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Cell-free DNA as a diagnostic and prognostic biomarker in pediatric rhabdomyosarcoma

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Abstract
PURPOSE Total cell-free DNA (cfDNA) and tumor-derived cfDNA (ctDNA) can be used to study tumor-derived genetic aberrations. We analyzed the diagnostic and prognostic potential of cfDNA and ctDNA, obtained from pediatric patients with rhabdomyosarcoma.METHODS cfDNA was isolated from diagnostic plasma samples from 57 patients enrolled in the EpSSG RMS2005 study. To study the diagnostic potential, shallow whole genome sequencing (shWGS) and cell-free reduced representation bisulphite sequencing (cfRRBS) were performed in a subset of samples and all samples were tested using droplet digital polymerase chain reaction to detect methylated RASSF1A (RASSF1A-M). Correlation with outcome was studied by combining cfDNA RASSF1A-M detection with analysis of our rhabdomyosarcoma-specific RNA panel in paired cellular blood and bone marrow fractions and survival analysis in 56 patients.RESULTS At diagnosis, ctDNA was detected in 16 of 30 and 24 of 26 patients using shallow whole genome sequencing and cfRRBS, respectively. Furthermore, 21 of 25 samples were correctly classified as embryonal by cfRRBS. RASSF1A-M was detected in 21 of 57 patients. The presence of RASSF1A-M was significantly correlated with poor outcome (the 5-year event-free survival [EFS] rate was 46.2% for 21 RASSF1A-M-positive patients, compared with 84.9% for 36 RASSF1A-M-negative patients [P < .001]). RASSF1A-M positivity had the highest prognostic effect among patients with metastatic disease. Patients both negative for RASSF1A-M and the rhabdomyosarcoma-specific RNA panel (28 of 56 patients) had excellent outcome (5-year EFS 92.9%), while double-positive patients (11/56) had poor outcome (5-year EFS 13.6%, P < .001).CONCLUSION Analyzing ctDNA at diagnosis using various techniques is feasible in pediatric rhabdomyosarcoma and has potential for clinical use. Measuring RASSF1A-M in plasma at initial diagnosis correlated significantly with outcome, particularly when combined with paired analysis of blood and bone marrow using a rhabdomyosarcoma-specific RNA panel.
Keywords
Cancer Research, Oncology

