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Original article
Cancer risk and survival in path_MMR carriers by gene and gender up to 75 years of age: a report from the Prospective Lynch Syndrome Database
  1. Pål Møller1,2,3,
  2. Toni T Seppälä4,
  3. Inge Bernstein5,6,
  4. Elke Holinski-Feder7,8,
  5. Paulo Sala9,
  6. D Gareth Evans10,11,
  7. Annika Lindblom12,
  8. Finlay Macrae13,14,
  9. Ignacio Blanco15,
  10. Rolf H Sijmons16,
  11. Jacqueline Jeffries17,
  12. Hans F A Vasen18,
  13. John Burn19,
  14. Sigve Nakken2,
  15. Eivind Hovig2,20,21,
  16. Einar Andreas Rødland2,
  17. Kukatharmini Tharmaratnam22,
  18. Wouter H de Vos tot Nederveen Cappel23,
  19. James Hill24,
  20. Juul T Wijnen25,
  21. Mark A Jenkins26,
  22. Kate Green10,11,
  23. Fiona Lalloo10,11,
  24. Lone Sunde6,27,28,
  25. Miriam Mints29,
  26. Lucio Bertario9,
  27. Marta Pineda15,
  28. Matilde Navarro15,
  29. Monika Morak7,8,
  30. Laura Renkonen-Sinisalo4,30,
  31. Mev Dominguez Valentin1,2,
  32. Ian M Frayling,
  33. John-Paul Plazzer13,
  34. Kirsi Pylvanainen31,
  35. Maurizio Genuardi32,
  36. Jukka-Pekka Mecklin33,
  37. Gabriela Moeslein,
  38. Julian R Sampson17,
  39. Gabriel Capella15,34
  40. in collaboration with The Mallorca Group
  1. 1 Department of Medical Genetics, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
  2. 2 Department of Tumor Biology, Institute of Cancer Research, The Norwegian Radium Hospital, part of Oslo University Hospital, Olso, Norway
  3. 3 Center for Hereditary Tumors, HELIOS-Klinikum Wuppertal, University of Witten-Herdecke, Wuppertal, Germany
  4. 4 Department of Gastrointestinal Surgery, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland
  5. 5 The Danish Hereditary Non-polyposis Colorectal Cancer Register, Clinical Research Centre, Copenhagen University Hospital, Hvidovre, Denmark
  6. 6 Department of Surgical Gastroenterology, Aalborg University Hospital, Aalborg, Denmark
  7. 7 Medizinische Klinik und Poliklinik IV, Campus Innenstadt, Klinikum der Universität München, Ziemssenstr, Germany
  8. 8 MGZ – Medizinisch Genetisches Zentrum, Munich, Germany
  9. 9 Unit of Hereditary Digestive Tract Tumors IRCCS Istituto Nazionale Tumori Milan, Milano, Italy
  10. 10 Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, London, UK
  11. 11 Manchester Centre for Genomic Medicine, University of Manchester, London, UK
  12. 12 Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
  13. 13 Colorectal Medicine and Genetics, The Royal Melbourne Hospital, Melborne, Australia
  14. 14 Department of Medicine, Melbourne University, Melborne, Australia
  15. 15 Hereditary Cancer Program, Institut Català d’Oncologia-IDIBELL, L’Hospitalet de Llobregat, Barcelona, Spain
  16. 16 Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
  17. 17 Division of Cancer and Genetics, Institute of Medical Genetics, Cardiff University School of Medicine, Heath Park, UK
  18. 18 Department of Gastroenterology and Hepatology, Leiden University Medical Centre, Leiden, The Netherlands
  19. 19 Institute of Genetic Medicine Newcastle University, Newcastle upon Tyne, UK
  20. 20 Institute of Cancer Genetics and Informatics, The Norwegian Radium Hospital, part of Oslo University Hospital, Olso, Norway
  21. 21 Department of Informatics, University of Oslo, Olso, Norway
  22. 22 Department of Mathematics and Statistics, Lancaster University, Lancaster, UK
  23. 23 Department of Gastroenterology and Hepatology, Isala Clinics, Zwolle, The Netherlands
  24. 24 Department of Surgery, Central Manchester University Hospitals NHS Foundation Trust and University of Manchester, London, UK
  25. 25 Department of Clinical Genetics and Department of Human Genetics Leiden, University Medical Centre, Leiden, The Netherlands
  26. 26 Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, Victoria, Australia
  27. 27 Department of Clinical Genetics, Aarhus University Hospital, Aarhus, Denmark
  28. 28 Department of Biomedicine, Aarhus University, Aarhus, Denmark
  29. 29 Department of Women’s and Children’s health, Division of Obstetrics and Gyneacology, Karolinska Institutet, Karolinska University Hospital, Solna, Stockholm, Sweden
  30. 30 Genome-Scale Biology Research Program, University of Helsinki, Helsinki, Finland
  31. 31 Department of Education and Science, Central Finland Health Care District, yväskylä, Finland
  32. 32 Institute of Genomic Medicine, "A. Gemelli" Faculty of Medicine, Catholic University of the Sacred Heart, Rome, Italy
  33. 33 University of Eastern Finland, Kuopio, Finland
  34. 34 Center for Hereditary Tumors, HELIOS-Klinikum Wuppertal, University of Witten-Herdecke, Wuppertal, Germany

