Mutational dynamics between primary and relapse neuroblastomas

Mutational dynamics between primary and relapse neuroblastomas. Schramm, A., Köster, J., Assenov, Y., Althoff, K., Peifer, M., Mahlow, E., Odersky, A., Beisser, D., Ernst, C., Henssen, A. G, Stephan, H., Schröder, C., Heukamp, L., Engesser, A., Kahlert, Y., Theissen, J., Hero, B., Roels, F., Altmüller, J., Nürnberg, P., Astrahantseff, K., Gloeckner, C., Preter, K. D., Plass, C., Lee, S., Lode, H. N, Henrich, K., Gartlgruber, M., Speleman, F., Schmezer, P., Westermann, F., Rahmann, S., Fischer, M., Eggert, A., & Schulte, J. H Nature Genetics, 47(8):872–877, Aug, 2015.

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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.

@Article{Schramm2015,
  author   = {Alexander Schramm and Johannes K\"{o}ster and Yassen Assenov and Kristina Althoff and Martin Peifer and Ellen Mahlow and Andrea Odersky and Daniela Beisser and Corinna Ernst and Anton G Henssen and Harald Stephan and Christopher Schr\"{o}der and Lukas Heukamp and Anne Engesser and Yvonne Kahlert and Jessica Theissen and Barbara Hero and Frederik Roels and Janine Altm\"{u}ller and Peter N\"{u}rnberg and Kathy Astrahantseff and Christian Gloeckner and Katleen De Preter and Christoph Plass and Sangkyun Lee and Holger N Lode and Kai-Oliver Henrich and Moritz Gartlgruber and Frank Speleman and Peter Schmezer and Frank Westermann and Sven Rahmann and Matthias Fischer and Angelika Eggert and Johannes H Schulte},
  journal  = {Nature Genetics},
  title    = {Mutational dynamics between primary and relapse neuroblastomas},
  year     = {2015},
  month    = {Aug},
  number   = {8},
  pages    = {872--877},
  volume   = {47},
  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.},
  doi      = {10.1038/ng.3349},
  keywords = {paper},
  url      = {http://dx.doi.org/10.1038/ng.3349},
}

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