Nuclear Pedigree Criteria of Suspected HNPCC

Abstract The criteria for the diagnosis of HNPCC established by the ICG-HNPCC are very restrictive as they do not allow for the diagnosis of a large number of "suspected HNPCC" cases - these are families which do no fulfill the strict diagnostic "Amsterdam criteria", but do present with several pedigree and clinical features characteristic for HNPCC. Several series of families suspected of harboring germline mutations in DNA mismatch repair genes have been studied for germline changes in DNA mismatch repair genes and a mutation rate of somewhere between 8-60% was found. Therefore a subgroup of members of the ICG-HNPCC has been working on pedigree/clinical diagnostic criteria for suspected HNPCC. Materials and methods Part I The study was based on two series of colorectal cancer (CRC) cases: 1) HNPCC - this group comprised 190 patients affected by CRC from randomly selected families which fulfilled the Amsterdam II criteria registered in Düsseldorf, Germany (102 cases of CRC), Denmark (18 CRCs), Leiden, Holland (23 CRCs) and Szczecin, Poland (47 CRCs). 2) Consecutive CRCs - this group comprised 629 (78.0%) of 806 individuals with CRC diagnosed in 1991-1997 in the city of Szczecin (ca. 400,000 of inhabitants), Poland. Nuclear pedigrees in both groups were compared for frequency of occurrence of clinical features, that have been shown to be associated with HNPCC. Part II 52 consecutive CRC cases from Szczecin, matching the criteria recognized in part I as appropriate for diagnosis of cases "suspected of HNPCC" were studied for the occurrence of germline hMSH2/hMLH1 constitutional mutations using "exon by exon" sequencing. Results The combination of features - i.e. the occurrence of an HNPCC associated cancer (CRC or cancer of the endometrium, small bowel or urinary tract) in a 1st degree relative of a CRC patient; at least one of the patients being diagnosed under age of 50 - appeared to be strongly associated to HNPCC with an OR - 161. Constitutional mutations were identified in 18 (10 MLH1 and 8 MSH2 mutations) of 52 (34%) cases matching the above features. Conclusions The results of our studies strongly suggest that it is possible to diagnose HNPCC with a high degree of accuracy on the basis of nuclear pedigree data and clinical features.