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  The Testing Process for HNPCC

By Miriam Komaromy, MD

Reviewed by Peggy Conrad, MS, CGC and Jonathan Terdiman, MD


If you think you may have inherited hereditary nonpolyposis colorectal cancer (HNPCC, also known as Lynch Syndrome) — a medical condition that increases your risk of developing colon cancer (as well as a number of other types of cancer) — you might ask your doctor for a genetic test thinking that it can immediately clarify your situation. Although this is a logical (and increasingly common) request, you need to understand that your doctor will only give you a genetic test under some very specific circumstances. First and foremost, your doctor will probably want to look at your family's medical history in order to assess your risk for HNPCC and determine whether you are a candidate for genetic testing.

Who Should Consider Testing?

Physicians and researchers regard a group of rules called the revised Amsterdam criteria as the gold standard for determining whether a family has the HNPCC syndrome. It's also the primary criteria for determining who should be offered genetic testing. You should be aware, however, that approximately fifty percent of families who meet these diagnostic criteria don't have any of the detectable mutations associated with HNPCC, just as there are a large number of families who do have detectable mutations but don't meet the revised Amsterdam criteria.


In a Nutshell: The Revised Amsterdam Criteria

The Amsterdam Criteria uses the 3-2-1 Rule to classify HNPCC families:

  • There have been three cases of either colon or rectal cancer or other HNPCC-associated cancers — endometrial, small intestine, urinary tract, or kidney (renal pelvis) — in the family
  • Spread over at least two generations
  • With one cancer patient having being diagnosed before age 50


Although there are no clear-cut guidelines about when testing is appropriate for families who do not meet the revised Amsterdam criteria, one rule of thumb is that genetic testing should be considered when a family meets any of the following conditions:

  • A family member has been diagnosed with colon cancer before age 40.
  • A family member has been diagnosed with colon cancer before age 50 and at least one additional family member has been diagnosed with colon cancer, rectal cancer, endometrial cancer, or another HNPCC-related cancer — ovarian, gastric, small intestine, pancreatic, hepatobiliary, urinary tract, kidney (renal pelvis) or brain.
  • Three or more family members have been diagnosed with colon, endometrial, or other HNPCC-related cancers-regardless of age.

Whether or not your family meets the revised Amsterdam criteria, genetic testing must begin with a family member who already has an HNPCC-associated cancer (whom doctors term an affected family member).

If the test turns up a mutation in an affected family member, other family members can then be tested for the same mutation. However, if doctors do not find a mutation in the affected family member, there's no point in testing other family members because the genetic cause of your family's cancers is not detectable with these tests.




Benefits of Genetic Testing

If genetic testing turns up a mutation in a member of your family who has been diagnosed with HNPCC, you now have some powerful information. Because you now know the genetic culprit for the cancer syndrome in your family, further testing can reveal which relatives have inherited the mutation (and will thus need intensive screening and surveillance to avoid colon cancer and other cancers) and which family members have not inherited the mutation (and can therefore follow general-population screening guidelines).




Limitations of Genetic Testing

Although genetic testing will turn up a characteristic mutation in some families who meet the revised Amsterdam Criteria, or have family medical histories suggestive of HNPCC, in the majority of these families no mutation will be found. The reasons for this are several:

  • The available tests are not perfect, which means a test could overlook a mutation in a gene it has been designed to study.
  • Commercially available tests do not exist for all of the genes that are known to cause HNPCC.
  • It's likely that scientists have not yet discovered several of the genes, and related mutations, that are responsible for HNPCC.




Which Genes Will Be Examined?

Genetics labs that offer HNPCC testing only examine these two genes: MLH1 and MSH2.
Although scientist have identified five genes — all of which function as DNA mismatch repair genes — that when mutated cause HNPCC, just two of them account for the vast majority of detectable mutations. Thus, genetics labs that offer HNPCC testing only examine these two genes: MLH1 and MSH2. This means that if your family has a mutation in a different gene, standard commercial tests will not reveal your risk for HNPCC. (Testing for mutations in the other three genes is generally only available when a specific HNPCC research project is underway.)




