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Hereditary Nonpolyposis Colorectal Cancer [Lynch Syndrome] and Microsatellite Instability [MSI Test]

A high microsatellite instability (MSI-H) can be used as a molecular genetic indication of the presence of the hereditary nonpolyposis colorectal cancer (HNPCC). The MSI test is the prerequisite for the targeted search of pathological mutations.

What is required? Scientific background Therapeutic consequences

What is required?

Non-tumorous tissue (e.g. a 2ml-EDTA-Haemogram-Monovette or paraffin-embedded normal tissue), the paraffin block containing the colorectal tumor tissue (we accept also six 7 µm sections of the tumor tissue mounted on slides) together with the necessary documents (see below) should be sent to the following address:

Oncoscreen GmbH
Postfach 10 08 64
07708 Jena
Germany

Please enclose:

Please do not forget to print the name and telephone number of the doctor treating the patient, for the purpose of our reply.

The specimen can be sent in a padded envelope without the need for cooling; however, it needs to arrive at the laboratory not later than four days after blood has been taken (no time limit if only paraffin embedded tissue is sent). Within Germany, we guarantee a reply within 7 working days after arrival of the package at Oncoscreen.

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Scientific background

The hereditary nonpolyposis colorectal cancer (HNPCC) is the most common type of the hereditary colorectal cancer. Reliable diagnosis of the type of cancer is the prerequisite of efficient and targeted clinical management of patients with heightened cancer susceptibility. This is especially crucial for both the patients themselves (to evaluate the risk of manifestation of a secondary tumor) and for the patients' family members. Immediate relatives of an HNPCC patient have a 50 % risk of manifesting the HNPCC.

One to several mutations in only 1 of the 6 so-called mismatch repair genes (MMR) are sufficient to cause the HNPCC. Therefore, if 1 MMR mutation is identified in a HNPCC patient, it is a good idea to screen all family members.

The HNPCC at-risk patient will be evaluated according to the Amsterdam or Bethesda criteria. However, only 30 % of all patients evaluated according to the Bethesda criteria and 85 % of the patients identified according to the more stringent Amsterdam criteria are carriers of the genetic HNPCC trait.


 Table 1:
The Amsterdam II Criteria
Three or more relatives with HNPCC associated cancer (colorectal cancer or cancer of the endometrium, small bowel, ureter or renal pelvis plus all of the following:
1. One affected patient should be a first-degree relative of the other two;
2. Two or more successive generations should be affected;
3. Cancer in one or more affected relatives should be diagnosed before the age of 50 years;
4. familial adenomatous polyposis should be excluded in any cases of colorectal cancer;
5. tumors should be verified by pathological examination

Table 2:
The Bethesda Criteria (mindestens ein Kriterium muss erfüllt sein)
1. Individuals with cancer in families that meet the Amsterdam criteria;
2. Individuals with 2 HNPCC-related cancers, including synchronous and metachronous colorectal cancers or associated extracolonic cancers (endometrial, ovarian, gastric, hepatobiliary, or small bowel cancer or transitional cell carcinoma of the renal pelvis or ureter);
3. Individuals with colorectal cancer and a first degree relative with colorectal cancer or HNPCC-related extracolonic cancer or colorectal adenoma; one of the cancers has to have been diagnosed at less than 45 years of age, and/or adenoma of the colon or rectum, diagnosed at less than 40 years of age;
4. Individuals with colorectal cancer or endometrial cancer at less than 45 years of age;
5. Individuals with right-sided colorectal cancer with an undifferentiated pattern (solid/cribriform) of a histopathology diagnosed at less than 45 years of age;
6. Individuals with signet-ring-cell-type colorectal cancer diagnosed at less than 45 years of age (>50% signet-ring cells);
7. AIndividuals with colorectal adenomas diagnosed at less than 40 years of age.

The MMR mutations may cause a so-called microsatellite instability. Microsatellites are short repetitive DNA fragments which are highly susceptible to mutations and thus show a high mutation rate when the DNA repair system is deficient. In the past, different panels of combinations of such microsatellite genetic markers were developed to reliably screen MMR mutations. In recent years two different combinations of microsatellite markers have been accepted by international panels as indicative of HNPCC.

Immunohistochemistry can support the search of the mutated MMR gene, but sequencing is finally the ultimate method of identifying the pathogenic mutation.

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Therapeutic consequences

If a patient is suspected of having HNPCC, the patient and the patient’s family should discuss this situation with their physician to develop an optimal strategy for therapy and preventive medical checkup.

Literature
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