Abstract

Background Most patients with path_MMR gene variants (Lynch syndrome (LS)) now survive both their first and subsequent cancers, resulting in a growing number of older patients with LS for whom limited information exists with respect to cancer risk and survival.

Objective and design This observational, international, multicentre study aimed to determine prospectively observed incidences of cancers and survival in path_MMR carriers up to 75 years of age.

Results 3119 patients were followed for a total of 24 475 years. Cumulative incidences at 75 years (risks) for colorectal cancer were 46%, 43% and 15% in path_MLH1, path_MSH2 and path_MSH6 carriers; for endometrial cancer 43%, 57% and 46%; for ovarian cancer 10%, 17% and 13%; for upper gastrointestinal (gastric, duodenal, bile duct or pancreatic) cancers 21%, 10% and 7%; for urinary tract cancers 8%, 25% and 11%; for prostate cancer 17%, 32% and 18%; and for brain tumours 1%, 5% and 1%, respectively. Ovarian cancer occurred mainly premenopausally. By contrast, upper gastrointestinal, urinary tract and prostate cancers occurred predominantly at older ages. Overall 5-year survival for prostate cancer was 100%, urinary bladder 93%, ureter 85%, duodenum 67%, stomach 61%, bile duct 29%, brain 22% and pancreas 0%. Path_PMS2 carriers had lower risk for cancer.

Conclusion Carriers of different path_MMR variants exhibit distinct patterns of cancer risk and survival as they age. Risk estimates for counselling and planning of surveillance and treatment should be tailored to each patient’s age, gender and path_MMR variant. We have updated our open-access website www.lscarisk.org to facilitate this.

  • cancer prevention
  • clinical trials
  • colorectal cancer screening
  • inherited cancers
  • HNPCC syndrome

This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/

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Footnotes

  • Contributors PåMø: Designed the study, managed the database and computed the results.PåMø, Julian Sampson and GC wrote the manuscript.EH, SN, EARø and KT calculated the confidence intervals to the cumulative incidences.EH and SN constructed the website calculating individual risks.All: Participated in study design, interpreting of results, commenting the manuscript and approved the final manuscript.

  • Competing interests John Burn has a patent for high speed low cost tumour profiling pending to John Burn and QuantuMDx.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data sharing statement The report is based on The Prospective Lynch Syndrome Database which is a joint venture by the contribuotrs and endorsed by EHTG (mallorca-gropu.org) Group and InSiGTH (insight-group.org). Formal ownerships and development of the activities will be discussed at this year joint meeting for EHTG and InSiGHT in Florence July 5th-8th this year. All interested are wellcomed to join.

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