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No Difference in Penetrance between Truncating and Missense/Aberrant Splicing Pathogenic Variants in MLH1 and MSH2: A Prospective Lynch Syndrome Database Study

by 1,2,3,*, 3,4, 2,5, 2,6, 7, 8, 9,10, 11,12, 2,3,13, 14, 3,4, 15,16, 17, 18, 2,3,19, 20, 21, 2,3,22, 23, 24, 25, 26, 27, 28, 29, 30, 30, 31, 32, 33, 34,35, 1,36, 1,37, 18, 18, 38, 39, 7, 40, 41, 3,42,43, 42,43, 7, 44, 45,46, 6, 47, 41, 42,43, 48, 48, 49, 13, 13, 13, 14, 14, 50, 51, 31, 31, 34,35, 34,35, 34, 23, 2,3,52, 53, 54,55, 54,55, 56, 8, 8, 57,58,59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 1, 29, 29, 4,16, 2,3,69, 2,3,55,70 and 1,2,3
1
Department of Tumor Biology, Institute of Cancer Research, The Norwegian Radium Hospital, 0379 Oslo, Norway
2
European Hereditary Tumour Group (EHTG), c/o Lindsays, Caledonian Exchange 19A Canning Street, Edinburgh EH3 8HE, UK
3
The International Society for Gastrointestinal Hereditary Tumours (InSiGHT), The Polyposis Registry, St Mark’s Hospital, Watford Road, Harrow, Middlesex HA1 3UJ, UK
4
Department of Medicine, Colorectal Medicine and Genetics, The Royal Melbourne Hospital, Melbourne, VIC 3050, Australia
5
Institute of Medical Genetics, Division of Cancer and Genetics, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, UK
6
Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, 04107 Leipzig, Germany
7
Institute of Human Genetics, National Center for Hereditary Tumor Syndromes, Medical Faculty, University Hospital Bonn, University of Bonn, 53127 Bonn, Germany
8
Melbourne School of Population and Global Health, Centre for Epidemiology and Biostatistics, The University of Melbourne, Parkville, VIC 3010, Australia
9
Department of Clinical Genetics, Aalborg University Hospital, 9000 Aalborg, Denmark
10
Department of Biomedicine, Aarhus University, DK-8000 Aarhus, Denmark
11
Department of Surgical Gastroenterology, Aalborg University Hospital, Aalborg University, 9100 Aalborg, Denmark
12
Department of Clinical Medicine, Aalborg University Hospital, Aalborg University, 9100 Aalborg, Denmark
13
Hereditary Cancer Program, Institut Català d’Oncologia-IDIBELL, L, Hospitalet de Llobregat, 08908 Barcelona, Spain
14
Gastroenterology Department, Hospital Clínic de Barcelona, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Institut d’Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, 08036 Barcelona, Spain
15
Department of Genomic Medicine, Royal Melbourne Hospital, University of Melbourne, Melbourne, VIC 3052, Australia
16
Department of Medicine, Royal Melbourne Hospital, University of Melbourne, Melbourne, VIC 3052, Australia
17
Department of Surgery and Cancer, St Mark’s Hospital, Imperial College London, London HA1 3UJ, UK
18
Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Manchester M13 9WL, UK
19
Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE1 7RU, UK
20
Larner College of Medicine, University of Vermont, Burlington, VT 05405, USA
21
Department of Gastroenterology and Hepatology, Isala Clinics, 8015 Zwolle, The Netherlands
22
Department of Genetics, University Medical Center Groningen, University of Groningen, 9713GZ Groningen, The Netherlands
23
Department of Clinical Genetics, Leids Universitair Medisch Centrum, 2300RC Leiden, The Netherlands
24
Division of Cancer Prevention and Genetics, IEO, European Institute of Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, IRCCS, 20141 Milan, Italy
25
Division of Cancer Prevention and Genetics, IEO, European Institute of Oncology, IRCCS, 20141 Milan, Italy
26
Ospedale di Circolo ASST Settelaghi, Centro di Ricerca Tumori Eredo-Familiari, Università dell’Insubria, 21100 Varese, Italy
27
Gastroenterology and Gastrointestinal Endoscopy Unit, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, 20132 Milan, Italy
28
Department of Molecular Medicine and Surgery, Karolinska Institutet, 171 76 Stockholm, Sweden
29
Grupo Colaborativo Uruguayo, Investigación de Afecciones Oncológicas Hereditarias (GCU), Hospital Fuerzas Armadas, Montevideo 11600, Uruguay
30
Programa Cáncer Heredo Familiar, Clínica Universidad de los Andes, Santiago 7550000, Chile
31
Department of Gastroenterology, Sackler Faculty of Medicine, Tel-Aviv Sourasky Medical Center, Tel-Aviv University, Tel-Aviv 64259, Israel
32
The Department of Gastroenterology, Gastro-Oncology Unit, High Risk and GI Cancer Prevention Clinic, Sheba Medical Center, Sheba 91120, Israel
33
Medical Genetics, Institute for Medical Genetics and Pathology, University Hospital Basel, 4031 Basel, Switzerland
34
Hereditary Cancer Program (PROCANHE), Hospital Italiano de Buenos Aires, Buenos Aires C1199ABB, Argentina
35
Instituto de Medicina Traslacional e Ingenieria Biomedica (IMTIB), CONICET IU, Hospital Italiano de Buenos Aires, Buenos Aires C1199ABB, Argentina
36
Centre for Cancer Cell Reprogramming (CanCell), Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, 4950 Oslo, Norway
37
Department of Informatics, Centre for Bioinformatics, University of Oslo, 0316 Oslo, Norway
38
Department of Surgery, Central Manchester University Hospitals NHS, Foundation Trust, University of Manchester, London M13 9WL, UK
39
Department of Gastroenterology and Hepatology, Leiden University Medical Centre, 2333 Leiden, The Netherlands