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MLA
Lak, Nathalie S. M., et al. “Cell-Free DNA as a Diagnostic and Prognostic Biomarker in Pediatric Rhabdomyosarcoma.” JCO PRECISION ONCOLOGY, vol. 7, American Society of Clinical Oncology (ASCO), 2023, doi:10.1200/po.22.00113.
APA
Lak, N. S. M., van Zogchel, L. M. J., Zappeij-Kannegieter, L., Javadi, A., Van Paemel, R., Vandeputte, C., … Stutterheim, J. (2023). Cell-free DNA as a diagnostic and prognostic biomarker in pediatric rhabdomyosarcoma. JCO PRECISION ONCOLOGY, 7. https://doi.org/10.1200/po.22.00113
Chicago author-date
Lak, Nathalie S.M., Lieke M.J. van Zogchel, Lily Zappeij-Kannegieter, Ahmad Javadi, Ruben Van Paemel, Charlotte Vandeputte, Katleen De Preter, et al. 2023. “Cell-Free DNA as a Diagnostic and Prognostic Biomarker in Pediatric Rhabdomyosarcoma.” JCO PRECISION ONCOLOGY 7. https://doi.org/10.1200/po.22.00113.
Chicago author-date (all authors)
Lak, Nathalie S.M., Lieke M.J. van Zogchel, Lily Zappeij-Kannegieter, Ahmad Javadi, Ruben Van Paemel, Charlotte Vandeputte, Katleen De Preter, Bram De Wilde, Mathieu Chicard, Yasmine Iddir, Gudrun Schleiermacher, Olivia Ruhen, Janet Shipley, Marta Fiocco, Johannes H.M. Merks, Max M. van Noesel, C. Ellen van der Schoot, Godelieve A.M. Tytgat, and Janine Stutterheim. 2023. “Cell-Free DNA as a Diagnostic and Prognostic Biomarker in Pediatric Rhabdomyosarcoma.” JCO PRECISION ONCOLOGY 7. doi:10.1200/po.22.00113.
Vancouver
1.
Lak NSM, van Zogchel LMJ, Zappeij-Kannegieter L, Javadi A, Van Paemel R, Vandeputte C, et al. Cell-free DNA as a diagnostic and prognostic biomarker in pediatric rhabdomyosarcoma. JCO PRECISION ONCOLOGY. 2023;7.
IEEE
[1]
N. S. M. Lak et al., “Cell-free DNA as a diagnostic and prognostic biomarker in pediatric rhabdomyosarcoma,” JCO PRECISION ONCOLOGY, vol. 7, 2023.
@article{01GVZNHRQR49HZW0J348Z0EKXW,
  abstract     = {{PURPOSE Total cell-free DNA (cfDNA) and tumor-derived cfDNA (ctDNA) can be used to study tumor-derived genetic aberrations. We analyzed the diagnostic and prognostic potential of cfDNA and ctDNA, obtained from pediatric patients with rhabdomyosarcoma.METHODS cfDNA was isolated from diagnostic plasma samples from 57 patients enrolled in the EpSSG RMS2005 study. To study the diagnostic potential, shallow whole genome sequencing (shWGS) and cell-free reduced representation bisulphite sequencing (cfRRBS) were performed in a subset of samples and all samples were tested using droplet digital polymerase chain reaction to detect methylated RASSF1A (RASSF1A-M). Correlation with outcome was studied by combining cfDNA RASSF1A-M detection with analysis of our rhabdomyosarcoma-specific RNA panel in paired cellular blood and bone marrow fractions and survival analysis in 56 patients.RESULTS At diagnosis, ctDNA was detected in 16 of 30 and 24 of 26 patients using shallow whole genome sequencing and cfRRBS, respectively. Furthermore, 21 of 25 samples were correctly classified as embryonal by cfRRBS. RASSF1A-M was detected in 21 of 57 patients. The presence of RASSF1A-M was significantly correlated with poor outcome (the 5-year event-free survival [EFS] rate was 46.2% for 21 RASSF1A-M-positive patients, compared with 84.9% for 36 RASSF1A-M-negative patients [P < .001]). RASSF1A-M positivity had the highest prognostic effect among patients with metastatic disease. Patients both negative for RASSF1A-M and the rhabdomyosarcoma-specific RNA panel (28 of 56 patients) had excellent outcome (5-year EFS 92.9%), while double-positive patients (11/56) had poor outcome (5-year EFS 13.6%, P < .001).CONCLUSION Analyzing ctDNA at diagnosis using various techniques is feasible in pediatric rhabdomyosarcoma and has potential for clinical use. Measuring RASSF1A-M in plasma at initial diagnosis correlated significantly with outcome, particularly when combined with paired analysis of blood and bone marrow using a rhabdomyosarcoma-specific RNA panel.}},
  articleno    = {{e2200113}},
  author       = {{Lak, Nathalie S.M. and van Zogchel, Lieke M.J. and Zappeij-Kannegieter, Lily and Javadi, Ahmad and Van Paemel, Ruben and Vandeputte, Charlotte and De Preter, Katleen and De Wilde, Bram and Chicard, Mathieu and Iddir, Yasmine and Schleiermacher, Gudrun and Ruhen, Olivia and Shipley, Janet and Fiocco, Marta and Merks, Johannes H.M. and van Noesel, Max M. and van der Schoot, C. Ellen and Tytgat, Godelieve A.M. and Stutterheim, Janine}},
  issn         = {{2473-4284}},
  journal      = {{JCO PRECISION ONCOLOGY}},
  keywords     = {{Cancer Research,Oncology}},
  language     = {{eng}},
  pages        = {{10}},
  publisher    = {{American Society of Clinical Oncology (ASCO)}},
  title        = {{Cell-free DNA as a diagnostic and prognostic biomarker in pediatric rhabdomyosarcoma}},
  url          = {{http://doi.org/10.1200/po.22.00113}},
  volume       = {{7}},
  year         = {{2023}},
}

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