Colorectal Cancer Genetic Testing

Colorectal Cancer Genetic Testing

Colorectal Cancer

How common is colorectal cancer?
About 5 of every 100 people (1 in 20) will develop colorectal cancer in their lifetime. Each year, colorectal cancer will strike approximately 150,000 people, and about 50,000 people will die of it, according to the National Cancer Institute. Colorectal cancer is the second most common cancer (after lung cancer) that affects both men and women.

What is colorectal cancer?
Colorectal cancer is the uncontrolled growth of cells in the colon and/or rectum. Cells that grow abnormally in the colon and rectum usually first develop into polyps, protruding growths that often look like mushrooms. These polyps form on the lining of the colon and rectum. Although almost all polyps are benign (meaning not cancerous), some can develop into cancer. Precancerous polyps are called adenomas. According to some studies, perhaps half of all people older than 60 have at least one adenoma.

What are the risk factors for colorectal cancer?
The strongest risk factor is age. More than 90 percent of people diagnosed with colorectal cancer are older than 50 (the average age is 65 – 70). Having a family history of colorectal cancer increases your risk. If you’ve ever had inflammatory bowel disease, such as Crohn’s disease or ulcerative colitis, that can put you at greater risk, too. Other risk factors include:

  • A poor diet (A good diet includes lots of fruit, vegetables and whole-grain foods, and very little saturated fats.)
  • Lack of exercise (inactivity)
  • Excessive alcohol use
  • Excessive weight (a body mass index greater than 25) or obesity

Is colorectal cancer inherited?
You can inherit a higher risk of getting colorectal cancer. About 10 – 15 percent of the people who have colon cancer have an inherited form of the disease. Of course, this means that most cases are not due to inherited risk factors.

How do I know if I have hereditary colorectal cancer?
Your health history and your family’s medical history will give your doctor clues as to whether or not you may have an inherited form of colorectal cancer. A genetic counselor will look for some of the following clues:

  • Several family members with colorectal cancer or related cancers, such as endometrial (uterine), ovarian, stomach, pancreatic, ureter, renal pelvis, brain, hepatobiliary tract or small-bowel cancer
  • Any of these cancers appearing before age 50
  • More than one cancer (such as endometrial and colon cancer) in the same person
  • Many colorectal adenomas (ranging from several polyps to thousands)
  • A large colorectal adenoma at a young age (younger than 45)
  • Unusual colorectal polyps, such as juvenile or hamartomatous (overgrowth of normal tissue) polyps

Different forms of inherited colorectal cancer may have the same features, so it is important to try to get as much detail about your family’s medical history as possible, especially medical records on relatives who have had cancer or colorectal polyps. This will allow your genetic counselor to figure out which, if any, of the hereditary forms of colorectal cancer could be in your family.

Hereditary Nonpolyposis Colorectal Cancer

What is hereditary nonpolyposis colorectal cancer?
The most common form of hereditary colorectal cancer is hereditary nonpolyposis colorectal cancer. (“Nonpolyposis” means there are only one or a few polyps on the colon and rectum rather than hundreds to thousands.) Hereditary nonpolyposis colorectal cancer accounts for about 1 percent to 3 percent of all cases of colorectal cancer.

Why should I learn if I have hereditary nonpolyposis colorectal cancer?
People in families with hereditary nonpolyposis colorectal cancer tend to develop colorectal cancer at a younger age — average age about 45 – 50 — compared to the overall average age of about 65 – 70 in the general population. Screening for colorectal cancer in these families usually starts at age 25. People with hereditary nonpolyposis colorectal cancer tend to develop polyps (and therefore cancer) more quickly than those who do not have an inherited form of the disease. If hereditary nonpolyposis colorectal cancer runs in your family, you need to get colorectal screenings more often. The more often you are screened, the more likely it is that your doctor will detect any polyps (and cancer) that have developed.

People with hereditary nonpolyposis colorectal cancer are at risk of cancers other than colorectal cancer, and often at even earlier ages. The second most common cancer in individuals with hereditary nonpolyposis colorectal cancer is endometrial (uterine) cancer, with an average age of onset about 50. Knowing whether a family has hereditary nonpolyposis colorectal cancer can help to determine what screening should be done.

What genes are involved in hereditary nonpolyposis colorectal cancer?
The genes that cause hereditary nonpolyposis colorectal cancer are called “mismatch repair” genes, or MMR genes for short. MMR genes make proteins that are responsible for correcting mistakes in the DNA when a cell divides into two. If these genes don’t work, each generation of cells will make more errors in the DNA sequence. Eventually, these cells could start to grow out of control and become a tumor. The two most common mismatch repair genes — MLH1 and MSH2 — account for almost 90% of cases. Other MMR genes associated with hereditary nonpolyposis colorectal cancer include MSH6 and PMS2. MSH6 is found in almost 10% of families with hereditary nonpolyposis colorectal cancer, while PMS2 is less common. There are other MMR genes, but their connection to hereditary nonpolyposis colorectal cancer is not as clear.