40
Institute of Pathology, University of Cologne, 50937 Cologne, Germany
41
Department of Surgery, Technische Universität Dresden, 01062 Dresden, Germany
42
Campus Innenstadt, Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, 80336 Munich, Germany
43
Center of Medical Genetics, 80335 Munich, Germany
44
Department of Internal Medicine, University Hospital Bonn, 53127 Bonn, Germany
45
Department of Applied Tumour Biology, Institute of Pathology, University Hospital Heidelberg, 69120 Heidelberg, Germany
46
Cooperation Unit Applied Tumour Biology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
47
Medical School, Institute of Human Genetics, Heinrich-Heine-University, 40225 Dusseldorf, Germany
48
Department of Medicine, Knappschaftskrankenhaus, Ruhr-University Bochum, D-44789 Bochum, Germany
49
Gynaecological Oncology Research Group, Manchester University NHS Foundation Trust, Manchester, UK and Division of Cancer Sciences, University of Manchester, Manchester M20 4GJ, UK
50
Centre de Recerca en Economia i Salut (CRES-UPF), Universitat de Barcelona, 08002 Barcelona, Spain
51
Division of Obstetrics and Gyneacology, Department of Women’s and Children’s Health, Karolinska Institutet, Karolinska University Hospital, Solna, 171 77 Stockholm, Sweden
52
Departments of Surgery, Central Finland Hospital Nova, University of Jyväskylä, 40620 Jyväskylä, Finland
53
Department of Education and Science, Sport and Health Sciences, Central Finland Hospital Nova, University of Jyväskylä, FI-40014 Jyväskylä, Finland
54
Applied Tumour Genomics Research Program, University of Helsinki, 00014 Helsinki, Finland
55
Department of Gastrointestinal Surgery, Helsinki University Central Hospital, University of Helsinki, 00280 Helsinki, Finland
56
Department of Medical and Clinical Genetics, University of Helsinki, 00014 Helsinki, Finland
57
Centre for Cancer Research, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne, VIC 3010, Australia
58
Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, VIC 3010, Australia
59
Genomic Medicine and Family Cancer Clinic, Royal Melbourne Hospital, Parkville, VIC 3010, Australia
60
Department of Health Science Research, Mayo Clinic Arizona, Phoenix, AZ 85054, USA
61
Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, ON M5G 1X5, Canada
62
Cancer Center, University of Hawaii, Honolulu, HI 96813, USA
63
Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109-1024, USA
64
Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
65
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA
66
The Danish HNPCC Register, Clinical Research Centre, Copenhagen University Hospital, 2560 Hvidovre, Denmark
67
Department of Clinical Genetics, Rigshospitalet, Copenhagen University Hospital, 2100 Copenhagen, Denmark
68
Gastro Unit, Copenhagen University Hospital, 2560 Hvidovre, Denmark
69
Surgical Center for Hereditary Tumors, Ev. Bethesda Khs Duisburg, University Witten-Herdecke, 58448 Herdecke, Germany
70
Department of Surgical Oncology, Johns Hopkins Hospital, Baltimore, MA 21287, USA
*
Author to whom correspondence should be addressed.
Academic Editor: Maria Lina Tornesello
J. Clin. Med. 2021, 10(13), 2856; https://doi.org/10.3390/jcm10132856
Received: 24 May 2021 / Revised: 15 June 2021 / Accepted: 16 June 2021 / Published: 28 June 2021
(This article belongs to the Special Issue Recent Advances in Colorectal Carcinogenesis and Prevention)
Background. Lynch syndrome is the most common genetic predisposition for hereditary cancer. Carriers of pathogenic changes in mismatch repair (MMR) genes have an increased risk of developing colorectal (CRC), endometrial, ovarian, urinary tract, prostate, and other cancers, depending on which gene is malfunctioning. In Lynch syndrome, differences in cancer incidence (penetrance) according to the gene involved have led to the stratification of cancer surveillance. By contrast, any differences in penetrance determined by the type of pathogenic variant remain unknown. Objective. To determine cumulative incidences of cancer in carriers of truncating and missense or aberrant splicing pathogenic variants of the MLH1 and MSH2 genes. Methods. Carriers of pathogenic variants of MLH1 (path_MLH1) and MSH2 (path_MSH2) genes filed in the Prospective Lynch Syndrome Database (PLSD) were categorized as truncating or missense/aberrant splicing according to the InSiGHT criteria for pathogenicity. Results. Among 5199 carriers, 1045 had missense or aberrant splicing variants, and 3930 had truncating variants. Prospective observation years for the two groups were 8205 and 34,141 years, respectively, after which there were no significant differences in incidences for cancer overall or for colorectal cancer or endometrial cancers separately. Conclusion. Truncating and missense or aberrant splicing pathogenic variants were associated with similar average cumulative incidences of cancer in carriers of path MLH1 and path_MSH2. View Full-Text
Keywords: MLH1; MSH2; penetrance; cancer incidence; truncating; missense; aberrant splicing; Lynch syndrome MLH1; MSH2; penetrance; cancer incidence; truncating; missense; aberrant splicing; Lynch syndrome
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Figure 1

