期刊
EBIOMEDICINE
卷 9, 期 -, 页码 120-129出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.ebiom.2016.05.029
关键词
Intra-tumor genetic heterogeneity; Pediatric solid tumors; Wilms tumor; Tumor evolution; Tumor multisampling; Molecular biomarkers; Copy number aberrations
资金
- Cancer Research UK
- CCLG
- CCLG Centres
- National Institute of Health Research (NIHR) Biomedical Research Centre at Great Ormond Street Hospital
- Cancer Research UK [C1188/A4614]
- Great Ormond Street Hospital Children's Charity [W1090]
- NIHR Academic Clinical Fellowship
- NIHR Academic Clinical Lectureship
- EU-FP7 P-medicine project: From data sharing and integration via VPH models to personalized medicine [270089]
- EU-FP7 project ENCCA [261474]
- Cancer Research UK [16358, 17297] Funding Source: researchfish
- Great Ormond Street Hospital Childrens Charity [V1405, W1090] Funding Source: researchfish
- Medical Research Council [MR/L016311/1] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0513-10046] Funding Source: researchfish
- The Francis Crick Institute [10110] Funding Source: researchfish
- MRC [MR/L016311/1] Funding Source: UKRI
The evolution of pediatric solid tumors is poorly understood. There is conflicting evidence of intra-tumor genetic homogeneity vs. heterogeneity (ITGH) in a small number of studies in pediatric solid tumors. A number of copy number aberrations (CNA) are proposed as prognostic biomarkers to stratify patients, for example 1q+ in Wilms tumor (WT); current clinical trials use only one sample per tumor to profile this genetic biomarker. We multisampled 20 WT cases and assessed genome-wide allele-specific CNA and loss of heterozygosity, and inferred tumor evolution, using Illumina CytoSNP12v2.1 arrays, a custom analysis pipeline, and the MEDICC algorithm. We found remarkable diversity of ITGH and evolutionary trajectories inWT. 1q+ is heterogeneous in the majority of tumors with this change, with variable evolutionary timing. We estimate that at least three samples per tumor are needed to detect >95% of cases with 1q+. In contrast, somatic 11p15 LOH is uniformly an early event inWT development. We find evidence of two separate tumor origins in unilateral disease with divergent histology, and in bilateral WT. We also show subclonal changes related to differential response to chemotherapy. Rational trial design to include biomarkers in risk stratification requires tumor multisampling and reliable delineation of ITGH and tumor evolution. (C) 2016 The Authors. Published by Elsevier B.V.
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