Christoph Engel1, Aysel Ahadova2, Toni T Seppälä3, Stefan Aretz4, Marloes Bigirwamungu-Bargeman5, Hendrik Bläker6, Karolin Bucksch7, Reinhard Büttner8, Wouter T de Vos Tot Nederveen Cappel9, Volker Endris10, Elke Holinski-Feder11, Stefanie Holzapfel4, Robert Hüneburg12, Maarten A J M Jacobs13, Jan J Koornstra14, Alexandra M Langers15, Anna Lepistö16, Monika Morak11, Gabriela Möslein17, Päivi Peltomäki18, Kirsi Pylvänäinen19, Nils Rahner20, Laura Renkonen-Sinisalo16, Karsten Schulmann21, Verena Steinke-Lange11, Albrecht Stenzinger10, Christian P Strassburg12, Paul C van de Meeberg22, Mariette van Kouwen23, Monique van Leerdam15, Deepak B Vangala24, Juda Vecht9, Marie-Louise Verhulst25, Magnus von Knebel Doeberitz2, Jürgen Weitz26, Silke Zachariae7, Markus Loeffler7, Jukka-Pekka Mecklin27, Matthias Kloor2, Hans F Vasen15. 1. Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany. Electronic address: christoph.engel@imise.uni-leipzig.de. 2. Department of Applied Tumour Biology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany; Cooperation Unit Applied Tumour Biology, German Cancer Research Center (DKFZ), Heidelberg, Germany. 3. Department of Surgery, Helsinki University Central Hospital, Helsinki, Finland; University of Helsinki, Helsinki, Finland; Johns Hopkins University, Surgical Oncology, Baltimore, Maryland. 4. Institute of Human Genetics, University of Bonn, Bonn, Germany; National Center for Hereditary Tumor Syndromes, University Hospital Bonn, Bonn, Germany. 5. Department of Gastroenterology & Hepatology, Medisch Spectrum Hospital, Enschede, The Netherlands. 6. Institute of Pathology, University Hospital Leipzig, Leipzig, Germany. 7. Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany. 8. Institute of Pathology, University of Cologne, Cologne, Germany. 9. Department of Gastroenterology & Hepatology, Isala Zwolle, Zwolle, The Netherlands. 10. Department of General Pathology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany. 11. Medizinische Klinik und Poliklinik IV, Campus Innenstadt, Klinikum der Universität München, Munich, Germany; Center of Medical Genetics, Munich, Germany. 12. National Center for Hereditary Tumor Syndromes, University Hospital Bonn, Bonn, Germany; Department of Internal Medicine I, University Hospital Bonn, Bonn, Germany. 13. Department of Gastroenterology & Hepatology, Amsterdam University Medical Center, Amsterdam, The Netherlands. 14. Department of Gastroenterology & Hepatology, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands. 15. Department of Gastroenterology & Hepatology, Leiden University Medical Center, Leiden, The Netherlands. 16. Department of Surgery, Helsinki University Central Hospital, Helsinki, Finland; Research Programs Unit, Genome-Scale Biology, University of Helsinki, Helsinki, Finland. 17. Center for Hereditary Tumors, HELIOS Klinikum Wuppertal, University Witten-Herdecke, Wuppertal, Germany. 18. Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland. 19. Department of Education and Science, Central Finland Hospital District, Jyväskylä, Finland. 20. Institute of Human Genetics, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany. 21. Department of Hematology and Oncology, Klinikum Hochsauerland, Meschede, Germany; MVZ Arnsberg, Medical Practice for Hematology and Oncology, Arnsberg, Germany. 22. Department of Gastroenterology & Hepatology, Slingeland Hospital, Doetinchem, The Netherlands. 23. Department of Gastroenterology & Hepatology, Radboud University Medical Centre, Nijmegen, The Netherlands. 24. Department of Medicine, Knappschaftskrankenhaus, Ruhr-University Bochum, Bochum, Germany. 25. Department of Gastroenterology & Hepatology, Maxima Medical Centre, Eindhoven, The Netherlands. 26. Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus of the Technical University Dresden, Dresden, Germany. 27. Department of Surgery, Central Finland Central Hospital, Jyväskylä, Finland; Faculty of Sport and Health Sciences, University of Jyväskylä, Jyväskylä, Finland.
