Introduction to Colorectal Cancer

Colorectal cancer is the third most common cancer seen in the United States, occurring equally in men and women. It is estimated to account for 11% of all new cancer cases, with an average age of diagnosis of 60 to 65 years. The lifetime colorectal cancer risk for the general population is 6%. Colorectal cancers have a high cure rate if they are found early, but unfortunately, most colorectal tumors do not cause symptoms until they have grown to a large size. For this reason, they are estimated to account for approximately 10% of all cancer deaths in the United States. In other words, the average American man or woman has a 2.6% risk of dying from colon cancer.

What is Colorectal Cancer

Colorectal cancer is cancer of the colon or rectum. The colon and rectum are parts of the digestive system that make up the large intestine. The large intestine absorbs water and nutrients from food after the food is digested by the stomach and small intestine. Anything left after this absorption process is then excreted from the body. Cancer can develop in any section of the large intestine and may have different symptoms depending upon where the cancer is located. Virtually all colorectal cancers begin as benign polyps (intestinal lining growths) which become cancerous. Because of this potential for cancer, it is generally recommended that polyps be removed when they are discovered.

Factors Contributing to Colorectal Cancer Risk

Several genetic and non-genetic factors are thought to contribute to the risk for colorectal cancer.

Non-genetic factors include:

  • Age: Approximately 90% of all colorectal cancers are found in people over the age of 50 years.

  • Recurrent intestinal polyps: A polyp is a mass of tissue that protrudes up from the lining of the intestine. Most polyps are harmless but some do become cancerous. This is important because it has been determined that an individual with recurrent intestinal polyps has a lifetime risk of 15 to 20% to develop colorectal cancer.

  • Inflammatory Bowel Disease (IBD): IBD is a disorder in which the colon is inflamed over a long period of time, and this inflammation can result in ulcers, or holes, in the lining of the bowel. This damage to the lining of the bowel can lead to cancer. An individual with IBD is estimated to have a lifetime colorectal cancer risk of 15 to 40%. This disease may, in fact, have some genetic basis; mutations in many different genes may lead to a susceptibility for IBD, which could then develop after exposure to an environmental trigger. More research needs to be done to clarify this genetic link. Two subtypes of IBD are Ulcerative Colitis and Crohn’s Disease.

  • Diet: A diet high in red meat and fat and low in fiber may increase the risk for colorectal cancer. These dietary risk factors are controversial.

  • Exercise: Individuals who do not exercise may have a higher risk for colorectal cancer.

  • Other: Smoking and alcohol consumption may somewhat increase the risk of developing colorectal cancer.

Factors that might provide some protection against the development of colorectal cancer are physical activity, aspirin and NSAIDs (Non-Steroidal Anti-Inflammatory Drugs), hormone (replacement) therapy, and a diet high in fruits, vegetables, calcium, folate, and fiber.

Sixty five to 85% of all colorectal cancers have no genetic cause (or are sporadic). However, several genetic risk factors are known to correlate with colorectal cancer, and about 10% of all colorectal cancers are caused by inherited mutations. Some of the hereditary colorectal cancers are: Familial Adenomatous Polyposis (FAP), Hereditary Non-Polyposis Colorectal Cancer (HNPCC), Muir-Torre syndrome, Peutz-Jeghers syndrome, Juvenile Polyposis syndrome, PTEN Hamartoma Tumor syndrome, and BLM gene heterozygotes. For a more in-depth discussion of these topics, see Hereditary Colorectal Cancers. For a more in-depth discussion of how the pathogenesis of all types of colorectal cancer cases, see Molecular Basis for Colorectal Cancer.

An estimated 10 to 30% of colorectal cancer cases appear to hereditary (familial) but no genetic causes have yet been determined for them. These cases may be due to high or low penetrance genes not yet discovered that are related to colorectal cancer.

Hereditary Colorectal Cancers

There are several genetic factors known to be associated with colorectal cancer. The following is a list and description of some inherited causes of colorectal cancer which are also associated with Ashkenazi Jewish ancestry:

  • Familial Adenomatous Polyposis (FAP): This syndrome is thought to account for approximately 1% of all colorectal cancers. An individual with FAP is estimated to have a lifetime colorectal cancer risk close to 100% without treatment.

    Most individuals with FAP develop polyps without symptoms, while others may have diarrhea, constipation, abdominal cramps, blood in stool, or weight loss. The only known risk factor is family history.

    FAP is caused by mutations in the APC gene, located on chromosome 5. APC is a tumor suppressor gene, and its job is to control cell growth. When both copies of the APC gene are not working properly, cells can grow out of control, leading to cancer. FAP is inherited in an autosomal dominant manner, and therefore every child of an individual with FAP has a 50% chance of inheriting the mutation in FAP. The majority of patients with FAP have an affected parent.

    This disorder has a connection to Ashkenazi Jewish ancestry and the connection is discussed further in Ashkenazi Jews and Colorectal Cancer.

  • Hereditary Non-Polyposis Colorectal Cancer (HNPCC): This is the most common of the inherited colorectal cancers and is though to account for 2 to 5% of all colorectal cancer cases. Hereditary Non-Polyposis Colorectal Cancer syndrome (HNPCC) is a colorectal cancer syndrome that occurs at any earlier age than is typically seen in the general population. In other words, it occurs at 40 to 45 years versus 60 to 65 years.

