title: Impact of Disseminated Neuroblastoma Cells on the Identification of the Relapse-Seeding Clone.
abstract: 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 andATRXdeletions. 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.Clin Cancer Res; 23(15); 4224-32. ©2017 AACR.
authors.affiliation: CCRI, Children's Cancer Research Institute, Vienna, Austria. peter.ambros@ccri.at reza.abbasi@ccri.at.
authors.forename: M Reza
authors.initials: MR
authors.lastname: Abbasi
authors.affiliation: CCRI, Children's Cancer Research Institute, Vienna, Austria.
authors.forename: Fikret
authors.initials: F
authors.lastname: Rifatbegovic
authors.affiliation: CCRI, Children's Cancer Research Institute, Vienna, Austria.
authors.forename: Clemens
authors.initials: C
authors.lastname: Brunner
authors.affiliation: St. Anna Children's Hospital, Vienna, Austria.
authors.forename: Georg
authors.initials: G
authors.lastname: Mann
authors.affiliation: CCRI, Children's Cancer Research Institute, Vienna, Austria.
authors.forename: Andrea
authors.initials: A
authors.lastname: Ziegler
authors.affiliation: CCRI, Children's Cancer Research Institute, Vienna, Austria.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Pötschger
authors.affiliation: Department of Pediatrics, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Roman
authors.initials: R
authors.lastname: Crazzolara
authors.affiliation: Department of Pediatric Hematology and Oncology, Wroclaw Medical University, Wroclaw, Poland.
authors.forename: Marek
authors.initials: M
authors.lastname: Ussowicz
authors.affiliation: Department of Pediatrics and Adolescent Medicine, Medical University of Graz, Graz, Austria.
authors.forename: Martin
authors.initials: M
authors.lastname: Benesch
authors.affiliation: Department of Pediatrics, Kepler University Clinic Linz, Linz, Austria.
authors.forename: Georg
authors.initials: G
authors.lastname: Ebetsberger-Dachs
authors.affiliation: Department of Pediatrics and Adolescent Medicine, University of Hong Kong, Hong Kong.
authors.forename: Godfrey C F
authors.initials: GCF
authors.lastname: Chan
authors.affiliation: Department of Pediatrics and Adolescent Medicine, Paracelsus Medical University, Salzburg, Austria.
authors.forename: Neil
authors.initials: N
authors.lastname: Jones
authors.affiliation: CCRI, Children's Cancer Research Institute, Vienna, Austria.|Department of Pediatrics, Medical University of Vienna, Vienna, Austria.
authors.forename: Ruth
authors.initials: R
authors.lastname: Ladenstein
authors.affiliation: CCRI, Children's Cancer Research Institute, Vienna, Austria.
authors.forename: Inge M
authors.initials: IM
authors.lastname: Ambros
authors.affiliation: CCRI, Children's Cancer Research Institute, Vienna, Austria. peter.ambros@ccri.at reza.abbasi@ccri.at.|Department of Pediatrics, Medical University of Vienna, Vienna, Austria.
authors.forename: Peter F
authors.initials: PF
authors.lastname: Ambros
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001854:Bone Marrow Cells / Q000473:pathology; D002675:Child, Preschool; D002888:Chromosomes, Human, Pair 19 / Q000235:genetics; D060965:Clonal Evolution / Q000235:genetics*; D018572:Disease-Free Survival; D005260:Female; D017353:Gene Deletion; D018740:Genetic Heterogeneity; D006801:Humans; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009364:Neoplasm Recurrence, Local / Q000235:genetics* / Q000473:pathology; D009367:Neoplasm Staging; D016609:Neoplasms, Second Primary / Q000235:genetics* / Q000473:pathology; D009360:Neoplastic Cells, Circulating / Q000473:pathology; D009447:Neuroblastoma / Q000235:genetics* / Q000473:pathology; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012008:Recurrence; D000075924:X-linked Nuclear Protein / Q000235:genetics
chemical_list: C092332:ATRX protein, human; D000075924:X-linked Nuclear Protein