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Nat Genet. 2015 Aug;47(8):872-7. doi: 10.1038/ng.3349. Epub 2015 Jun 29.

Mutational dynamics between primary and relapse neuroblastomas.

Author information

1
Pediatric Oncology and Hematology, University Children's Hospital Essen, University of Duisburg-Essen, Essen, Germany.
2
Genome Informatics, Institute of Human Genetics, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
3
Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), Heidelberg, Germany.
4
1] Department of Translational Genomics, University of Cologne, Cologne, Germany. [2] Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.
5
NEO New Oncology, Cologne, Germany.
6
Pediatric Oncology and Hematology, University Children's Hospital, Cologne, Germany.
7
1] Cologne Center for Genomics, University of Cologne, Cologne, Germany. [2] Human Genetics, University Hospital Cologne, Cologne, Germany.
8
1] Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany. [2] Cologne Center for Genomics, University of Cologne, Cologne, Germany. [3] Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
9
Pediatric Oncology and Hematology, Charité University Medicine, Berlin, Germany.
10
Centre for Medical Genetics, Ghent University Hospital, Ghent, Belgium.
11
1] Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), Heidelberg, Germany. [2] German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), Heidelberg, Germany.
12
Computer Science, TU Dortmund, Dortmund, Germany.
13
Pediatric Oncology and Hematology, University Medicine Greifswald, Greifswald, Germany.
14
Neuroblastoma Genomics, B087, German Cancer Research Center (DKFZ), Heidelberg, Germany.
15
1] Genome Informatics, Institute of Human Genetics, University Hospital Essen, University of Duisburg-Essen, Essen, Germany. [2] Computer Science, TU Dortmund, Dortmund, Germany.
16
1] Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany. [2] Pediatric Oncology and Hematology, University Children's Hospital, Cologne, Germany.
17
1] Pediatric Oncology and Hematology, Charité University Medicine, Berlin, Germany. [2] German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), Heidelberg, Germany.
18
1] Pediatric Oncology and Hematology, University Children's Hospital Essen, University of Duisburg-Essen, Essen, Germany. [2] Pediatric Oncology and Hematology, Charité University Medicine, Berlin, Germany. [3] German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), Heidelberg, Germany.

Abstract

Neuroblastoma is a malignancy of the developing sympathetic nervous system that is often lethal when relapse occurs. We here used whole-exome sequencing, mRNA expression profiling, array CGH and DNA methylation analysis to characterize 16 paired samples at diagnosis and relapse from individuals with neuroblastoma. The mutational burden significantly increased in relapsing tumors, accompanied by altered mutational signatures and reduced subclonal heterogeneity. Global allele frequencies at relapse indicated clonal mutation selection during disease progression. Promoter methylation patterns were consistent over disease course and were patient specific. Recurrent alterations at relapse included mutations in the putative CHD5 neuroblastoma tumor suppressor, chromosome 9p losses, DOCK8 mutations, inactivating mutations in PTPN14 and a relapse-specific activity pattern for the PTPN14 target YAP. Recurrent new mutations in HRAS, KRAS and genes mediating cell-cell interaction in 13 of 16 relapse tumors indicate disturbances in signaling pathways mediating mesenchymal transition. Our data shed light on genetic alteration frequency, identity and evolution in neuroblastoma.

PMID:
26121086
DOI:
10.1038/ng.3349
[Indexed for MEDLINE]

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