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Cancer genetics
Short report
Role of germline aberrations affecting CTNNA1, MAP3K6 and MYD88 in gastric cancer susceptibility
  1. Robbert D A Weren1,
  2. Rachel S van der Post2,
  3. Ingrid P Vogelaar1,
  4. J Han van Krieken2,
  5. Liesbeth Spruijt1,
  6. Jan Lubinski3,
  7. Anna Jakubowska3,
  8. Urszula Teodorczyk3,
  9. Cora M Aalfs4,
  10. Liselotte P van Hest5,
  11. Carla Oliveira6,7,8,
  12. Eveline J Kamping1,
  13. Hans K Schackert9,
  14. Guglielmina N Ranzani10,
  15. Encarna B Gómez García11,
  16. Frederik J Hes12,
  17. Elke Holinski-Feder13,
  18. Maurizio Genuardi14,
  19. Margreet G E M Ausems15,
  20. Rolf H Sijmons16,
  21. Anja Wagner17,
  22. Lizet E van der Kolk18,
  23. Annemieke Cats19,
  24. Inga Bjørnevoll20,
  25. Nicoline Hoogerbrugge1,
  26. Marjolijn J L Ligtenberg1,2
  1. 1 Department of Human Genetics, Radboud university medical center, Nijmegen, The Netherlands
  2. 2 Department of Pathology, Radboud university medical center, Nijmegen, The Netherlands
  3. 3 Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland
  4. 4 Department of Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands
  5. 5 Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands
  6. 6 Expression Regulation in Cancer Group, Instituto de Investigação e Inovação em Saúde, Porto, Portugal
  7. 7 Department of Cancer Genetics, Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal
  8. 8 Department of Pathology and Oncology, Faculty of Medicine, University of Porto, Porto, Portugal
  9. 9 Department of Surgical Research, Universitätsklinikum Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
  10. 10 Department of Biology and Biotechnology, University of Pavia, Pavia, Italy
  11. 11 Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, The Netherlands
  12. 12 Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands
  13. 13 Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Munich, Germany
  14. 14 Institute of Genomic Medicine, Catholic University of the Sacred Heart, Milan, Italy
  15. 15 Department of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands
  16. 16 Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
  17. 17 Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands
  18. 18 Family Cancer Clinic, The Netherlands Cancer Institute, Amsterdam, The Netherlands
  19. 19 Department of Gastrointestinal Oncology, The Netherlands Cancer Institute/Antoni van Leeuwenhoek, Amsterdam, The Netherlands
  20. 20 Department of Medical Genetics, St Olav’s Hospital, Trondheim, Norway
  1. Correspondence to Professor Marjolijn J L Ligtenberg, Department of Human Genetics, Radboud University Medical Center, Nijmegen 6525 GA, The Netherlands; Marjolijn.Ligtenberg{at}radboudumc.nl

Abstract

Background In approximately 10% of all gastric cancer (GC) cases, a heritable cause is suspected. A subset of these cases have a causative germline CDH1 mutation; however, in most cases the cause remains unknown. Our objective was to assess to what extent these remaining cases may be explained by germline mutations in the novel candidate GC predisposing genes CTNNA1, MAP3K6 or MYD88.

Methods We sequenced a large cohort of unexplained young and/or familial patients with GC (n=286) without a CDH1germline mutation for germline variants affecting CTNNA1, MAP3K6 and MYD88 using a targeted next-generation sequencing approach based on single-molecule molecular inversion probes.

Results Predicted deleterious germline variants were not encountered in MYD88, but recurrently observed in CTNNA1 (n=2) and MAP3K6 (n=3) in our cohort of patients with GC. In contrast to deleterious variants in CTNNA1, deleterious variants in MAP3K6 also occur frequently in the general population.

Conclusions Based on our results MAP3K6 should no longer be considered a GC predisposition gene, whereas deleterious CTNNA1 variants are confirmed as an infrequent cause of GC susceptibility. Biallelic MYD88 germline mutations are at most a very rare cause of GC susceptibility as no additional cases were identified.

  • cancer: gastric
  • heritability
  • ctnna1 – map3k6 – myd88
  • next generation sequencing

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/

https://doi.org/10.1136/jmedgenet-2017-104962

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    Footnotes

    • RDAW and RSP contributed equally.

    • Contributors RDAW, RSvdP, IPV, NH and MJLL were responsible for study concept and design. Pathology review was performed by RSvdP. All authors were responsible for data acquisition. Data analysis and interpretation were performed by RDAW, RSvdP and MJLL. RDAW, RSvdP, NH and MJLL wrote the manuscript, with assistance and final approval of all authors.

    • Funding This study was funded by KWF Kankerbestrijding (grant number KUN 2013-5876, RSvdP).

    • Competing interests None declared.

    • Patient consent Detail has been removed from this case description/these case descriptions to ensure anonymity. The editors and reviewers have seen the detailed information available and are satisfied that the information backs up the case the authors are making.

    • Ethics approval This study was approved by the medical ethics committee of the Radboud university medical center, reference number 2013/201.

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