What are the risks associated with having these altered genes?

  Risk Of Colorectal Cancer Before Age 85
Risk Of Endometrial Cancer Before Age 85
In Women With 2 normal MLH1 and MSH2 genes 5% to 6% 2% to 3% With an altered MLH1 or MSH2 gene 60% to 85% 30% to 60%   In Men With 2 normal MLH1 and MSH2 genes 5% to 6% does not apply With an altered MLH1 or MSH2 gene 60% to 85% does not apply

Should You Be Tested?

How can I find out if I have hereditary nonpolyposis colorectal cancer?
Hereditary nonpolyposis colorectal cancer can be difficult to diagnose. If you or your family is concerned, talk to a specialist who is familiar with all the different features of hereditary nonpolyposis colorectal cancer and the complexities of testing.

What does my family’s medical history show?
Before you are tested, your doctor or genetic counselor will assess your risk of hereditary nonpolyposis colorectal cancer by learning about your health history and that of your family. Your doctor or genetic counselor may suspect hereditary nonpolyposis colorectal cancer if you have any one of the following:

  • Three relatives with colon cancer, in which one person is a first-degree relative of the other two (for example, a father and two children) AND colon cancer is present in at least two successive generations AND at least one case of colon cancer was diagnosed before age 50
  • Two cases of related cancer in your history (for example, colorectal, endometrial, small intestine, ureter, renal pelvis)
  • Colorectal cancer in your history AND a first-degree relative with a related cancer (diagnosed before age 45) or colonic adenoma (diagnosed before age 40)
  • Colorectal or endometrial cancer diagnosed before age 45
  • Right-sided colon cancer diagnosed before age 45
  • One or more adenomas diagnosed before age 40

What types of screening tests exist?
A direct test for changes in the sequence of your genes may not be the first test recommended for you or your family. Instead, your doctor may suggest one or more preliminary tests that look for other changes typical of people with hereditary nonpolyposis colorectal cancer. Tests include:

Microsatellite-Instability (MSI) Testing
Part of your DNA is made of short sequences that repeat over and over again. These regions are called microsatellites. When a mismatch-repair (MMR) gene is mutated, the microsatellite sequences become “unstable,” meaning that these sequences of DNA keep changing sizes as the cells divide. Microsatellite-instability testing detects this instability. An unstable region could mean that one or more of your MMR genes is mutated, which may mean that you have hereditary nonpolyposis colorectal cancer.

Tumors with microsatellite instability are not always caused by an alteration in a gene involved in hereditary nonpolyposis colorectal cancer and not all related tumors will have microsatellite instability. However, microsatellite-instability testing is a good way to determine which people may be at higher risk of having hereditary nonpolyposis colorectal cancer.

MSI testing is done by comparing tumor tissue removed during surgery to normal tissue (not on a blood sample, as with other genetic tests).

Immunohistochemistry Testing
Immunohistochemistry (IHC) testing is performed on tissue samples from a colorectal tumor. IHC testing detects the presence of proteins made from the mismatch-repair genes — most commonly MLH1, MSH2 and MSH6. If the test indicates that one of these proteins is missing or levels of protein are low, you may have hereditary nonpolyposis colorectal cancer.

In general, MSI testing points out more people who have hereditary nonpolyposis colorectal cancer than IHC testing does. Because IHC testing also is performed on tumor tissue, the test is sometimes done at the same time as MSI testing. Or it can be done when direct gene testing does not reveal a mutation in the MLH1 or MSH2 genes. In this case, IHC testing can help to figure out if one of these genes is involved, even if the direct genetic test is negative. If testing shows that hereditary nonpolyposis colorectal cancer may be in your family, your next step may be to get direct genetic testing for the genes involved.

What is direct genetic testing?
Direct genetic testing refers to testing for alterations in the most common genes involved in hereditary nonpolyposis colorectal cancer. Clinical testing is now available to look at the DNA sequence in the three most common hereditary nonpolyposis colorectal cancer genes: MLH1, MSH2 and MSH6

At least 20% of mutations in MSH2 and 5% of mutations in MLH1 are large deletions or genetic rearrangements that are not detected by DNA sequence analysis. These deletions can be tested by other DNA testing methods.

