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HNPCC - MLH1, MSH2, MSH6, PMS2

Lynch Syndrome

Clinical Features

Hereditary Non-Polyposis Colon Cancer (HNPCC) represents 5 to 8% of all colon and rectum cancers and is thus the most common form of autosomal dominant inherited cancer diseases of the large intestine. The indication for inherited tumor diseases is found in the family anamnesis; more than 3 affected family members and/or a diagnosis prior to 50 years of age (Amsterdam Criteria) indicates an autosomal dominant cancer disease of the large intestine.
Inherited colon cancer diseases can be divided into two entities. Approximately 60% of cases are caused by mutations in the DNA repair genes MLH1, MSH2, MSH6, and PMS2. Tumors show high-grade microsatellite instability and most often a loss of expression in one of the DNA repair genes, in which a germline mutation can usually be detected. This form of HNPCC is also called Lynch Syndrome.
Patients affected by Lynch Syndrome not only develop tumors in the gastrointestinal tract but also have a higher risk of developing stomach, endometrium, urothelium tissue, hepatobiliary system, central nervous system, ovarian, and skin cancers. Unique to Lynch Syndrome is the shortened adenoma-carcinoma sequence. This means that even small adenomas can potentially evolve into carcinomas. It is therefore important to identify affected families and recommend the appropriate preventative care program of annual check-ups.
Approximately 40% of cases show no microsatellite instability despite positive family anamnesis and cannot be attributed to a mutation in the DNA repair genes. This form of tumor disease is not accompanied by a heightened risk of developing cancer outside of the gastrointestinal tract and shows no signs of a shortened adenoma-carcinoma sequence.
Due to the heightened risk of developing related cancers and the shortened adenoma-carcinoma sequence, these two categories of inherited colorectal cancer require two different forms of preventative care. This can be considered the basis of molecular genetic differentiation.

Indication for molecular genetic testing

Patients with a germline mutation in one of the DNA repair genes fulfill the Amsterdam Criteria in up to 60% of cases. In order to classify the remainder of affected patients, the Bethesda Criteria serve as an indication for the molecular genetic analysis of tumor tissue (microsatellite analysis and immunohistochemistry).

Amsterdam I Criteria (all criteria need to be fulfilled):

• At least 3 family members with histologically confirmed colorectal cancer
• One of these must be a first-degree relative
• Diseases in at least 2 consecutive generations
• At least one patient diagnosed with colorectal cancer prior to the age of 50
• Familiar Adenomatous Polyposis coli (FAP) has been excluded

Amsterdam II Criteria (all criteria need to be fulfilled):

• At least 3 family members with HNPCC-related cancer (colon/rectum, endometrium, small intestine, renal pelvis/ureter, stomach)
• One of these must be a first-degree relative
• Diseases in at least 2 consecutive generations
• At least one patient diagnosed with cancer prior to the age of 50
• Familiar Adenomatous Polyposis coli (FAP) has been excluded

Bethesda Criteria (revised; at least one criterion must be fulfilled):

• Colorectal cancer, diagnosed prior to 50 years of age
• Synchronous/metachronous colon/rectum cancer or HNPCC-related tumor disease (endometrium, renal pelvis/ureter, small intestine, stomach, pancreas, biliary tract, ovaries, hepatobiliary system, brain [usually glioblastomas], sebaceous adenomas, and keratoacanthomas), regardless of age
• Colorectal cancer with a morphology typical of MSI, diagnosed prior to 60 years of age
• Patient with colorectal cancer and at least one first-degree relative with an HNPCC-related tumor disease (see above) and at least one tumor diagnosed prior to 50 years of age
• Patient with colorectal cancer and at least two first- or second-degree relatives with an HNPCC-related tumor disease (see above), regardless of age.

Genetic Information

Lynch Syndrome is caused by genetic mutations in the DNA repair genes MLH1 (located on chromosome 3; 3p21.3), MSH2 (chromosome 2; 2p21p22), MSH6 (chromosome 2; 2p16), and PMS2 (chromosome 7; 7p22). Tumors develop in enteric cells when a germline mutation inherited from one parent exists in combination with a non-functional second gene copy. These tumor cells have no DNA repair activity, as evidenced by microsatellite instability in the tumor tissue.
Diagnostic approach
Suspicion of an inherited tumor disease should be supplemented by a detailed family anamnesis and genetic counseling, followed by microsatellite and immunohistochemical analysis of the tumor tissue. Pathological findings should be followed by molecular genetic analysis of the DNA repair genes.

Prevalence

There are approximately 70,000 newly diagnosed cases of colorectal cancer in Germany each year. Of these, approximately 5% are suspected cases of autosomal dominant inherited tumor disease; approximately 3% of all colorectal cancers are found to be caused by genetic mutations in DNA repair genes.
Note:
The documentation of test results follows in accordance with the research of the German Cancer Aid (Deutsche Krebshilfe).

Diagnostic