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Prevention, diagnosis and molecular characterisation of mismatch repair defect-related hereditary cancers of the digestive system

Final Report Summary - MMR-RELATED CANCER (Prevention, detection and molecular characterisation of mismatch repair-related hereditary cancers of the digestive system)

The aim of this project was to increase our knowledge on the genetic and molecular basis of two disease entities linked to mismatch repair (MMR) defects, namely hereditary non-polyposis colorectal cancer (HNPCC) or Lynch syndrome, and familial gastric cancer (FGC). This increased knowledge has helped us in improving genetic screening and set up comprehensive functional assays, to determine pathogenicity of unclassified variants (UVs) found in MMR genes in patients and their family members. Furthermore, we aimed to improve early detection of polyps / tumours in individuals at risk and when tumours are identified, tumour-mutation-profiles were used as an indicator for disease prognosis and treatment.

In HNPCC, identification of MMR gene mutations has helped in identifying individuals at risk when a clear pathogenic mutation was found. A large proportion of families, however, have mutations of which the pathogenic nature is uncertain (unclassified variants or UVs) or have no mutation at all. These findings made us speculate that more genes might exist and / or that the UVs identified play a more important role in disease development then currently thought.

Our project has made considerable progress in our goal to improve genetic testing, improve early detection of polyps / tumours in individuals at risk for MMR-related cancer syndromes, and improve clinical management of HNPCC and FGC patients. Specifically:
- We have not found new MMR-related genes
- We came to the conclusion that 'new types of mutations' in the old genes likely play an important role in these MMR related cancer syndromes.
- Comprehensive functional assays to determine the role of unclassified variants in MMR-related genes are set up and used to test a large set of UVs.
- We have shown proof of principle for a very sensitive PCR for MSI testing. We have available a mutation profile of MMR tumours, which gives a better insight in tumour development, and can be instrumental in clinical management / tumour treatment.
- We have identified 16 putative new MSI target genes.
- We have a database filled with functionally analysed UVs publically available.

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