Carriers of pathogenic MLH1, MSH2, and MSH6 germline variants show differences in adenoma and colorectal cancer development and molecular tumour characteristics

Christoph Engel1, Aysel Ahadova2,3, Toni Seppälä4,5,6, Stefan Aretz7,8, Marloes Bigirwamungu-Bargeman9, Hendrik Bläker10, Karolin Bucksch1, Reinhard Büttner11, Wouter de Vos tot Nederveen Cappel12, Evelien Dekker13, Volker Endris14, Elke Holinski-Feder15,16, Stefanie Holzapfel7,8, Robert Hüneburg8,17, Maarten A.J.M. Jacobs18, Jan J. Koornstra19, Alexandra M. Langers20, Anna Lepistö4,21, Monika Morak15,16, Gabriela Möslein22, Kirsi Pylvänäinen23, Nils Rahner24, Laura Renkonen-Sinisalo4,21, Karsten Schulmann25,26, Verena Steinke-Lange15,16, Christian P. Strassburg8,17, Paul C. van de Meeberg27, Mariette van Kouwen28, Monique van Leerdam29, Deepak B. Vangala30, Juda Vecht31, Marie-Louise Verhulst32, Magnus von Knebel Doeberitz2,3, Jürgen Weitz33, Silke Zachariae1, Markus Loeffler1, Jukka-Pekka Mecklin34,35, Matthias Kloor2,3, Hans F. Vasen36

1Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany. 2Department of Applied Tumour Biology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany. 3Cooperation Unit Applied Tumour Biology, German Cancer Research Center (DKFZ), Heidelberg, Germany. 4Department of Surgery, Helsinki University Central Hospital, Helsinki, Finland. 5University of Helsinki, Helsinki, Finland. 6Johns Hopkins Hospital, Surgical Oncology, Baltimore, MD, USA. 7Institute of Human Genetics, University of Bonn, Bonn, Germany. 8National Center for Hereditary Tumor Syndromes, University Hospital Bonn, Bonn, Germany. 9Department of Gastroenterology & Hepatology, Medisch Spectrum Hospital, Enschede, Netherlands. 10Institute of Pathology, University Hospital Leipzig, Leipzig, Germany. 11Institute of Pathology, University of Cologne, Cologne, Germany. 12Department of Gastroenterology & Hepatology, Isala Clinics, Zwolle, Netherlands. 13Department of Gastroenterology & Hepatology, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, Netherlands. 14Department of General Pathology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany. 15Medizinische Klinik und Poliklinik IV, Campus Innenstadt, Klinikum der Universität München, Munich, Germany. 16Center of Medical Genetics, Munich, Germany. 17Department of Internal Medicine I, University Hospital Bonn, Bonn, Germany. 18Department of Gastroenterology & Hepatology, Amsterdam University Medical Center, Amsterdam, Netherlands. 19Department of Gastroenterology & Hepatology, University Medical Centre Groningen, University of Groningen, Groningen, Netherlands. 20Department of Gastroenterology & Hepatology, Leiden University Medical Centre, Leiden, Netherlands. 21Research Programs Unit, Genome-Scale Biology, University of Helsinki, Helsinki, Finland. 22Center for Hereditary Tumors, HELIOS Klinikum Wuppertal, University Witten-Herdecke, Wuppertal, Germany. 23Department of Education and Science, Central Finland Hospital District, Jyväskylä, Finland. 24Institute of Human Genetics, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany. 25Department of Hematology and Oncology, Klinikum Hochsauerland, Meschede, Germany. 26MVZ Arnsberg, Medical Practice for Hematology and Oncology, Arnsberg, Germany. 27Department of Gastroenterology & Hepatology, Slingeland Hospital, Doetinchem, Netherlands. 28Department of Gastroenterology & Hepatology, Radboud University Medical Centre, Nijmegen, Netherlands. 29Department of Gastroenterology and Hepatology, Netherlands Cancer Institute, Amsterdam, Netherlands. 30Department of Medicine, Knappschaftskrankenhaus, Ruhr-University Bochum, Bochum, Germany. 31Department of Gastroenterology & Hepatology, Isala Clinics, Zwolle, The Netherlands, Zwolle, Netherlands. 32Department of Gastroenterology & Hepatology, Maxima Medical Centre, Eindhoven, Netherlands. 33Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus of the Technical University Dresden, Dresden, Germany. 34Department of Surgery, Central Finland Central Hospital, Jyväskylä, Finland. 35Faculty of Sport and Health Sciences, University of Jyväskylä, Jyväskylä, Finland. 36Department of Gastroenterology and Hepatology, Leiden University Medical Centre, Leiden, Netherlands

Abstract

Objectives: Lynch syndrome (LS) is caused by inherited pathogenic variants in mismatch repair (MMR) genes and is primarily associated with an increased risk of colorectal cancer (CRC). Recent studies suggest that LS-CRC can develop through different pathways. We assessed MMR gene-specific patterns of adenoma and CRC risk, as well as frequencies of somatic APC and CTNNB1 mutations characterizing different CRC development pathways.

Methods: 2,747 LS patients with pathogenic germline variants in MLH1, MSH2, or MSH6 gene were followed prospectively regarding adenoma and CRC development. Somatic mutation data from 48 CRCs were re-evaluated by grouping tumor characteristics by the affected MMR gene.

Results: Advanced adenoma risk was higher in MSH2 vs. MLH1 (17.8% vs 7.7%, p<0.001) carriers, as was the frequency of somatic APC mutations in MSH2- vs. MLH1-associated CRCs (75% vs. 11%, p=0.015). In contrast, MLH1-associated CRCs presented more frequently with somatic CTNNB1 mutations compared to MSH2-associated CRCs (50% vs. 7%, p=0.002). Both MLH1 and MSH2 carriers showed higher frequencies of incident cancer than MSH6 carriers (11.3% and 11.4% vs. 4.7%; p=0.001 and p=0.003, respectively). Of the three MSH6-associated CRCs none carried a somatic CTNNB1 mutation, but all three samples presented with a somatic APC mutation.

Conclusions: Adenoma and CRC development in patients with distinct pathogenic MMR gene variants are attributable to different molecular pathways, potentially explaining the variation in the efficacy of colonoscopy. These differences indicate that LS screening and management guidelines should be revisited and tailored to the MMR gene affected.

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