Oral Presentation Advances in Neuroblastoma Research Congress 2016

Distal chromosome 6q-deletion defines a subgroup of ultra-high risk neuroblastoma patients (#76)

Pauline Depuydt 1 2 , Valentina Boeva 3 4 5 6 , Peter F Ambros 7 8 , Shahab Asgharzadeh 9 10 , Edward F Attiyeh 11 12 13 , Valérie Combaret 14 , Raffaella Defferrari 15 , Matthias Fischer 16 17 , Toby D Hocking 18 , Michael Hogarty 11 12 , Meredith Irwin 19 , Susan Kreissman 20 , Ruth Ladenstein 7 8 , Geneviève Laureys 21 , Wendy London 22 , Katia Mazzocco 15 , Akira Nakagawara 23 , Rosa Noguera 24 25 , Julie Park 26 27 , Frank Speleman 1 2 , Gian Paolo Tonini 28 29 , Domonique Valteau-Couanet 30 , Luigi Varesio 31 , John M Maris 11 12 13 32 , Gudrun Schleiermacher 33 34 , Katleen De Preter 1 2
  1. Center for Medical Genetics, Ghent University, Ghent, Belgium
  2. Cancer Research Institute Ghent (CRIG), Ghent University, Ghent
  3. Institut Curie, Paris, France
  4. U900, Inserm, Paris, France
  5. Mines ParisTech, Fontainebleau, France
  6. PSL Research University, Paris, France
  7. CCRI, Children's Cancer Research Institute, Vienna, Austria
  8. Department of Pediatrics, Medical University of Vienna, Vienna, Austria
  9. Division of Hematology/Oncology, Children's Hospital Los Angeles, Los Angeles, CA 90027, USA
  10. Keck School of Medicine, University of Southern California, Los Angeles, CA 90027, USA
  11. Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA
  12. Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
  13. Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA
  14. Laboratoire de Recherche Translationnelle, Centre Léon-Bérard, Lyon Cedex 08, France
  15. Department of Pathology, Istituto Giannina Gaslini, Genova , Italy
  16. Department of Pediatric Oncology and Hematology, Medical Faculty, University Children's Hospital Cologne, University of Cologne, Cologne, Germany
  17. Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany
  18. Department of Human Genetics, McGill University, Montreal, Quebec, Canada
  19. Division of Hematology-Oncology, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
  20. Department of Pediatrics, Duke University School of Medicine, Durham, North Carolina, USA
  21. Department of Pediatric Hematology and Oncology, Ghent University Hospital, Ghent, Belgium
  22. Dana-Farber Children's Hospital Cancer and Blood Disorders Center, Harvard Medical School, Boston, Massachusetts, USA
  23. Saga Medical Center KOSEIKAN, Saga, Japan
  24. Pathology Department, Medical School, University of Valencia, Valencia, Spain
  25. Medical Research Foundation INCLIVA, Valencia, Spain
  26. Seattle Children's Hospital, Seattle, Washington, USA
  27. University of Washington, Seattle, Washington, USA
  28. Laboratory of Neuroblastoma, Onco/Haematology Laboratory, University of Padua, Padova , Italy
  29. Pediatric Research Institute (IRP)-Città della Speranza, Padova, Italy
  30. Institut Gustave Roussy, Universite Paris Sud, Paris, France
  31. Laboratory of Molecular Biology, Istituto Giannina Gaslini, Genova, Italy
  32. Abramson Family Cancer Research Institute, Philadelphia, PA 19104, USA
  33. Recherche Translationelle en Oncologie Pédiatrique (RTOP) and Department of Pediatric Oncology, Institut Curie, Paris, France
  34. U830, INSERM, Paris, France

P.Depuydt/V.Boeva:shared first authors

G.Schleiermachter/K.De Preter:shared last authors

 

Prognostic classification of high-risk neuroblastoma patients remains challenging. The aim of this study was to define genomic biomarkers for upfront identification of ultra-high-risk patients that will develop resistance to chemotherapy.

High-resolution array-CGH profiles of diagnostic tumor samples from 570 high-risk neuroblastoma patients were collected from 8 collaborative groups. To correct for possible inter-platform variability, raw data were transformed to a common genome build and segmented using SegAnnDB.

First, datasets from seven European centres were used for training (n=317), while the COG-cohort (n=253) was used for validation of the classifier. We built a classifier using the regions with differential copy numbers (logistic regression analysis) in two extreme training groups, i.e. high-risk patients that die within 18 months and high-risk patients that survive with at least 5 years event-free follow-up. However, this classifier could not discriminate patients with ultra-high-risk in the validation cohort. A possible explanation is that the different cohorts have slightly different population characteristics and treatment protocols.

Second, when we investigated the prognostic power of individual aberrations in both cohorts, we identified regions that are prognostic in one cohort but not in the other, including 1p-deletion and 1q-gain which do not predict poor outcome in the COG cohort. Data from other cohorts will be collected to validate a classifier based on regions that are prognostic across different cohorts.

Indeed, both cohorts also share copy number aberrations that are prognostic, including MYCN-amplification, 4p-deletion and distal 6q-deletion (below -0.3 log relative copy number). Most significant results were observed for 6q-deletion which defines a small subgroup of ultra-high-risk patients with extremely poor outcoma as 92% (12/13) and 100% (9/9) of the training and validation patients with this aberration died of disease.

In conclusion, we identified distal 6q-deletions (more distal to ARID1B previously described in neuroblastoma) that mark neuroblastoma patients for fatal outcome. Further studies are ongoing to identify the 6q-gene/regulatory element that drives the aggressiveness of this disease.