Genomics

Dataset Information

65

Genomes of Relapsing Neuroblastoma


ABSTRACT: Neuroblastoma is a malignancy of the developing sympathetic nervous system that is often lethal when relapse occurs, but the molecular mechanisms behind this process are poorly defined. We here used whole-exome sequencing, mRNA expression, array CGH and DNA methylation analysis to holistically characterize 16 paired samples from neuroblastoma patients at diagnosis and relapse. 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 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 gene, YAP. Recurrent new mutations in HRAS, KRAS, DOCK8 and genes mediating cell-cell interaction in 13/16 relapse tumors also indicate disturbances in signaling pathways mediating mesenchymal transition. Our data shed first light on genetic alteration frequency, identity and evolution in neuroblastoma.

ORGANISM(S): Homo sapiens  

PROVIDER: EGAS00001001387 | EGA |

REPOSITORIES: EGA

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Publications

Mutational dynamics between primary and relapse neuroblastomas.

Schramm Alexander A   Köster Johannes J   Assenov Yassen Y   Althoff Kristina K   Peifer Martin M   Mahlow Ellen E   Odersky Andrea A   Beisser Daniela D   Ernst Corinna C   Henssen Anton G AG   Stephan Harald H   Schröder Christopher C   Heukamp Lukas L   Engesser Anne A   Kahlert Yvonne Y   Theissen Jessica J   Hero Barbara B   Roels Frederik F   Altmüller Janine J   Nürnberg Peter P   Astrahantseff Kathy K   Gloeckner Christian C   De Preter Katleen K   Plass Christoph C   Lee Sangkyun S   Lode Holger N HN   Henrich Kai-Oliver KO   Gartlgruber Moritz M   Speleman Frank F   Schmezer Peter P   Westermann Frank F   Rahmann Sven S   Fischer Matthias M   Eggert Angelika A   Schulte Johannes H JH  

Nature genetics 20150629 8


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 relaps  ...[more]

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