MDPI and ACS Style

Dominguez-Valentin, M.; Plazzer, J.-P.; Sampson, J.R.; Engel, C.; Aretz, S.; Jenkins, M.A.; Sunde, L.; Bernstein, I.; Capella, G.; Balaguer, F.; Macrae, F.; Winship, I.M.; Thomas, H.; Evans, D.G.; Burn, J.; Greenblatt, M.; de Vos tot Nederveen Cappel, W.H.; Sijmons, R.H.; Nielsen, M.; Bertario, L.; Bonanni, B.; Tibiletti, M.G.; Cavestro, G.M.; Lindblom, A.; Valle, A.D.; Lopez-Kostner, F.; Alvarez, K.; Gluck, N.; Katz, L.; Heinimann, K.; Vaccaro, C.A.; Nakken, S.; Hovig, E.; Green, K.; Lalloo, F.; Hill, J.; Vasen, H.F.A.; Perne, C.; Büttner, R.; Görgens, H.; Holinski-Feder, E.; Morak, M.; Holzapfel, S.; Hüneburg, R.; von Knebel Doeberitz, M.; Loeffler, M.; Rahner, N.; Weitz, J.; Steinke-Lange, V.; Schmiegel, W.; Vangala, D.; Crosbie, E.J.; Pineda, M.; Navarro, M.; Brunet, J.; Moreira, L.; Sánchez, A.; Serra-Burriel, M.; Mints, M.; Kariv, R.; Rosner, G.; Piñero, T.A.; Pavicic, W.H.; Kalfayan, P.; Broeke, S.W.t.; Mecklin, J.-P.; Pylvänäinen, K.; Renkonen-Sinisalo, L.; Lepistö, A.; Peltomäki, P.; Hopper, J.L.; Win, A.K.; Buchanan, D.D.; Lindor, N.M.; Gallinger, S.; Marchand, L.L.; Newcomb, P.A.; Figueiredo, J.C.; Thibodeau, S.N.; Therkildsen, C.; Hansen, T.V.O.; Lindberg, L.; Rødland, E.A.; Neffa, F.; Esperon, P.; Tjandra, D.; Möslein, G.; Seppälä, T.T.; Møller, P. No Difference in Penetrance between Truncating and Missense/Aberrant Splicing Pathogenic Variants in MLH1 and MSH2: A Prospective Lynch Syndrome Database Study. J. Clin. Med. 2021, 10, 2856. https://doi.org/10.3390/jcm10132856

