Genetic testing of the mismatch repair genes in our clinical practice – Case report of two HNPCC families

Introduction: Occurrence of colorectal cancer is sporadic in significant number of cases, but we have to concentrate the familial and the autosomal dominant conditions, too. Hereditary Nonpolyposis Colorectal Cancer syndrome (HNPCC or Lynch-syndrome) is characterized by early onset CRC and endometrial cancer, although the incidence of other malignant tumours, e.g. cancers of the stomach, urothelium, small bowel and ovarium, is also increased in HNPCC patients. HNPCC is autosomal dominantly inherited and is associated with germline mutations in at least six mismatch repair (MMR) genes (MLH1, MSH2, MSH6, PMS1 and PMS2, EPCAM). The identification of carriers is usually based on screening individuals from families fulfilling international criteria for the syndrome, namely Amsterdam criteria or less stringent criteria referred to as the Bethesda guidelines.

Mutations in MLH1 (MIM# 120436) and MSH2 (MIM# 120435) are considered the major cause of HNPCC, since germline alterations of these genes have been found to be responsible for more than 90% of mutation carrier HNPCC families.

Methods: In our clinical practise we attend nine HNPCC families, and two of them have been maped by genetical examination completely. First step was the screening the families by the Amsterdam criteria for the syndrome, and after it we have assigned who is the index case people. Immunohistochemical examinations of the index cases's pathological sample showed one MLH1 and one MSH2 allel-lost. Genetic testing from the blood-samples indentified the MMR gene mutations in the index cases exactly. After the genetic examinations of the index cases their family member were tested. The tests showed two carriers and to genetically healthy people in these two families.

Conclusion: After the genetic examination we can relieve the mutation free relatives of the suspicion of hereditary malignant illness, and we definitely manage the correct gastroenterological controll of genetically high risk relatives. Naturally we intend genetic examinations in the other HNPCC families in our practise.