期刊
CLINICAL CANCER RESEARCH
卷 24, 期 4, 页码 939-949出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-17-1586
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资金
- Annenberg Foundation
- Nelia and Amadeo Barletta Foundation (FNAB)
- Association Hubert Gouin Enfance et Cancer
- Associations Enfants et Sante, Les Bagouz a Manon, Les amis de Claire
- SiRIC/INCa [INCa-DGOS-4654]
- CEST of Institute Curie
- Agence Nationale de la Recherche (Investissements d'Avenir program) [ANR-10-EQPX-03, ANR-10-INBS-09-08]
- Canceropole Ile-de-France
- SiRIC-Curie program SiRIC [INCa-DGOS- 4654]
- [PHRC IC2007-09]
Purpose: Neuroblastoma displays important clinical and genetic heterogeneity, with emergence of new mutations at tumor progression. Experimental Design: To study clonal evolution during treatment and follow-up, an innovative method based on circulating cell-free DNA (cfDNA) analysis by whole-exome sequencing (WES) paired with target sequencing was realized in sequential liquid biopsy samples of 19 neuroblastoma patients. Results: WES of the primary tumor and cfDNA at diagnosis showed overlap of single-nucleotide variants (SNV) and copy number alterations, with 41% and 93% of all detected alterations common to the primary neuroblastoma and cfDNA. CfDNA WES at a second time point indicated a mean of 22 new SNVs for patients with progressive disease. Relapse-specific alterations included genes of the MAPK pathway and targeted the protein kinase A signaling pathway. Deep coverage target sequencing of intermediate time points during treatment and follow-up identified distinct subclones. For 17 seemingly relapse-specific SNVs detected by cfDNA WES at relapse but not tumor or cfDNA WES at diagnosis, deep coverage target sequencing detected these alterations in minor subclones, with relapse-emerging SNVs targeting genes of neuritogenesis and cell cycle. Furthermore a persisting, resistant clone with concomitant disappearance of other clones was identified by a mutation in the ubiquitin protein ligase HERC2. Conclusions: Modelization of mutated allele fractions in cfDNA indicated distinct patterns of clonal evolution, with either a minor, treatment-resistant clone expanding to a major clone at relapse, or minor clones collaborating toward tumor progression. Identification of treatment-resistant clones will enable development of more efficient treatment strategies. (C) 2017 AACR.
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