AMA Style

Dominguez-Valentin M, Plazzer J-P, Sampson JR, Engel C, Aretz S, Jenkins MA, Sunde L, Bernstein I, Capella G, Balaguer F, Macrae F, Winship IM, Thomas H, Evans DG, Burn J, Greenblatt M, de Vos tot Nederveen Cappel WH, Sijmons RH, Nielsen M, Bertario L, Bonanni B, Tibiletti MG, Cavestro GM, Lindblom A, Valle AD, Lopez-Kostner F, Alvarez K, Gluck N, Katz L, Heinimann K, Vaccaro CA, Nakken S, Hovig E, Green K, Lalloo F, Hill J, Vasen HFA, Perne C, Büttner R, Görgens H, Holinski-Feder E, Morak M, Holzapfel S, Hüneburg R, von Knebel Doeberitz M, Loeffler M, Rahner N, Weitz J, Steinke-Lange V, Schmiegel W, Vangala D, Crosbie EJ, Pineda M, Navarro M, Brunet J, Moreira L, Sánchez A, Serra-Burriel M, Mints M, Kariv R, Rosner G, Piñero TA, Pavicic WH, Kalfayan P, Broeke SWt, Mecklin J-P, Pylvänäinen K, Renkonen-Sinisalo L, Lepistö A, Peltomäki P, Hopper JL, Win AK, Buchanan DD, Lindor NM, Gallinger S, Marchand LL, Newcomb PA, Figueiredo JC, Thibodeau SN, Therkildsen C, Hansen TVO, Lindberg L, Rødland EA, Neffa F, Esperon P, Tjandra D, Möslein G, Seppälä TT, Møller P. No Difference in Penetrance between Truncating and Missense/Aberrant Splicing Pathogenic Variants in MLH1 and MSH2: A Prospective Lynch Syndrome Database Study. Journal of Clinical Medicine. 2021; 10(13):2856. https://doi.org/10.3390/jcm10132856

Chicago/Turabian Style

Dominguez-Valentin, Mev, John-Paul Plazzer, Julian R. Sampson, Christoph Engel, Stefan Aretz, Mark A. Jenkins, Lone Sunde, Inge Bernstein, Gabriel Capella, Francesc Balaguer, Finlay Macrae, Ingrid M. Winship, Huw Thomas, Dafydd G. Evans, John Burn, Marc Greenblatt, Wouter H. de Vos tot Nederveen Cappel, Rolf H. Sijmons, Maartje Nielsen, Lucio Bertario, Bernardo Bonanni, Maria G. Tibiletti, Giulia M. Cavestro, Annika Lindblom, Adriana D. Valle, Francisco Lopez-Kostner, Karin Alvarez, Nathan Gluck, Lior Katz, Karl Heinimann, Carlos A. Vaccaro, Sigve Nakken, Eivind Hovig, Kate Green, Fiona Lalloo, James Hill, Hans F.A. Vasen, Claudia Perne, Reinhard Büttner, Heike Görgens, Elke Holinski-Feder, Monika Morak, Stefanie Holzapfel, Robert Hüneburg, Magnus von Knebel Doeberitz, Markus Loeffler, Nils Rahner, Jürgen Weitz, Verena Steinke-Lange, Wolff Schmiegel, Deepak Vangala, Emma J. Crosbie, Marta Pineda, Matilde Navarro, Joan Brunet, Leticia Moreira, Ariadna Sánchez, Miquel Serra-Burriel, Miriam Mints, Revital Kariv, Guy Rosner, Tamara A. Piñero, Walter H. Pavicic, Pablo Kalfayan, Sanne W.t. Broeke, Jukka-Pekka Mecklin, Kirsi Pylvänäinen, Laura Renkonen-Sinisalo, Anna Lepistö, Päivi Peltomäki, John L. Hopper, Aung K. Win, Daniel D. Buchanan, Noralane M. Lindor, Steven Gallinger, Loïc L. Marchand, Polly A. Newcomb, Jane C. Figueiredo, Stephen N. Thibodeau, Christina Therkildsen, Thomas V.O. Hansen, Lars Lindberg, Einar A. Rødland, Florencia Neffa, Patricia Esperon, Douglas Tjandra, Gabriela Möslein, Toni T. Seppälä, and Pål Møller. 2021. "No Difference in Penetrance between Truncating and Missense/Aberrant Splicing Pathogenic Variants in MLH1 and MSH2: A Prospective Lynch Syndrome Database Study" Journal of Clinical Medicine 10, no. 13: 2856. https://doi.org/10.3390/jcm10132856

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