Cancer Incidence and Spectrum Among Children With Genetically Confirmed Beckwith-Wiedemann Spectrum in Germany: A Retrospective Cohort Study.

August 01, 2020

Sümeyye Cöktü 1, Claudia Spix 2, Melanie Kaiser 2, Jasmin Beygo 3, Stephanie Kleinle 4, Nadine Bachmann 5,6, Nicolai Kohlschmidt 7, Dirk Prawitt 8, Alf Beckmann 9, Ruediger Klaes 10, Claudia Nevinny-Stickel-Hinzpeter 11, Steffi Döhnert 12, Cornelia Kraus 13, Gundula Kadgien 14, Inga Vater 15, Saskia Biskup 16, Michael Kutsche 17, Jürgen Kohlhase 18, Thomas Eggermann 19, Martin Zenker 20, Christian P Kratz 21.

Abstract

Background: Beckwith-Wiedemann syndrome (BWS) is a cancer predisposition syndrome caused by defects on chromosome 11p15.5. The quantitative cancer risks in BWS patients depend on the underlying (epi)genotype but have not yet been assessed in a population-based manner.

Methods: We identified a group of 321 individuals with a molecularly confirmed diagnosis of BWS and analysed the cancer incidence up to age 15 years and cancer spectrum by matching their data with the German Childhood Cancer Registry.

Results: We observed 13 cases of cancer in the entire BWS cohort vs 0.4 expected. This corresponds to a 33-fold increased risk (standardised incidence ratio (SIR) = 32.6; 95% confidence interval = 17.3-55.7). The specific cancers included hepatoblastoma (n = 6); nephroblastoma (n = 4); astrocytoma (n = 1); neuroblastoma (n = 1) and adrenocortical carcinoma (n = 1). The cancer SIR was highest in patients with a paternal uniparental disomy of 11p15.5 (UPDpat). A high cancer risk remained when cases of cancer diagnosed prior to the BWS diagnosis were excluded.

Conclusions: This study confirms an increased cancer risk in children with BWS. Our findings suggest that the highest cancer risk is associated with UPDpat. We were unable to confirm an excessive cancer risk in patients with IC1 gain of methylation (IC1-GOM) and this finding requires further investigation.

  1. Department of Pediatric Hematology and Oncology, Hannover Medical School, Carl-Neuberg-Str. 1, Hannover, 30625, Germany.
  2. German Childhood Cancer Registry, Institute for Medical Biostatistics, Epidemiology and Informatics, University Medical Center Mainz, Obere Zahlbacher Str. 69, Mainz, 55131, Germany.
  3. Institut für Humangenetik, Universitätsklinikum Essen, Universität Duisburg-Essen, Hufelandstr. 55, Essen, 45147, Germany.
  4. MGZ, Medizinisch Genetisches Zentrum München, Bayerstr. 3-5, München, 80335, Germany.
  5. Bioscientia Ingelheim, Konrad-Adenauer-Str.17, Ingelheim, 55218, Germany.
  6. Limbach Genetics, Medizinische Genetik Mainz Prof. Bergmann & Kollegen, Mainz, Germany.
  7. Institut für Klinische Genetik und Tumorgenetik Bonn, Maximilianstraße 28d, Bonn, 53111, Germany.
  8. Center for Paediatrics and Adolescent Medicine, University Medical Center, Langenbeckstr. 1, Mainz, 55101, Germany.
  9. MVZ Dr. Eberhard & Partner Dortmund, Humangenetik, Brauhausstr.4, Dortmund, 44137, Germany.
  10. SYNLAB MVZ Humangenetik Mannheim GmbH, Harrlachweg 1, Mannheim, 68163, Germany.
  11. SYNLAB MVZ Humane Genetik München, Lindwurmstr. 23, München, 80337, Germany.
  12. Mitteldeutscher Praxisverbund Humangenetik – Überörtliche Gemeinschaftspraxis, Friedrichstr. 38/40, Dresden, 01067, Germany.
  13. Humangenetisches Institut, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Schwabachanlage 10, Erlangen, 91054, Germany.
  14. MVZ für Humangenetik und Molekularpathologie, Robert-Koch-Str. 10, Rostock, 18059, Germany.
  15. Institut für Humangenetik, Universitätsklinikum Schleswig-Holstein, Campus Kiel, Arnold-Heller-Str. 3, Haus 10, Kiel, 24105, Germany.
  16. Praxis für Humangenetik / CeGaT, Paul-Ehrlich-Str. 23, Tübingen, 72076, Germany.
  17. Gemeinschaftspraxis für Humangenetik & Genetische Labore (Peters, Kleier, Preusse), Altonaer Str. 61-63, Hamburg, 20357, Germany.
  18. Praxis für Humangenetik Freiburg, Heinrich-von-Stephan-Str. 5, Freiburg, 79100, Germany.
  19. Institute of Human Genetics, University Hospital RWTH Aachen, Pauwelsstr. 30, Aachen, 52074, Germany.
  20. Institute of Human Genetics, University Hospital Magdeburg, Leipziger Str. 44, Magdeburg, 39120, Germany.
  21. Department of Pediatric Hematology and Oncology, Hannover Medical School, Carl-Neuberg-Str. 1, Hannover, 30625, Germany. kratz.christian@mh-hannover.de.