Manon Suerink1, Heleen M van der Klift2, Sanne W Ten Broeke1, Olaf M Dekkers3, Inge Bernstein4,5, Gabriel Capellá Munar6, Encarna Gomez Garcia7, Nicoline Hoogerbrugge8,9, Tom G W Letteboer10, Fred H Menko11, Annika Lindblom12,13, Arjen Mensenkamp14, Pal Moller15, Theo A van Os16, Nils Rahner17, Bert J W Redeker16, M J W Olderode-Berends, Maran Olderode18, Liesbeth Spruijt9, Yvonne J Vos18, Anja Wagner19, Hans Morreau20, Frederik J Hes1, Hans F A Vasen21, Carli M Tops1, Juul T Wijnen3, Maartje Nielsen1. 1. Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands. 2. Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands. 3. Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands. 4. Surgical Gastroenterology Department, Aalborg University Hospital, Aalborg, Denmark. 5. Danish HNPCC Registry, Copenhagen, Denmark. 6. Laboratori de Recerca Translacional, Catalan Institute of Oncology, Barcelona (ICO-IDIBELL), Spain. 7. Department of Clinical Genetics, Maastricht University Medical Centre, Maastricht, The Netherlands. 8. Department of Clinical Genetics, Radboud University Medical Centre, Nijmegen, The Netherlands. 9. Department of Oncology, Radboud University Medical Centre, Nijmegen, The Netherlands. 10. Department of Clinical Genetics, University Medical Centre Utrecht, Utrecht, The Netherlands. 11. Netherlands Cancer Institute, Amsterdam, The Netherlands. 12. Department of Clinical Genetics, Karolinska Institutet, Karolinska University Hospital, Solna, Stockholm, Sweden. 13. Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden. 14. Department of Clinical Genetics, VU Medical Centre, Amsterdam, The Netherlands. 15. Department of Medical Genetics, Research Group Inherited Cancer, Oslo University Hospital, Oslo, Norway. 16. Department of Clinical Genetics, Academic Medical Centre, Amsterdam, The Netherlands. 17. Institut für Humangenetik und Anthropologie, Dusseldorf, Germany. 18. Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. 19. Department of Clinical Genetics, Erasmus Medical Centre, Rotterdam, The Netherlands. 20. Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands. 21. Department of Gastroenterology, Leiden University Medical Center, Leiden, The Netherlands.
Abstract
PURPOSE: Lynch syndrome (LS), a heritable disorder with an increased risk of primarily colorectal cancer (CRC) and endometrial cancer (EC), can be caused by mutations in the PMS2 gene. We wished to establish whether genotype and/or parent-of-origin effects (POE) explain (part of) the reported variability in severity of the phenotype. METHODS: European PMS2 mutation carriers (n = 381) were grouped and compared based on RNA expression and whether the mutation was inherited paternally or maternally. RESULTS: Mutation carriers with loss of RNA expression (group 1) had a significantly lower age at CRC diagnosis (51.1 years vs. 60.0 years, P = 0.035) and a lower age at EC diagnosis (55.8 years vs. 61.0 years, P = 0.2, nonsignificant) compared with group 2 (retention of RNA expression). Furthermore, group 1 showed slightly higher, but nonsignificant, hazard ratios (HRs) for both CRC (HR: 1.31, P = 0.38) and EC (HR: 1.22, P = 0.72). No evidence for a significant parent-of-origin effect was found for either CRC or EC. CONCLUSIONS: PMS2 mutation carriers with retention of RNA expression developed CRC 9 years later than those with loss of RNA expression. If confirmed, this finding would justify a delay in surveillance for these cases. Cancer risk was not influenced by a parent-of-origin effect.Genet Med 18 4, 405-409.
PURPOSE: Lynch syndrome (LS), a heritable disorder with an increased risk of primarily colorectal cancer (CRC) and endometrial cancer (EC), can be caused by mutations in the PMS2 gene. We wished to establish whether genotype and/or parent-of-origin effects (POE) explain (part of) the reported variability in severity of the phenotype. METHODS: European PMS2 mutation carriers (n = 381) were grouped and compared based on RNA expression and whether the mutation was inherited paternally or maternally. RESULTS: Mutation carriers with loss of RNA expression (group 1) had a significantly lower age at CRC diagnosis (51.1 years vs. 60.0 years, P = 0.035) and a lower age at EC diagnosis (55.8 years vs. 61.0 years, P = 0.2, nonsignificant) compared with group 2 (retention of RNA expression). Furthermore, group 1 showed slightly higher, but nonsignificant, hazard ratios (HRs) for both CRC (HR: 1.31, P = 0.38) and EC (HR: 1.22, P = 0.72). No evidence for a significant parent-of-origin effect was found for either CRC or EC. CONCLUSIONS: PMS2 mutation carriers with retention of RNA expression developed CRC 9 years later than those with loss of RNA expression. If confirmed, this finding would justify a delay in surveillance for these cases. Cancer risk was not influenced by a parent-of-origin effect.Genet Med 18 4, 405-409.
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