Poster Presentation Advances in Neuroblastoma Research Congress 2016

Mutational dynamics between primary and relapse neuroblastoma involve the Hippo/YAP1 pathway and genes relevant for epithelial-mesenchymal transition (#296)

Johannes H Schulte 1 , Daniela Beisser 2 , Yasen Assenov 3 , Johannes Köster 2 , Corinna Ernst 2 , Anton Henssen 4 , Anne Engesser 5 , Yvonne Kahlert 5 , Jessica Theissen 5 , Barbara Hero 5 , Katleen De Preter 6 , Christopher Plass 3 , Holger Lode 7 , Kathy Astrahantseff 4 , Kai Henrich 1 , Maritz Gartlgruber 1 , Kerstin Schönfeld 4 , Frank Speleman 6 , Peter Schmezer 3 , Frank Westermann 1 , Sven Rahmann 2 , Alexander Schramm 8 , Matthias Fischer 5 , Angelika Eggert 4
  1. Neuroblastoma Genomics, German Cancer Research Center (DKFZ), Heidelberg, Germany
  2. Genome Informatics, Institute of Human Genetics, University Hospital Essen, Essen, Germany
  3. Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), Heidelberg, Germany
  4. Pediatric Oncology/Hematology/SCT, Charité University Medicine, Berlin, Germany
  5. Pediatric Oncology and Hematology, University Children's Hospital Cologne, Cologne, Germany
  6. Centre for Medical Genetics, Ghent University Hospital, Ghent, Belgium
  7. Pediatric Oncology and Hematology, University Medicine Greifswald, Greifswald, Germany
  8. Pediatric Oncology and Hematology, University Children's Hospital Essen, Essen, Germany

The molecular mechanisms behind neruoblastoma relapse are poorly defined. We here used whole exome sequencing, mRNA expression analysis, array CGH and DNA methylation analysis to holistically characterize 16 paired samples from neuroblastoma patients at diagnosis and relapse. Global allele frequencies at relapse indicated clonal mutation selection in addition to de novo mutations during disease progression. Promoter methylation patterns were consistent over disease course and patient specific. No relapse tumor acquired new mutations in previously identified neuroblastoma driver genes, but MYCN amplification was acquired in one. Inactivating mutations in the putative PTPN14 tumor suppressor and a relapse specific increase in the mRNA expression based pathway activity score for the PTPN14 target gene, YAP and the Hippo-Pathway, were identified, and represent the first hint for Hippo/YAP signaling involvement in neuroblastoma relapse. Recurrant new mutations in HRAS, KRAS, DOCK8, and genes mediating cell-cell interaction in 13 of 16 relapse tumors also point to disturbances in signaling pathways mediating epithelial-mesenchymal transition. Our results indicate a role for epithelial-mesenchymal transition processes and their modulation by genomically altered upstream signaling in neuroblastoma recurrence.