Interpreting Your Test Results

Your test results can come back positive, indeterminate, or negative. Your genetic counselor or doctor should explain your test results and help you understand what each of these results means for you and your family.

Positive. If you test positive for one of the genetic mutations associated with HNPCC, it means that the lab found a harmful change in one of the genes that scientists know causes HNPCC. In other words, you've inherited the genetic abnormality that causes HNPCC and with it, the accompanying high risk for developing HNPCC-associated cancers.

Indeterminate. If your test result is indeterminate, this means the lab found a genetic change (sometimes called a genetic variant), but not one that has been clearly shown to predispose an individual to HNPCC. If you get this kind of test result, it may be helpful to test other affected family members to determine whether the mutation appears to be associated with the disease in your family.

An indeterminate test result should be interpreted as inconclusive — not as proof that you do not have HNPCC.
It's important to understand that if you've received an indeterminate result on a genetic test, all members of your family should still consider themselves to be at high risk for HNPCC-associated cancers, since genetic testing cannot help you sort out individual risk among your relatives.

Negative. If your test results are negative, this means the lab found no genetic change. This can either be good news or uninformative. The reason? If there is a known mutation in an affected member of your family — that is, if a genetic mutation has already been identified as the culprit for your family's cancer-then your negative result is reassuring: you know that you did not inherit the mutation and thus are at no greater risk for cancer than are members of the population at large.

If, however, you are the first affected family member to be tested and your result is negative, you must simply consider it uninformative — that is, the test didn't unearth a genetic basis for your family's cancer. In this situation experts don't usually consider further testing of unaffected family members to be useful and thus don't recommend it.

Note, however, that in this case a negative genetic test result does not mean that your family is at low risk for cancer; it only means that the available tests have not determined the genetic cause for your family's clinically diagnosed HNPCC. If your family has a history suggestive of HNPCC, family members should still consider themselves to be at high risk for HNPCC-associated cancers since genetic testing cannot rule out those who are not at risk.



Additional Genetic Tests

Some genetic professionals recommend testing begin with molecular tests on tumor samples.

Some genetics professionals recommend that rather than starting with a blood test, HNPCC testing begin with molecular tests on tumor samples from affected family members. The most common of these is called microsatellite instability (MSI) testing. If these MSI tests are abnormal, a patient is more likely to have HNPCC and the patient can go on to have blood testing to look for a mutation in an HNPCC-related gene.

To understand MSI testing, you need to know that microsatellites are repeated sequences of DNA. Every individual has microsatellites; they are both common and normal. However, in cells with mismatch repair gene mutations — the kind of mutations that cause HNPCC — some of these sequences accumulate errors and become longer or shorter. The appearance of abnormally long or short microsatellites in an individual's DNA is referred to as microsatellite instability.

Because tumor samples are routinely collected during cancer surgery, sometimes MSI testing can be performed on stored tumor samples even after a cancer patient has died. This can be useful if no living family members have cancer, since testing must begin with a tumor sample from a family member who has (or had) an HNPCC-associated cancer.


Aaltonen, L. A., R. Salovaara, et al. (1998). Incidence of hereditary nonpolyposis colorectal cancer and the feasibility of molecular screening for the disease. New England Journal of Medicine 338: 1481-1487.

Petersen, G., J. Brensinger, et al. (1999). Genetic testing and counseling for hereditary forms of colorectal cancer. Cancer 86: 1720-30.

Syngal, S., E. Fox, et al. (1999). Interpretation of genetic test results for hereditary nonpolyposis colorectal cancer: implications for clinical predisposition testing. JAMA 282: 247-253.

Syngal, S. (2000). Hereditary nonpolyposis colorectal cancer: A call for attention. J Clin Oncology 18(11): 2189-91.

Terdiman, J., P. Conrad, et al. (1999). Genetic testing in hereditary colorectal cancer: indications and procedures. Am J Gastroenterology 94(9): 2344-2356.


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