• Christoph Engel, Aysel Ahadova, Toni T Seppälä, Stefan Aretz, Marloes Bigirwamungu-Bargeman, Hendrik Bläker, Karolin Bucksch, Reinhard Büttner, Wouter T de Vos Tot Nederveen Cappel, Volker Endris, Elke Holinski-Feder, Stefanie Holzapfel, Robert Hüneburg, Maarten A J M Jacobs, Jan J Koornstra, Alexandra M Langers, Anna Lepistö, Monika Morak, Gabriela Möslein, Päivi Peltomäki, Kirsi Pylvänäinen, Nils Rahner, Laura Renkonen-Sinisalo, Karsten Schulmann, Verena Steinke-Lange, Albrecht Stenzinger, Christian P Strassburg, Paul C van de Meeberg, Mariette van Kouwen, Monique van Leerdam, Deepak B Vangala, Juda Vecht, Marie-Louise Verhulst, Magnus von Knebel Doeberitz, Jürgen Weitz, Silke Zachariae, Markus Loeffler, Jukka-Pekka Mecklin, Matthias Kloor, Hans F Vasen, German HNPCC Consortium, the Dutch Lynch Syndrome Collaborative Group, and Finnish Lynch Syndrome Registry.
• Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany. Electronic address: christoph.engel@imise.uni-leipzig.de.
• Gastroenterology. 2020 Apr 1; 158 (5): 1326-1333.

Background & AimsLynch 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.MethodsWe 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.ResultsRisk 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.ConclusionsIn 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.Copyright © 2020 AGA Institute. Published by Elsevier Inc. All rights reserved.

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