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Cited by 17Cancer Genomics and DiagnosticsSarcoma Diagnosis and TreatmentChromatin Remodeling and Cancer

The DOI matches its Crossref record; 39 of the 39 references it cites were found in a registry or an index.

Detection and utility of cell-free and circulating tumour DNA in bone and soft-tissue sarcomas

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Tsoi, Kim M., Gokgoz, Nalan, Darville-O'Quinn, Paige, Prochazka, Patrick, Malekoltojari, Ainaz, Griffin, Anthony M., Ferguson, Peter C., Wunder, Jay S., Andrulis, Irene L.·2021·Bone & Joint Research
DOI 10.1302/2046-3758.109.bjr-2021-0014.r1PMC PMC8479566
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Abstract

Aims Cell-free DNA (cfDNA) and circulating tumour DNA (ctDNA) are used for prognostication and monitoring in patients with carcinomas, but their utility is unclear in sarcomas. The objectives of this pilot study were to explore the prognostic significance of cfDNA and investigate whether tumour-specific alterations can be detected in the circulation of sarcoma patients. Methods Matched tumour and blood were collected from 64 sarcoma patients (n = 70 samples) prior to resection of the primary tumour (n = 57) or disease recurrence (n = 7). DNA was isolated from plasma, quantified, and analyzed for cfDNA. A subset of cases (n = 6) underwent whole exome sequencing to identify tumour-specific alterations used to detect ctDNA using digital droplet polymerase chain reaction (ddPCR). Results Cell-free was present in 69 of 70 samples above 0.5 ng/ml. Improved disease-free survival was found for patients with lower cfDNA levels (90% vs 48% at one-year for ≤ 6 ng/ml and > 6 ng/ml, respectively; p = 0.005). Digital droplet PCR was performed as a pilot study and mutant alleles were detectable at 0.5% to 2.5% of the wild type genome, and at a level of 0.25 ng tumour DNA. Tumour-specific alterations (ctDNA) were found in five of six cases. Conclusion This work demonstrates the feasibility and potential utility of cfDNA and ctDNA as biomarkers for bone and soft-tissue sarcomas, despite the lack of recurrent genomic alterations. A larger study is required to validate these findings. Cite this article: Bone Joint Res 2021;10(9):602–610.

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Crossref · 10.1302/2046-3758.109.bjr-2021-0014.r1

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Figures

Fig. 1 Cell-free DNA fragment size assessment by capillary electrophoresis. Lane L contains the molecular weight ladder; Lanes 1 to 11 contain extracted DNA samples for 11 individual cases. All samples tested contained signal peaks corresponding to DNA fragments of 140 bp to 200 bp, consistent with cell-free DNA (blue arrow). The purple lines indicate the upper marker (10,380 bp) while the green lines indicate the lower marker (35 bp).
Fig. 1 Cell-free DNA fragment size assessment by capillary electrophoresis. Lane L contains the molecular weight ladder; Lanes 1 to 11 contain extracted DNA samples for 11 individual cases. All samples tested contained signal peaks corresponding to DNA fragments of 140 bp to 200 bp, consistent with cell-free DNA (blue arrow). The purple lines indicate the upper marker (10,380 bp) while the green lines indicate the lower marker (35 bp).CC BY-NC-ND · PubMed Central
Fig. 2 Disease-free and overall survival for sarcoma patients depending on amount of cell-free DNA (cfDNA) at time of surgery. a) Patients with ≤ 6 ng/ml cfDNA have significantly better disease-free survival than patients with > 6 ng/ml cfDNA (90% vs 48% at one year for ≤ 6 ng/ml and > 6 ng/ml, respectively; p = 0.005, univariate analysis). b) With available numbers, a significant difference in overall survival was not detected in patients based on the level of cfDNA (p = 0.064, univariate analysis).
Fig. 2 Disease-free and overall survival for sarcoma patients depending on amount of cell-free DNA (cfDNA) at time of surgery. a) Patients with ≤ 6 ng/ml cfDNA have significantly better disease-free survival than patients with > 6 ng/ml cfDNA (90% vs 48% at one year for ≤ 6 ng/ml and > 6 ng/ml, respectively; p = 0.005, univariate analysis). b) With available numbers, a significant difference in overall survival was not detected in patients based on the level of cfDNA (p = 0.064, univariate analysis).CC BY-NC-ND · PubMed Central
Fig. 3 Detection of tumour-specific alterations in sarcoma. Results for a representative case of localized extremity undifferentiated pleomorphic sarcoma. Whole exome sequencing of the primary tumour revealed a COL19A1-G125A variant. a) Results of a dilutional assay, demonstrating our ability to detect this tumour-specific variant at 0.5% of the wild type genome with droplet polymerase chain reaction (ddPCR). b) Results demonstrating that the COL19A1-G125A variant was detectable in the patient’s plasma. Shown are ddPCR results for DNA extracted from the patient’s 1) a non-template control, 2) whole blood (i.e. wild-type; 20 ng DNA), 3) tumour (10 ng DNA), and 4) plasma (i.e. circulating tumour DNA; 10 ng DNA). Green = wild-type-positive droplets; blue = variant-positive droplets; orange = variant/wild-type positive droplets; grey = negative droplets. VAF, variant allele frequency.
Fig. 3 Detection of tumour-specific alterations in sarcoma. Results for a representative case of localized extremity undifferentiated pleomorphic sarcoma. Whole exome sequencing of the primary tumour revealed a COL19A1-G125A variant. a) Results of a dilutional assay, demonstrating our ability to detect this tumour-specific variant at 0.5% of the wild type genome with droplet polymerase chain reaction (ddPCR). b) Results demonstrating that the COL19A1-G125A variant was detectable in the patient’s plasma. Shown are ddPCR results for DNA extracted from the patient’s 1) a non-template control, 2) whole blood (i.e. wild-type; 20 ng DNA), 3) tumour (10 ng DNA), and 4) plasma (i.e. circulating tumour DNA; 10 ng DNA). Green = wild-type-positive droplets; blue = variant-positive droplets; orange = variant/wild-type positive droplets; grey = negative droplets. VAF, variant allele frequency.CC BY-NC-ND · PubMed Central

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  1. Hemming ML, 2019, JCO Precis Oncol, 2019

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Authors
Tsoi, K. M., Gokgoz, N., Darville-O'Quinn, P., Prochazka, P., Malekoltojari, A., Griffin, A. M., Ferguson, P. C., Wunder, J. S., & Andrulis, I. L.
Affiliations
  • University of Toronto (CA)
  • Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Canada
  • Lunenfeld-Tanenbaum Research Institute (CA)
Corresponding author
Tsoi, Kim M.
ORCID
Venue
Bone & Joint Research
Publisher
British Editorial Society of Bone & Joint Surgery
Published
2021-09-01
Volume
10
Issue
9
Pages
602-610
ISSN
2046-3758 (ISSN-L)
DOI
10.1302/2046-3758.109.bjr-2021-0014.r1
PMC
PMC8479566
OpenAlex
W3201200552
Cited by
17
References
39
Citations by year
2026: 5 · 2025: 8 · 2024: 2 · 2023: 1 · 2022: 1
FWCI
0.40
Type
journal article
Language
en
Open access
Licence
Locations
  • Bone and Joint Research (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
  • Health Sciences › Medicine › Oncology › Sarcoma Diagnosis and Treatment
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
Keywords
cell-free DNA, circulating tumor DNA, bone sarcoma, soft tissue sarcoma, prognostic factors, disease-free survival, liquid biopsy, droplet digital PCR

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