Abstract
BACKGROUND & AIMS: Lynch syndrome is caused by variants in DNA mismatch repair (MMR) genes and associated with an increased risk of colorectal cancer (CRC). In patients with Lynch syndrome, CRCs can develop via different pathways. We studied associations between Lynch syndrome-associated variants in MMR genes and risks of adenoma and CRC and somatic mutations in APC and CTNNB1 in tumors in an international cohort of patients. METHODS: We combined clinical and molecular data from 3 studies. We obtained clinical data from 2747 patients with Lynch syndrome associated with variants in MLH1, MSH2, or MSH6 from Germany, the Netherlands, and Finland who received at least 2 surveillance colonoscopies and were followed for a median time of 7.8 years for development of adenomas or CRC. We performed DNA sequence analyses of 48 colorectal tumors (from 16 patients with mutations in MLH1, 29 patients with mutations in MSH2, and 3 with mutations in MSH6) for somatic mutations in APC and CTNNB1. RESULTS: Risk of advanced adenoma in 10 years was 17.8% in patients with pathogenic variants in MSH2 vs 7.7% in MLH1 (P < .001). Higher proportions of patients with pathogenic variants in MLH1 or MSH2 developed CRC in 10 years (11.3% and 11.4%) than patients with pathogenic variants in MSH6 (4.7%) (P = .001 and P = .003 for MLH1 and MSH2 vs MSH6, respectively). Somatic mutations in APC were found in 75% of tumors from patients with pathogenic variants in MSH2 vs 11% in MLH1 (P = .015). Somatic mutations in CTNNB1 were found in 50% of tumors from patients with pathogenic variants in MLH1 vs 7% in MSH2 (P = .002). None of the 3 tumors with pathogenic variants in MSH6 had a mutation in CTNNB1, but all had mutations in APC. CONCLUSIONS: In an analysis of clinical and DNA sequence data from patients with Lynch syndrome from 3 countries, we associated pathogenic variants in MMR genes with risk of adenoma and CRC, and somatic mutations in APC and CTNNB1 in colorectal tumors. If these findings are confirmed, surveillance guidelines might be adjusted based on MMR gene variants.
BACKGROUND & AIMS:Lynch syndrome is caused by variants in DNA mismatch repair (MMR) genes and associated with an increased risk of colorectal cancer (CRC). In patients with Lynch syndrome, CRCs can develop via different pathways. We studied associations between Lynch syndrome-associated variants in MMR genes and risks of adenoma and CRC and somatic mutations in APC and CTNNB1 in tumors in an international cohort of patients. METHODS: We combined clinical and molecular data from 3 studies. We obtained clinical data from 2747 patients with Lynch syndrome associated with variants in MLH1, MSH2, or MSH6 from Germany, the Netherlands, and Finland who received at least 2 surveillance colonoscopies and were followed for a median time of 7.8 years for development of adenomas or CRC. We performed DNA sequence analyses of 48 colorectal tumors (from 16 patients with mutations in MLH1, 29 patients with mutations in MSH2, and 3 with mutations in MSH6) for somatic mutations in APC and CTNNB1. RESULTS: Risk of advanced adenoma in 10 years was 17.8% in patients with pathogenic variants in MSH2 vs 7.7% in MLH1 (P < .001). Higher proportions of patients with pathogenic variants in MLH1 or MSH2 developed CRC in 10 years (11.3% and 11.4%) than patients with pathogenic variants in MSH6 (4.7%) (P = .001 and P = .003 for MLH1 and MSH2 vs MSH6, respectively). Somatic mutations in APC were found in 75% of tumors from patients with pathogenic variants in MSH2 vs 11% in MLH1 (P = .015). Somatic mutations in CTNNB1 were found in 50% of tumors from patients with pathogenic variants in MLH1 vs 7% in MSH2 (P = .002). None of the 3 tumors with pathogenic variants in MSH6 had a mutation in CTNNB1, but all had mutations in APC. CONCLUSIONS: In an analysis of clinical and DNA sequence data from patients with Lynch syndrome from 3 countries, we associated pathogenic variants in MMR genes with risk of adenoma and CRC, and somatic mutations in APC and CTNNB1 in colorectal tumors. If these findings are confirmed, surveillance guidelines might be adjusted based on MMR gene variants.
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