TY - JOUR
T1 - Molecular Characterization of Circulating Tumor DNA in Pediatric Rhabdomyosarcoma: A Feasibility Study
AU - Ruhen, Olivia
AU - Lak, Nathalie S.M.
AU - Stutterheim, Janine
AU - Danielli, Sara G.
AU - Chicard, Mathieu
AU - Iddir, Yasmine
AU - Saint-Charles, Alexandra
AU - Di Paolo, Virginia
AU - Tombolan, Lucia
AU - Gatz, Susanne A.
AU - Aladowicz, Ewa
AU - Proszek, Paula
AU - Jamal, Sabri
AU - Stankunaite, Reda
AU - Hughes, Deborah
AU - Carter, Paul
AU - Izquierdo, Elisa
AU - Wasti, Ajla
AU - Chisholm, Julia C.
AU - George, Sally L.
AU - Pace, Erika
AU - Chesler, Louis
AU - Aerts, Isabelle
AU - Pierron, Gaelle
AU - Zaidi, Sakina
AU - Delattre, Olivier
AU - Surdez, Didier
AU - Kelsey, Anna
AU - Hubank, Michael
AU - Bonvini, Paolo
AU - Bisogno, Gianni
AU - Di Giannatale, Angela
AU - Schleiermacher, Gudrun
AU - Schäfer, Beat W.
AU - Tytgat, Godelieve A.M.
AU - Shipley, Janet
PY - 2022/10
Y1 - 2022/10
N2 - PURPOSE Rhabdomyosarcomas (RMS) are rare neoplasms affecting children and young adults. Efforts to improve patient survival have been undermined by a lack of suitable disease markers. Plasma circulating tumor DNA (ctDNA) has shown promise as a potential minimally invasive biomarker and monitoring tool in other cancers; however, it remains underexplored in RMS. We aimed to determine the feasibility of identifying and quantifying ctDNA in plasma as a marker of disease burden and/or treatment response using blood samples from RMS mouse models and patients. METHODS We established mouse models of RMS and applied quantitative polymerase chain reaction (PCR) and droplet digital PCR (ddPCR) to detect ctDNA within the mouse plasma. Potential driver mutations, copy-number alterations, and DNA breakpoints associated with PAX3/7-FOXO1 gene fusions were identified in the RMS samples collected at diagnosis. Patient-matched plasma samples collected from 28 patients with RMS before, during, and after treatment were analyzed for the presence of ctDNA via ddPCR, panel sequencing, and/or whole-exome sequencing. RESULTS Human tumor-derived DNA was detectable in plasma samples from mouse models of RMS and correlated with tumor burden. In patients, ctDNA was detected in 14/18 pretreatment plasma samples with ddPCR and 7/7 cases assessed by sequencing. Levels of ctDNA at diagnosis were significantly higher in patients with unfavorable tumor sites, positive nodal status, and metastasis. In patients with serial plasma samples (n = 18), fluctuations in ctDNA levels corresponded to treatment response. CONCLUSION Comprehensive ctDNA analysis combining high sensitivity and throughput can identify key molecular drivers in RMS models and patients, suggesting potential as a minimally invasive biomarker. Preclinical assessment of treatments using mouse models and further patient testing through prospective clinical trials are now warranted.
AB - PURPOSE Rhabdomyosarcomas (RMS) are rare neoplasms affecting children and young adults. Efforts to improve patient survival have been undermined by a lack of suitable disease markers. Plasma circulating tumor DNA (ctDNA) has shown promise as a potential minimally invasive biomarker and monitoring tool in other cancers; however, it remains underexplored in RMS. We aimed to determine the feasibility of identifying and quantifying ctDNA in plasma as a marker of disease burden and/or treatment response using blood samples from RMS mouse models and patients. METHODS We established mouse models of RMS and applied quantitative polymerase chain reaction (PCR) and droplet digital PCR (ddPCR) to detect ctDNA within the mouse plasma. Potential driver mutations, copy-number alterations, and DNA breakpoints associated with PAX3/7-FOXO1 gene fusions were identified in the RMS samples collected at diagnosis. Patient-matched plasma samples collected from 28 patients with RMS before, during, and after treatment were analyzed for the presence of ctDNA via ddPCR, panel sequencing, and/or whole-exome sequencing. RESULTS Human tumor-derived DNA was detectable in plasma samples from mouse models of RMS and correlated with tumor burden. In patients, ctDNA was detected in 14/18 pretreatment plasma samples with ddPCR and 7/7 cases assessed by sequencing. Levels of ctDNA at diagnosis were significantly higher in patients with unfavorable tumor sites, positive nodal status, and metastasis. In patients with serial plasma samples (n = 18), fluctuations in ctDNA levels corresponded to treatment response. CONCLUSION Comprehensive ctDNA analysis combining high sensitivity and throughput can identify key molecular drivers in RMS models and patients, suggesting potential as a minimally invasive biomarker. Preclinical assessment of treatments using mouse models and further patient testing through prospective clinical trials are now warranted.
UR - https://www.mendeley.com/catalogue/c0186fe3-944a-36b6-a090-4f317ce69e15/
U2 - 10.1200/po.21.00534
DO - 10.1200/po.21.00534
M3 - Article
C2 - 36265118
SN - 2473-4284
JO - JCO precision oncology
JF - JCO precision oncology
IS - 6
ER -