Genetic testing usually is done when hereditary nonpolyposis colorectal cancer already has been established in a family. Typically, a person who has had cancer is the first family member to undergo this type of testing. Finding a gene alteration means that other family members who have not been diagnosed with cancer can be tested for this same alteration to determine their risk.

Should I have direct genetic testing
Not necessarily. Your genetic counselor may recommend testing a relative first, especially if your relative has had any of these issues:

  • Colorectal or endometrial cancer diagnosed at the youngest age out of all your relatives
  • More than one primary colorectal cancer
  • One or more adenomas diagnosed at an early age (before age 45)

Because of the difficulty in interpreting hereditary nonpolyposis colorectal cancer genetic test results, it is ideal to test a relative with the above history first. In general, it is NOT recommended that the first person in the family to be tested is someone without a personal history of adenomas or cancer. Note: Because of limitations of the test, only about 50 percent to 60 percent of people with a strong family history of hereditary nonpolyposis colorectal cancer have a positive result on tests for mutations in mismatch-repair genes. Unfortunately, this means that up to half the families/people with this type of cancer have a negative test result.

What if a family member tests positive for a mutation?
In this case, you can be tested for the same mutation that was found in your relative. If you are tested and found to have the same mutation, you are at increased risk of colorectal cancer and possibly other cancers.

If your result is negative, you do not have the increased risk of cancer that your relatives with the altered gene do. You can, however, still develop cancer (most cancers are not hereditary), and you will still need to be monitored based on your age and personal health history. But you do not have a very high risk of colorectal cancer (and of endometrial cancer, if you are female). Because the mutation does not skip generations, you cannot pass the altered gene on to your children.

There are certain exceptions to this. For instance, if you have a strong family history of cancer on both sides of your family (your mom’s side and your dad’s side), it is possible that both sides have a gene alteration. Although you may test negative for the gene mutation from one side of the family, you may still be at increased risk from the other side. Your genetic counselor can review this with you in more detail.

Understanding Test Results And Options

How Do I Make Sense Of The Results?

The results of a genetic test are not always black and white. Even for a person who has survived cancer, testing may not give a clear answer. There are three possible test results:

A positive test result shows that you have a mutation in the MLH1, MSH2 or MSH6 gene. This means you have an increased risk of cancer. The test, however, cannot tell you if or when you will develop cancer (or a second cancer if you already have had one or have one now). Although the risk is high, some people with these mutated genes never develop cancer.

At this time, most experts agree that intensive cancer screening should start at a young age for people with an MLH1, MSH2 or MSH6 mutation. People with mutations in MSH6 appear to have a lower risk of cancer as compared to people with mutations in the MLH1 or MSH2 genes.

You may be the first person in your family to undergo testing for hereditary nonpolyposis colorectal cancer. If you have a strong family history of hereditary nonpolyposis colorectal cancer and have had cancer but your test result is negative, it could mean one of the following:

  • Your cancer was caused by a mutation in the genes tested, but because of the limitations of the tests, the mutation was not detected (a false-negative result).
  • Your cancer was caused by a different mutated gene that was not tested. The tests do not look for every possible gene associated with hereditary nonpolyposis colorectal cancer. A different hereditary colorectal cancer (and therefore a different gene) may be responsible for your cancer or your family member’s cancer.
  • Your family does not have an inherited form of colorectal cancer.

Your genetic counselor may recommend immunohistochemistry testing, which may show that an undetected mutation in either the MLH1 or the MSH2 gene is responsible for hereditary nonpolyposis colorectal cancer in your family.

Please note that if your doctor has not established that hereditary nonpolyposis colorectal cancer may be responsible for your or your family’s history, or that you are not the appropriate person to be tested, genetic testing is usually not recommended. If genetic testing is done in these cases, your genetic counselor or doctor should be able to discuss what a negative test result means for you and your family.

A variant result is a “maybe” answer. In some cases, the lab will eventually decide that the alteration is important and you have an increased risk of cancer. In other cases, the lab may decide that the variant probably won’t increase your risk of cancer. At the time you get your test result, the lab may not know the right answer. Your genetic counselor or doctor will help you sort through what a variant result means for you and your family.

Personal Questions

Why would I want to know if I have an altered gene?
Knowing that you have an altered gene could:

  • Help you to figure out if you are at increased risk of developing colorectal and other types of cancer
  • Help you to make decisions about preventive surgery or medications
  • Help other family members to understand their risk of cancer
  • Help to explain why you or other family members developed cancer
  • Help you to decide when you need to start screening examinations for cancer
  • Help you to make decisions about childbearing
  • Motivate you or your family to get screening tests and go to the doctor.

