Manon Suerink1, Mar Rodríguez-Girondo2, Heleen M van der Klift3, Chrystelle Colas4,5, Laurence Brugieres6, Noémie Lavoine6, Marjolijn Jongmans7,8,9, Gabriel Capellá Munar10, D Gareth Evans11, Michael P Farrell12, Maurizio Genuardi13,14, Yael Goldberg15, Encarna Gomez-Garcia16, Karl Heinimann17, Jessica I Hoell18, Stefan Aretz19,20, Kory W Jasperson21, Inbal Kedar15, Mitul B Modi22,23, Sergey Nikolaev24, Theo A M van Os25, Tim Ripperger26, Daniel Rueda27, Leigha Senter28, Wenche Sjursen29,30, Lone Sunde31, Christina Therkildsen32, Maria G Tibiletti33,34, Alison H Trainer35, Yvonne J Vos36, Anja Wagner37, Ingrid Winship38, Katharina Wimmer39, Stefanie Y Zimmermann40, Hans F Vasen41, Christi J van Asperen3, Jeanine J Houwing-Duistermaat2, Sanne W Ten Broeke3,36, Maartje Nielsen3. 1. Department of Clinical Genetics, Leiden University Medical Centre, Leiden, The Netherlands. m.suerink@lumc.nl. 2. Department of Medical Statistics and Bioinformatics, Leiden University Medical Centre, Leiden, The Netherlands. 3. Department of Clinical Genetics, Leiden University Medical Centre, Leiden, The Netherlands. 4. Department of Genetics, Institut Curie, Paris Sciences Lettres Research University, Paris, France. 5. Sorbonne Universités, UPMC Univ Paris 06, INSERM, CNRS, Centre de Recherche Saint-Antoine, Paris, France. 6. Child and Adolescent Cancer Department, Gustave Roussy Cancer Campus, Villejuif, France. 7. Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands. 8. Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands. 9. Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands. 10. Laboratori de Recerca Translacional, Catalan Institute of Oncology, Barcelona, Spain. 11. Division of Evolution and Genomic Medicine, MAHSC, University of Manchester, St Mary's Hospital, Manchester, UK. 12. Department of Cancer Genetics, Mater Private Hospital, Dublin, Ireland. 13. UOC Genetica Medica, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Rome, Italy. 14. Istituto di Medicina Genomica, Università Cattolica del Sacro Cuore, Rome, Italy. 15. The Raphael Recanati Genetics Institute, Rabin Medical Center, Petah Tikva, Israel. 16. Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, The Netherlands. 17. Research Group Human Genomics, Department of Biomedicine, University of Basel, and Medical Genetics, University Hospital Basel, Basel, Switzerland. 18. Department of Pediatric Oncology, Hematology and Clinical Immunology, University Children's Hospital, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany. 19. Institute of Human Genetics, University of Bonn, Bonn, Germany. 20. Center for Hereditary Tumor Syndromes, University Hospital Bonn, Bonn, Germany. 21. Ambry Genetics, Aliso Viejo, CA, USA. 22. Pennsylvania Hospital of University of Pennsylvania Health System, Philadelphia, PA, USA. 23. Gujarat Cancer & Research Institute, B.J.Medical College, Ahmedabad, India. 24. Inserm U981, Gustave Roussy Cancer Campus, Université Paris-Saclay, Villejuif, France. 25. Department of Clinical Genetics, Amsterdam UMC, locatie AMC, Amsterdam, The Netherlands. 26. Department of Human Genetics, Hannover Medical School, Hannover, Germany. 27. Hereditary Cancer Laboratory, University Hospital Doce de Octubre, i+12 Research Institute, Madrid, Spain. 28. The Ohio State University, Comprehensive Cancer Center, Division of Human Genetics, Columbus, USA. 29. Department of Medical Genetics, St Olav University Hospital, Trondheim, Norway. 30. Norwegian University of Science and Technology, Trondheim, Norway. 31. Department of Clinical Genetics, Aarhus University Hospital, Skejby, Denmark. 32. The HNPCC Register, Clinical Research Centre, Copenhagen University Hospital, Hvidovre, Denmark. 33. Department of Pathology, Ospedale di Circolo ASST Settelaghi, Varese, Italy. 34. Centro di Ricerca per lo studio dei tumori eredo-familiari, Università dell'Insubria, Varese, Italy. 35. Familial Cancer Centre, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. 36. Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. 37. Department of Clinical Genetics, Erasmus University Medical Centre, Rotterdam, The Netherlands. 38. Genomic Medicine, Royal Melbourne Hospital, The University of Melbourne, Melbourne, VIC, Australia. 39. Division of Human Genetics, Medical University Innsbruck, Innsbruck, Austria. 40. Pediatric Hematology and Oncology, University Hospital, Frankfurt, Germany. 41. Department of Gastroenterology & Hepatology, Leiden University Medical Centre, Leiden, The Netherlands.
