gms | German Medical Science

HNPCC is an autosomal dominant cancer predisposition to colorectal cancer and other malignancies. The evaluation of many questions regarding HNPCC requires clinically and genetically well characterized HNPCC patient cohorts of reasonable size. Since 1999, the German HNPCC Consortium has established a registry for HNPCC families. In a multi-disciplinary approach, six university hospitals collect clinical data of HNPCC families or patients suspected of HNPCC, provide genetic and clinical counselling, tumour tissue analysis, molecular genetic workup, predictive testing and surveillance examinations. Data storage, quality control and biostatistical analyses are performed centrally. A reference pathology center is in charge of histopathology data. To date the study cohort of the German HNPCC encompasses more than 2500 unrelated patients suspected of HNPCC. Up to now studies on this cohort have produced important results in various fields: In patients meeting the strict Amsterdam criteria 71% of the tumours exhibited high microsatellite instability (MSI-H); this proportion was 37% in patients meeting less stringent criteria. Immunohistochemical analysis (IHC) of tumour tissue cannot be recommended to fully substitute microsatellite analysis (MSA). Nonetheless, IHC is important to indicate the gene which is likely to be affected. To combine both methods efficiently, a novel novel sequential strategy that can be used to minimize costs of screening diagnostics was established. The mutation detection rate in patients with MSI-H tumours was 56%. Of note, two mutations were overrepresented: MSH2,c.942+3A>T and MLH1,c.1489_1490insC; the latter mutation was uncovered as a frequent founder mutation German HNPCC patients. Disease modifying SNPs for HNPCC mutation carriers were analysed for CyclinD, RNASEL and p53. Studies on genotype-phenotype correlation revealed that MLH1 mutation carriers have a younger age at diagnosis than MSH2 mutation carriers both in regard to first cancer (41 vs. 44 years) and to first CRC (42 vs. 46 years). The rate of CRC was higher in MLH1 versus MSH2 mutation carriers. Gastric cancer was the third most common malignancy, a finding that has impact on future HNPCC surveillance recommendations.

The German HNPCC Consortium is supported by the Deutsche Krebshilfe.