Why would I not want to know if I have an altered gene?
Finding out you have an altered gene could:

  • Make you anxious or worried
  • Make you feel pressured to make decisions about preventive surgery
  • Make you feel guilty about the possibility that you could pass (or have passed) the gene on to your children
  • Make you less likely to go to the doctor or receive screenings because of the fear of what may be found
  • Give your family information that they do not want, causing them to resent you
  • Make it harder for you to get or keep insurance

How do most people react to a positive result?
For some people, finding out about a hereditary nonpolyposis colorectal cancer gene mutation can be devastating emotionally. Others feel a sense of relief in knowing what they suspected to be true all along or at finding out a reason for the cancer.

Some people choose not to be tested because they are concerned about their reactions. If you are having a hard time coping with your results, ask your genetic counselor about resources. In some cases, your doctor may refer you to a therapist or mental health professional.

How do most people react to a negative result?
If you or your family has a diagnosis of hereditary nonpolyposis colorectal cancer, a negative result can be frustrating. This means that everybody who is closely related to a person with cancer in the family should be screened for cancer.

If someone in your family has a known gene mutation, it may be difficult to feel truly happy if your test result is negative. Some people in this situation feel guilty. These feelings are normal. Discuss them with your genetic counselor, who can provide support. If these feelings become overwhelming, it may be useful to speak with a mental health professional.

How do most people react to a variant result?
Variant results can be the most frustrating to receive. You may find it difficult to deal with the uncertainty if you have an unfamiliar mutation or if the laboratory can provide little information. Unfortunately, variant results can be common when testing the genes involved in hereditary nonpolyposis colorectal cancer.

Over time, laboratories reinterpret many variant results as negative results. However, in some cases, variant results are deemed positive. In either case, the laboratory will contact your genetic counselor as soon as it is confident about the result. This may take months or years. (The actual test result comes back in the time stated, but the interpretation of the result may change over time as more information is learned about the particular variant.) In the meantime, you may be in limbo about what this means for you and your family. Genetic counselors understand that living with uncertainty after going through the process of genetic testing can be emotionally draining. If you feel that you are not coping well, ask your genetic counselor to help you find a mental-health professional.

How will my results affect my family members?
Genetic testing is a family affair. Your family history often determines whether you should have a genetic test. It is hard to get background information without being open with your family. You should discuss genetic testing as a family, so you will know how other family members feel about your search for this information and about genetic testing in general.

Should I share my results with my family?
You generally have no legal obligation to share genetic information that you learn through testing, but many doctors recommend telling other family members so they can benefit from the information. Your results may give them the opportunity to learn more about their risk of cancer.


What screenings should I have if I test positive?
For a person who has not had cancer but has tested positive, most experts agree on the following recommendations starting at age 25 (or 10 years before the youngest person in the family was diagnosed, whichever is earlier):

  • Colonoscopy every one to two years (every year beginning at age 40)

For women, starting at age 25 to 30:

  • A pelvic exam and Pap test (as a screening for cervical cancer) once a year. This should begin at age 18 or earlier if sexually active, and is recommended for all women.
  • A transvaginal ultrasound once a year to check the uterus and ovaries for cancer or precancerous conditions may be helpful, although this has not been proven effective at decreasing the rate of gynecological cancers.
  • Random endometrial biopsy (taking a small amount of tissue from the uterine lining to check for the presence of cancer cells) once a year. Often, this test is done about six months after an annual transvaginal ultrasound, so every six months you have some type of test to look for the presence of uterine cancer. Again, this may be helpful, but has not been proven effective the way colon cancer screening has.

Other possible tests depend on your personal or family history and may include:

  • For gastrointestinal cancers: An upper endoscopy once a year to look at parts of the upper gastrointestinal tract, such as the stomach and duodenum. This may be effective in preventing cancer, but has not been proven. Liver-function tests with abdominal ultrasound or some other type of imaging once a year is sometimes suggested, but is not proven to prevent cancer.
  • For urological cancers: A urology visit once a year that includes urinalysis/cytology, cystoscopy and ultrasound to check for problems with kidney and ureter function could be considered.
  • For skin cancer: A skin exam once a year may be considered.
  • For brain cancer: Periodic brain magnetic resonance imaging may be considered, but there are no trials to prove it is effective and there are no clinical guidelines about this type of screening.

How effective is screening?
Colonoscopy is a good screening tool. Sigmoidoscopy does not look at the whole colon, and is not a good screening tool for hereditary nonpolyposis colorectal cancer. Most doctors would not recommend removing a healthy colon to prevent cancer. Even for a person who has had cancer, screening can be very effective without considering preventative surgery. However, this issue should be discussed fully with your doctor so that you know the risks, benefits and limitations of colectomy (removal of the colon).

