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Original research
First estimates of diffuse gastric cancer risks for carriers of CTNNA1 germline pathogenic variants
  1. Marie Coudert1,
  2. Youenn Drouet2,3,
  3. Hélène Delhomelle1,
  4. Magali Svrcek4,
  5. Patrick R Benusiglio5,
  6. Florence Coulet5,
  7. Dana Farengo Clark6,
  8. Bryson W Katona7,
  9. Liselotte P van Hest8,
  10. Lizet E van der Kolk9,
  11. Annemieke Cats10,
  12. Jolanda M van Dieren10,
  13. Bita Nehoray11,
  14. Thomas Slavin12,
  15. Isabel Spier13,
  16. Robert Hüneburg14,
  17. Silvana Lobo15,16,
  18. Carla Oliveira17,18,
  19. Lise Boussemart19,
  20. Laure Masson20,
  21. Jean Chiesa21,
  22. Mathias Schwartz1,
  23. Bruno Buecher1,
  24. Lisa Golmard1,
  25. Anne-Marie Bouvier22,
  26. Valérie Bonadona2,23,
  27. Dominique Stoppa-lyonnet1,24,
  28. Christine Lasset2,3,
  29. Chrystelle Colas1,24
  1. 1Département de Génétique, Institut Curie, Paris, France
  2. 2CNRS UMR 5558 LBBE, Université de Lyon, Villeurbanne, France
  3. 3Département Prévention et Santé Publique, Centre Léon Bérard, Lyon, France
  4. 4AP-HP, Saint-Antoine Hospital, Department of Pathology, Sorbonne Université, Paris, France
  5. 5Département de Génétique Médicale, AP-HP, Hôpital Pitié-Salpêtrière, Sorbonne Université, Paris, France
  6. 6Division of Hematology and Oncology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
  7. 7Division of Gastroenterology and Hepatology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
  8. 8Department of Clinical Genetics, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
  9. 9Family Cancer Clinic, Netherlands Cancer Institute, Amsterdam, The Netherlands
  10. 10Department of Gastrointestinal Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands
  11. 11Division of Clinical Cancer Genomics, City of Hope, Duarte, California, USA
  12. 12Departments of Medical Oncology and Population Sciences, City of Hope, Duarte, California, USA
  13. 13Institute of Human Genetics/National Center for Hereditary Tumor Syndromes, University Hospital Bonn, Bonn, Germany
  14. 14Department of Internal Medicine/National Center for Hereditary Tumor Syndromes, University Hospital Bonn, Bonn, Germany
  15. 15IPATIMUP—Institut of Molecular Pathology and Immunology, University of Porto, Porto, Portugal
  16. 16i3s, Universidade do Porto Instituto de Investigação e Inovação em Saúde, Porto, Portugal
  17. 17Instituto de Investigação e Inovação em Saúde & Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal
  18. 18Faculty of Medicine, University of Porto, Porto, Portugal
  19. 19Service de Dermatologie, Hotel Dieu, Nantes, France
  20. 20Dermatologie, CHU Rennes, Rennes, France
  21. 21Génétique, Hopital Universitaire Caremeau, Nimes, France
  22. 22Digestive Cancer Registry of Burgundy, UMR 1231, Réseau FRANCIM (réseau Français des registres du cancer), Burgundy Franche-Comté University, Dijon, France
  23. 23Unité Clinique d’Oncologie génétique, Centre Leon Berard, Lyon, France
  24. 24INSERM U830, Université de Paris, Paris, France
  1. Correspondence to Dr Chrystelle Colas, Département de Génétique, Institut Curie, Paris, France; chrystelle.colas{at}curie.fr

Abstract

Background Pathogenic variants (PV) of CTNNA1 are found in families fulfilling criteria for hereditary diffuse gastric cancer (HDGC) but no risk estimates were available until now. The aim of this study is to evaluate diffuse gastric cancer (DGC) risks for carriers of germline CTNNA1 PV.

Methods Data from published CTNNA1 families were updated and new families were identified through international collaborations. The cumulative risk of DGC by age for PV carriers was estimated with the genotype restricted likelihood (GRL) method, taking into account non-genotyped individuals and conditioning on all observed phenotypes and genotypes of the index case to obtain unbiased estimates. A non-parametric (NP) and the Weibull functions were used to model the shape of penetrance function with the GRL. Kaplan-Meier incidence curve and standardised incidence ratios were also computed. A ‘leave-one-out’ strategy was used to evaluate estimate uncertainty.

Results Thirteen families with 46 carriers of PV were included. The cumulative risks of DGC at 80 years for carriers of CTNNA1 PV are 49% and 57%, respectively with the Weibull GRL and NP GRL methods. Risk ratios to population incidence reach particularly high values at early ages and decrease with age. At 40 years, they are equal to 65 and 833, respectively with the Weibull GRL and NP GRL.

Conclusion This is the largest series of CTNNA1 families that provides the first risk estimates of GC. These data will help to improve management and surveillance for these patients and support inclusion of CTNNA1 in germline testing panels.

  • medical oncology
  • gastroenterology
  • genetic predisposition to disease
  • genetic counseling

Data availability statement

Data are available on reasonable request.

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Data availability statement

Data are available on reasonable request.

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Footnotes

  • Twitter @PBenusiglio

  • MC and YD contributed equally.

  • Contributors MC, YD, CC contributed to conduct, reporting, conception and design of the study. MC, HD, MS, PRB, FC, DFC, BWK, LPvH, AC, JMvD, BN, TS, IS, RH, LB, LM, JC, BB, A-MB, CC contributed to acquisition of data. MC, YD, CO, SL, IS, LG, MS, VB, DS-I, CL and CC contributed to analysis and interpretation of data. CC act as a guarantor.

  • Funding This research is supported by the European Reference on Genetic Tumour Risk Syndromes (ERN GENTURIS)—Project ID No 739547. ERN GENTURIS is partly co-funded by the European Union within the framework of the Third Health Programme ‘ERN-2016-Framework Partnership Agreement 2017-2021’. The work was also supported by the project PTDC/BTM-TEC/6706/2020 (LEGOH) funded by ERDF funds through the COMPETE 2020—POCI, Portugal 2020, and by The Portuguese Foundation for Science and Technology (FCT). SL was supported by the PhD fellowship Ref. 2020.05773.BD.

  • Competing interests None declared.

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

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.