Abstracts presented at the XVIth symposium of The Netherlands Foundation for the Detection of Hereditary Tumours, 'New Developments in Hereditary Cancer', 31 January 2003, Utrecht, The Netherlands

s presented at the XVIth symposium of The Netherlands Foundation for the Detection of Hereditary Tumours, ‘New Developments in Hereditary Cancer’, 31 January 2003, Utrecht, The Netherlands Genomic deletions in PMS2: a cause of HNPCC? Y. Hendriks, H. van der Klift, H. Morreau, P. Franken, C. Tops, T. van Os, S. Jagmohan-Changur, H. Vasen, M. Breuning, A. Bröcker-Vriends, J. Wijnen and R. Fodde 1 Center for Human and Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands; 2 Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands; 3 Department of Clinical Genetics South-East Netherlands, Maastricht, The Netherlands; 4 Foundation for the Detection of Hereditary Tumours, Leiden, The Netherlands PMS2 is one of the mismatch repair (MMR) genes and is located on chromosome 7p22. PMS2 is a MutL homologue and is involved in repair of single-base mismatches and in repair of insertion-deletion loops. Mouse studies have shown that PMS2 null mice develop lymphomas and sarcomas and that the tumours show micro satellite instability (MSI). Nicolaides et al. described in 1994 a germline mutation in PMS2 in an individual from an HNPCC family. Other reported studies in HNPCC families and HNPCC suspect families have not revealed mutations in PMS2. However, mutations have been described in three Turcot families. Autosomal recessive inheritance was suggested in these families. We performed southern analysis of PMS2 in a large cohort of HNPCC families and HNPCC suspected families. All families were negative for mutations in MLH1, MSH2 and MSH6. We identified 4 large genomic deletions. One family fulfils the Amsterdam II criteria, the others don’t. Mutation analysis was performed in as many affected and at risk carriers as possible. MSI-analysis and immunohistochemistry (IHC) for the MMR proteins was performed in tumours from affected individuals. Three of the families are small and in the fourth segregation was not fully complete. Possibly phenocopies occurred in this family. MSI analysis and IHC in HNPCC related tumours from proven carriers showed an MSI-H phenotype and absent staining for PMS2, whereas MLH1, MSH2 and MSH6 stained positively. From our results it is probable that PMS2 is involved in HNPCC. Whether the deletions we found alone are sufficient to cause the phenotype is unclear. More research is required in larger groups of families to determine whether deletions in PMS2 are inherited in a autosomal fashion, whether presymptomatic testing can be offered and what the phenotype of deletions in PMS2 is. Immunohistochemical expression (IHC) and microsatellite instability (MSI) analysis in families with clustering of colorectal cancer M. van Puijenbroek, A. E. de Jong, C. Tops, J. Wijnen, M. Ausems, P. F. Franken, A. H. J. T. Bröcker-Vriends, R. Fodde, Th. van Os, H. MeijersHeijboer, H. F. A. Vasen and H. Morreau 1 Department of Pathology, 2 Department of Gastroenterology, 3 Center of Human and Clinical Genetics, Leiden Medical University Center, Leiden, The Netherlands; 4 The Netherlands Foundation for the Detection of Hereditary Tumours, Leiden, The Netherlands; 5 Department of Clinical Genetics, University Hospital Maastricht, Leiden, The Netherlands; 6 Department of Clinical Genetics, Erasmus MC, Rotterdam, The Netherlands Background: Hereditary nonpolyposis colorectal cancer (HNPCC) is caused by germline mutations in DNA-MMR genes. Due to the heterogeneity of the mutation spectrum of these genes, screening for mutations is both time-consuming and expensive. Immunohistochemical (IHC) and microsatellite instability (MSI) analysis can be used as pre-screening methods to identify patients with a possible MMR defect. In 1997 the Bethesda criteria have been proposed that can be used to select families for the determination of MSI. Aims: 1) to assess the yield of MSI-analysis and IHC-staining in families that meet the various Bethesda criteria and 2) to assess the additional value of PMS2 staining. Methods: Clinical data and tumours were collected from 517 individuals from families with clustering of colorectal cancer (CRC). The pedigrees were numbered according to the Bethesda criteria. MSIanalysis was performed using the five markers recommended by the 1997 workshop. IHC-staining was performed according to standard procedures for hMLH1, hMSH2, hMSH6 en PMS2. Results: 262 pedigrees scored Bethesda positive. A MSI-high/low phenotype in CRC tumors was observed in 21–50% of families that meet the various Bethesda 1