Plasma DNA-based molecular diagnosis, prognostication, and monitoring of patientswith EWSR1 fusion-positive sarcomas Journal Article
| Authors: | Shukla, N. N.; Patel, J. A.; Magnan, H.; Zehir, A.; You, D.; Tang, J.; Meng, F.; Samoila, A.; Slotkin, E. K.; Ambati, S. R.; Chou, A. J.; Wexler, L. H.; Meyers, P. A.; Peerschke, E. I.; Viale, A.; Berger, M. F.; Ladanyi, M. |
| Article Title: | Plasma DNA-based molecular diagnosis, prognostication, and monitoring of patientswith EWSR1 fusion-positive sarcomas |
| Abstract: | Purpose Ewing sarcoma (ES) and desmoplastic small round cell tumors (DSRCTs) are aggressive sarcomas molecularly characterized by EWSR1 gene fusions. As pathognomonic genomic events in these respective tumor types, EWSR1 fusions represent robust potential biomarkers for disease monitoring. Methods To investigate the feasibility of identifying EWSR1 fusions in plasma-derived cell-free DNA(cfDNA) from patients withESandDSRCT,weevaluated two complementary approaches in samples from 17 patients with radiographic evidence of disease. The first approach involved identification of patient-specific genomicEWSR1fusion breakpoints in formalin-fixed, paraffinembedded tumorDNAusing a broad, hybridization capture-based next-generation sequencing (NGS) panel, followed by design of patient-specific droplet digital polymerase chain reaction (ddPCR) assays for plasma cfDNA interrogation. The second approach used a disease-tailored targeted hybridization capture-based NGS panel applied directly to cfDNA, which included EWSR1 as well as several other genes with potential prognostic use. Results EWSR1 fusions were identified in 11 of 11 (100%) ES and five of six (83%) DSRCT cfDNA samples by ddPCR, whereas 10 of 11 (91%) and four of six (67%) were identified byNGS. The ddPCR approach had higher sensitivity, ranging between 0.009% and 0.018%. However, the hybrid capture-based NGS assay identified the precise fusion breakpoints in the majority of cfDNA samples, as well as mutations in TP53 and STAG2, two other recurrent, clinically significant alterations in ES, all without prior knowledge of the tumor genotype. Conclusion These results provide a compelling rationale for an integrated approach using both NGS and ddPCR for plasma cfDNA-based biomarker evaluations in prospective cooperative group studies. © 2018 American Society of Clinical Oncology. |
| Keywords: | adolescent; adult; child; clinical article; controlled study; human tissue; school child; young adult; unclassified drug; human cell; sensitivity and specificity; polymerase chain reaction; gene; genotype; patient monitoring; protein p53; ewing sarcoma; sarcoma; cancer genetics; feasibility study; dna; gene identification; gene fusion; cancer tissue; radiodiagnosis; dna determination; desmoplastic small round cell tumor; molecular diagnosis; ewsr1 gene; stag2 gene; tp53 gene; next generation sequencing; cancer prognosis; human; male; female; priority journal; article; cell free nucleic acid; plasma derived cell free dna |
| Journal Title: | JCO Precision Oncology |
| Volume: | 2017 |
| Issue: | 1 |
| ISSN: | 2473-4284 |
| Publisher: | American Society of Clinical Oncology |
| Date Published: | 2017-12-01 |
| Language: | English |
| DOI: | 10.1200/po.16.00028 |
| PROVIDER: | scopus |
| PUBMED: | 29629425 |
| DOI/URL: | |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledge in the PDF -- Corresponding authors is MSK author: Neerav Shukla -- Source: Scopus |
Altmetric
Citation Impact
BMJ Impact Analytics
MSK Authors
Related MSK Work