inherited changes in the APC gene, a tumor suppressor gene that helps keep cell growth in check. Changes in the APC gene can result in hundreds of polyps forming in the colon. FAP has 3 subtypes: attenuated FAP (AFAP), Turcot syndrome, and Gardner syndrome.
  
  Related Reading: What Causes Colon Polyps?
  
  
• Lynch syndrome (hereditary non-polyposis colon cancer, or HNPCC) is caused by changes in genes that help damaged DNA repair itself. Mutations of genes like MLH1, MSH2, MLH3, MSH6, PMS1, and PMS2 keep DNA errors from being fixed. This can affect growth-regulating genes, thus leading to the possible development of cancer. Mutations in MSH2 and MLH1 are the most common mutations that cause HNPCC.

Rare inherited syndromes linked to colon and rectal cancers and their associated genes include: 

• Peutz-Jeghers syndrome: caused by inherited changes in the tumor-suppressor gene STK11 (LKB1).
• MUTYH-associated polyposis: caused by mutations in the MUTYH gene, which plays a role in how the cell checks the accuracy of DNA when cells divide.
• Oligopolyposis (POLE, POLD1): a polyp count greater than anticipated in average-risk patients but falls short of the polyp count required for a FAP diagnosis.
• Cowden syndrome: part of a spectrum of conditions known collectively as PTEN hamartoma tumor syndromes. Approximately 85% of patients diagnosed with Cowden syndrome have an identifiable (PTEN) pathogenic variant.

Acquired Gene Mutations and Colorectal Cancer

There are also genes that, when mutated, can lead to colorectal cancer. Unlike inherited mutations that affect the entire body, acquired mutations only affect cells that come from the original mutated cell. These mutated cells then begin to multiply, resulting in cancer. Certain risk factors such as smoking, diet, and UV radiation from the sun may play a role in the development of these mutations, but overall, the reason behind what causes most of them is unclear at this time.