    HNPCC predominately occurs on the right side of the colon (versus throughout the entire colon as is seen in FAP or mainly on the left side of the colon as is seen in sporadic cancer). This is important for surveillance because polyps on the right side of the colon are beyond the reach of a flexible sigmoidoscopy examination. HNPCC also predisposes an individual to tumors outside of the colon such as cancer of the uterus (endometrium), stomach, ovaries, urinary tract, biliary tract, brain, and small intestine.

    HNPCC is caused by mutations that can occur in a number of different mismatch repair genes. What is mismatch repair? Every time a cell makes a copy of itself, it has to copy its DNA. Whenever DNA is copied, mistakes can be made. Mismatch repair is the process by which the cell fixes mistakes in order to maintain the accuracy of DNA replication. This process is similar to a “spellchecker” in a word processing program. Ordinarily, uncorrected mistakes occur very rarely. However, if any of the several proteins involved in mismatch repair are not functioning correctly, these uncorrected mistakes can occur more often. These errors accumulate and can interrupt effective gene functioning and can lead to cancer.

    Mutations causing HNPCC display autosomal dominant inheritance and therefore every child of an individual with HNPCC has a 50% chance of inheriting the mismatch repair gene mutation known to occur in the family. An individual with a HNPCC mutation is estimated to have a lifetime colorectal cancer risk of 70 to 80%.

    This disorder has a connection to Ashkenazi Jewish ancestry which is covered more extensively in Ashkenazi Jews and Colorectal Cancer.

  • BLM Gene Heterozygotes: The BLM gene is known to cause Bloom Syndrome when both copies of the gene are mutated. Two recent studies have suggested that a mutation in just one copy of the BLM gene may be sufficient to increase the risk of colorectal cancer. In one of the studies, carriers of one mutation in the BLM gene were up to three times more likely to have developed colorectal cancer. Further studies need to be done on this topic. Bloom Syndrome occurs at a higher incidence in the Ashkenazi Jewish population and is covered more extensively in the Bloom Syndrome section.

Surveillance for Colorectal Cancer

The American Cancer Society recommends the following surveillance techniques for individuals at an average risk of colorectal cancer beginning at the age of 50 years:

  • Yearly fecal occult blood test: This test looks for blood in the feces.

  • Yearly digital rectal examination: This involves the insertion of a gloved finger into the rectum to feel for polyps.

  • Flexible sigmoidoscopy every 5 years: This is a procedure in which the physician looks at only the lower segment of the colon through a flexible lighted instrument.

  • Colonoscopy every 5 to 10 years: This is a procedure in which the physician looks at the entire colon through a flexible lighted instrument. This is the “gold standard” of all screening techniques.

  • Barium enema X-ray every 5 to 10 years: This is an X-ray of the bowel after receiving an enema with a substance that increases the visibility of the colon and rectum on X-ray.

If polyps are found during surveillance, they are removed and analyzed since they may possibly become cancerous or may already be cancerous. If they are benign, surveillance continues as described above. If they are cancerous, then treatment may occur as described in the section Management of Colorectal Cancer.

Genetic Testing for Familial Colorectal Cancers

Genetic testing for a predispositional disease has several technical and ethical issues associated with it. Ethical and emotional issues are discussed in depth in Non-Technical Aspects of Genetic Disease. Because of these many issues, the American Society of Cancer and Oncology (ASCO) has released a position statement about predispositional testing. In summary, predispositional testing should only be offered when:

  • There is a strong family history of cancer

  • The test can be adequately interpreted

  • Results will influence medical management of the patient or family member

  • Laboratories commit to validation of testing methodologies

In order for the test to be adequately interpreted, the ordering physician needs to be trained in predispositional genetic testing. It is important that genetic testing be done through a center that specializes in cancer genetic counseling.

However, there are several complicating factors that might occur. First, a mutation might not be found in any affected individuals of a family with a clinical diagnosis. Second, testing can be expensive and a family member may not be able to afford testing if they have no insurance. Third, there is the potential for discrimination, in terms of health insurance, employment, and life insurance. See Non-Technical Aspects of Genetic Testing for a more in-depth discussion. Fourth, genetic information cannot be unlearned once it has been discovered. It is important that this testing be handled with prior education of both the parent and child and results need to be carefully and clearly given. For this reason, it is important that genetic testing be done through a center that specializes in cancer genetic counseling.

Ashkenazi Jews and Colorectal Cancer

Coming soon!

Additional Information

Click here to see:
Technical information about colorectal cancer
Cancer and heredity basics
Introduction to breast cancer

Other Links:
National Cancer Institute
Colon Cancer Information from and the National Institute of Health present: What You Need To Know About™ Cancer of the Colon and Rectum

CDC Factsheets
Basic Colon Screening for Patients
More Colon Cancer Screening for Patients

Colon Cancer Alliance
Contains fact sheets, lists clinical trials and information about becoming involved with clinical trials, genetics, news, advocacy and legislative efforts, and information on support groups.

Colorectal Cancer Fact Sheet from the Human Genome Education Model Project – Georgetown University Medical Center