Open AccessMesenchymal Neuroblastoma Cells Are Undetected by Current mRNA Marker Panels: The Development of a Specific Neuroblastoma Mesenchymal Minimal Residual Disease Panel
Author(s) -
Esther M. van Wezel,
Lieke M. J. van Zogchel,
Jalenka van Wijk,
Ilse Timmerman,
Ngoc-Kim Vo,
Lily ZappeijKannegieter,
Boris Decarolis,
Thorsten Simon,
Max M. van Noesel,
Jan J. Molenaar,
Tim van Groningen,
Rogier Versteeg,
Huib N. Caron,
C. Ellen van der Schoot,
Jan Koster,
Johan van Nes,
Godelieve A.M. Tytgat
Publication year - 2019
Publication title -
jco precision oncology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.405
H-Index - 22
ISSN - 2473-4284
DOI - 10.1200/po.18.00413
Subject(s) - neuroblastoma , minimal residual disease , mesenchymal stem cell , bone marrow , pathology , real time polymerase chain reaction , cancer research , biology , medicine , cell culture , gene , genetics
PURPOSE Patients with neuroblastoma in molecular remission remain at considerable risk for disease recurrence. Studies have found that neuroblastoma tissue contains adrenergic (ADRN) and mesenchymal (MES) cells; the latter express low levels of commonly used markers for minimal residual disease (MRD). We identified MES-specific MRD markers and studied the dynamics of these markers during treatment.PATIENTS AND METHODS Microarray data were used to identify genes differentially expressed between ADRN and MES cell lines. Candidate genes were then studied using real-time quantitative polymerase chain reaction in cell lines and control bone marrow and peripheral blood samples. After selecting a panel of markers, serial bone marrow, peripheral blood, and peripheral blood stem cell samples were obtained from patients with high-risk neuroblastoma and tested for marker expression; survival analyses were also performed.RESULTS PRRX1, POSTN, and FMO3 mRNAs were used as a panel for specifically detecting MES mRNA in patient samples. MES mRNA was detected only rarely in peripheral blood; moreover, the presence of MES mRNA in peripheral blood stem cell samples was associated with low event-free survival and overall survival. Of note, during treatment, serial bone marrow samples obtained from 29 patients revealed a difference in dynamics between MES mRNA markers and ADRN mRNA markers. Furthermore, MES mRNA was detected in a higher percentage of patients with recurrent disease than in those who remained disease free (53% v 32%, respectively; P = .03).CONCLUSION We propose that the markers POSTN and PRRX1, in combination with FMO3, be used for real-time quantitative polymerase chain reaction–based detection of MES neuroblastoma mRNA in patient samples because these markers have a unique pattern during treatment and are more prevalent in patients with poor outcome. Together with existing markers of MRD, these new markers should be investigated further in large prospective studies.