Journal
CLINICAL CANCER RESEARCH
Volume 23, Issue 15, Pages 4224-4232Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-16-2082
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Funding
- St. Anna Kinderkrebsforschung
- Austrian National Bank (ONB) [15114, 16611]
- Austrian Science Fund (FWF) [I 2799-B28]
- European Union's Seventh Framework Program (FP7) under the project ENCCA [HEALTH-F2-2011-261474]
- Austrian Science Fund (FWF) [I2799] Funding Source: Austrian Science Fund (FWF)
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Purpose: Tumor relapse is the most frequent cause of death in stage 4 neuroblastomas. Since genomic information on the relapse precursor cells could guide targeted therapy, our aim was to find the most appropriate tissue for identifying relapse-seeding clones. Experimental design: We analyzed 10 geographically and temporally separated samples of a single patient by SNP array and validated the data in 154 stage 4 patients. Results: In the case study, aberrations unique to certain tissues and time points were evident besides concordant aberrations shared by all samples. Diagnostic bone marrow-derived disseminated tumor cells (DTCs) as well as the metastatic tumor and DTCs at relapse displayed a 1q deletion, not detected in any of the seven primary tumor samples. In the validation cohort, the frequency of 1q deletion was 17.8%, 10%, and 27.5% in the diagnostic DTCs, diagnostic tumors, and DTCs at relapse, respectively. This aberration was significantly associated with 19q and ATRX deletions. We observed a significant increased likelihood of an adverse event in the presence of 19q deletion in the diagnostic DTCs. Conclusions: Different frequencies of 1q and 19q deletions in the primary tumors as compared with DTCs, their relatively high frequency at relapse, and their effect on event-free survival (19q deletion) indicate the relevance of analyzing diagnostic DTCs. Our data support the hypothesis of a branched clonal evolution and a parallel progression of primary and metastatic tumor cells. Therefore, searching for biomarkers to identify the relapse-seeding clone should involve diagnostic DTCs alongside the tumor tissue. (C) 2017 AACR.
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