Abstract
PURPOSE: Biallelic pathogenic variants in the mismatch repair (MMR) genes cause a recessive childhood cancer predisposition syndrome known as constitutional mismatch repair deficiency (CMMRD). Family members with a heterozygous MMR variant have Lynch syndrome. We aimed at estimating cancer risk in these heterozygous carriers as a novel approach to avoid complicated statistical methods to correct for ascertainment bias. METHODS: Cumulative colorectal cancer incidence was estimated in a cohort of PMS2- and MSH6-associated families, ascertained by the CMMRD phenotype of the index, by using mutation probabilities based on kinship coefficients as analytical weights in a proportional hazard regression on the cause-specific hazards. Confidence intervals (CIs) were obtained by bootstrapping at the family level. RESULTS: The estimated cumulative colorectal cancer risk at age 70 years for heterozygous PMS2 variant carriers was 8.7% (95% CI 4.3-12.7%) for both sexes combined, and 9.9% (95% CI 4.9-15.3%) for men and 5.9% (95% CI 1.6-11.1%) for women separately. For heterozygous MSH6 variant carriers these estimates are 11.8% (95% CI 4.5-22.7%) for both sexes combined, 10.0% (95% CI 1.83-24.5%) for men and 11.7% (95% CI 2.10-26.5%) for women. CONCLUSION: Our findings are consistent with previous reports that used more complex statistical methods to correct for ascertainment bias. These results underline the need for MMR gene-specific surveillance protocols for Lynch syndrome.
PURPOSE: Biallelic pathogenic variants in the mismatch repair (MMR) genes cause a recessive childhood cancer predisposition syndrome known as constitutional mismatch repair deficiency (CMMRD). Family members with a heterozygous MMR variant have Lynch syndrome. We aimed at estimating cancer risk in these heterozygous carriers as a novel approach to avoid complicated statistical methods to correct for ascertainment bias. METHODS: Cumulative colorectal cancer incidence was estimated in a cohort of PMS2- and MSH6-associated families, ascertained by the CMMRD phenotype of the index, by using mutation probabilities based on kinship coefficients as analytical weights in a proportional hazard regression on the cause-specific hazards. Confidence intervals (CIs) were obtained by bootstrapping at the family level. RESULTS: The estimated cumulative colorectal cancer risk at age 70 years for heterozygous PMS2 variant carriers was 8.7% (95% CI 4.3-12.7%) for both sexes combined, and 9.9% (95% CI 4.9-15.3%) for men and 5.9% (95% CI 1.6-11.1%) for women separately. For heterozygous MSH6 variant carriers these estimates are 11.8% (95% CI 4.5-22.7%) for both sexes combined, 10.0% (95% CI 1.83-24.5%) for men and 11.7% (95% CI 2.10-26.5%) for women. CONCLUSION: Our findings are consistent with previous reports that used more complex statistical methods to correct for ascertainment bias. These results underline the need for MMR gene-specific surveillance protocols for Lynch syndrome.
Entities:
Keywords:
HNPCC; MSH6; PMS2; bMMRD; colon cancer risk
Authors: Mohammed N AlAli; Abdulrahman H Zikry; Sulaiman A AlShammari; Mohammed Ayesh Zayed; Mohammed Alswayyed; Omar A AlObeed Journal: Cureus Date: 2022-04-30
Authors: Mev Dominguez-Valentin; 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 Gareth Evans; John Burn; Marc Greenblatt; Wouter H de Vos Tot Nederveen Cappel; Rolf H Sijmons; Maartje Nielsen; Lucio Bertario; Bernardo Bonanni; Maria Grazia Tibiletti; Giulia Martina Cavestro; Annika Lindblom; Adriana Della 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 Alejandra Piñero; Walter Hernán Pavicic; Pablo Kalfayan; Sanne W Ten Broeke; Jukka-Pekka Mecklin; Kirsi Pylvänäinen; Laura Renkonen-Sinisalo; Anna Lepistö; Päivi Peltomäki; John L Hopper; Aung Ko Win; Daniel D Buchanan; Noralane M Lindor; Steven Gallinger; Loïc Le Marchand; Polly A Newcomb; Jane C Figueiredo; Stephen N Thibodeau; Christina Therkildsen; Thomas V O Hansen; Lars Lindberg; Einar Andreas Rødland; Florencia Neffa; Patricia Esperon; Douglas Tjandra; Gabriela Möslein; Toni T Seppälä; Pål Møller Journal: J Clin Med Date: 2021-06-28 Impact factor: 4.241