Screening for uterine and ovarian cancer, however, has not been proven to be effective in finding cancer at an early stage. Therefore, most experts recommend that women who test positive for a hereditary nonpolyposis colorectal cancer gene mutation consider removing the uterus and ovaries (hysterectomy with oophorectomy) at an age when they are not considering having (more) children, usually at about age 40.

None of the other screening tests mentioned above (endoscopy, abdominal ultrasound, brain MRI) have been proven effective in patients with hereditary nonpolyposis colorectal cancer.

What screenings should I have if I test negative?
If you test negative for a mutation known to be in your family, your risk of cancer is probably the same as that of the average person. You should still be monitored for cancer, but not as often or as early as someone who tests positive for a mutation. Colorectal cancer screening for people in the general population should begin at age 50. These screenings generally include:

  • Yearly fecal occult blood test and flexible sigmoidoscopy every five years
  • Colonoscopy every 10 years
  • Double-contrast barium enema every five years

For specifics, see the latest screening recommendations from the American Cancer Society.

Women without genetic mutations usually are not screened for uterine cancer. Part of your routine gynecological care includes a yearly pelvic exam with a Pap smear (to check for cervical cancer) starting at age 18, or earlier if you are sexually active. Your screening recommendations may be different:

  • If there are risk factors for cancer or precancerous conditions in your personal or family medical history
  • If you have a family history that could indicate a different hereditary cancer
  • If you have a family history of cancer on the other side of the family (the side without the known hereditary nonpolyposis colorectal cancer gene mutation)

If you test negative and no mutation has previously been found in your family, your screening recommendations may range anywhere from that of an average person to that of a person with hereditary nonpolyposis colorectal cancer. People who have already had cancer need to be followed more closely than those who have not. Your doctor can help you to figure out what kind of screening is appropriate.

What screenings should I have if I receive a variant result?
If you have gotten a “maybe” answer, the screening recommendations for you depend on your history, your family history and how likely it is that hereditary nonpolyposis colorectal cancer is present in your family. In this case, your doctor can help you to make a plan for screening and prevention.

In general, other family members are not tested for variant results, unless the laboratory is trying to do research about them and wants to collect more information. In this case, other family members who have had cancer may be tested. Keep in mind that this may not give your family more information about what your variant result means.

Test Details

Who does the test?
Most genetic counselors will help you find some appropriate labs, based on costs and benefits.

What is the cost of the test?
Costs vary from lab to lab:

  • Microsatellite-instability testing usually costs about $300 to $400.
  • Microsatellite instability testing with immunohistochemistry testing costs about $800.
  • Direct gene testing for MLH1 , MSH2 and MSH6 costs from $700 to $1,000 per gene, and might be slightly less for a panel of all three genes at once. Some labs perform all three genes in one panel, while others do MLH1 and MSH2 together with MSH6 as a separate test.

Because immunohistochemistry testing is sometimes done with other tests, there may be an additional charge.

How long does it take to get results?
It takes approximately one to two months. But it may take several weeks to obtain and prepare tumor samples for microsatellite-instability testing or immunohistochemistry testing.

Does insurance pay for the test?
Most health insurance companies pay for “diagnostic testing,” which means the test is being done to confirm a diagnosis in a person who already has symptoms. However, there are many different plans, and you should check whether diagnostic genetic testing is a covered service before having the test performed.

Many insurance companies will not pay for a predictive test (a test for a person who does not have symptoms), especially if there is nothing that can be done to prevent the condition (no change in patient management). In the case of hereditary colorectal cancer, there is a change in management for a person known to have the genetic changes. It is important to check with your insurance company before testing to find out what your coverage level is for the different types of tests.

Can my insurance company raise my rates or drop my coverage if I test positive?
In 2008, the U.S. government passed a law called GINA (Genetic Information Nondiscrimination Act). This law prohibits discrimination by health insurers and employers on the basis of genetic information. Learn more here.

Also, this may depend on whether or not you have group insurance or are self-employed. Both federal and state laws usually cover people with group insurance, whereas state laws cover only people who are self-employed. Also, the Federal Health Insurance Portability and Accountability Act prohibits health-insurance discrimination based on any “health-status-related factor” (including genetic information) by group health plans. Unfortunately, this act does not apply to those who are self-employed.

Some states have enacted legislation to cover these gaps. Most states prohibit health-insurance companies from using genetic information to deny coverage. Other states require specific justification for the use of genetic information in denying a claim.

These laws generally do not cover life insurance, long-term care or disability insurance. People whose employers provide life and disability coverage are unlikely to have this insurance affected by a genetic test result.

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