Skip to main content

Advertisement

SpringerLink
Log in

Cell-free DNA concentration and fragment size fraction correlate with FDG PET/CT-derived parameters in NSCLC patients

  • Original Article
  • Published:
European Journal of Nuclear Medicine and Molecular Imaging Aims and scope Submit manuscript

Abstract

Purpose

The aim of our study was to investigate the correlation between cfDNA concentration and fragment size fraction with FDG PET/CT- and CT-derived parameters in untreated NSCLC patient.

Methods

Fifty-three patients diagnosed of locally advanced or metastatic NSCLC who had undergone FDG PET/CT, CT and cfDNA analysis prior to any treatment were included in this retrospective study. CfDNA concentration was measured by fluorometry and fragment size fractions were determined by microchip electrophoresis. [18F]F-FDG PET/CT was performed and standardised uptake values (SUV), metabolic tumour volume (MTV) and total lesion glycolysis (TLG) were calculated for primary, extrapulmonary and total disease. CT scans were evaluated according to RECIST 1.1 criteria.

Results

CfDNA concentration showed a positive correlation with extrapulmonary MTV (r2 = 0.36, P = 0.009), and extrapulmonary TLG (r2 = 0.35, P = 0.009) and their whole-body (wb) ratios. Higher concentrations of total cfDNA were found in patients with liver lesions. Short fragments of cfDNA (100–250 bp) showed a positive correlation with extrapulmonary MTV (r2 = 0.49, P = 0.0005) and extrapulmonary TLG (r2 = 0.39, P = 0.006) and their respective wb ratios, and a negative correlation with SUVmean (r2 = −0.31, P = 0.03) and SUVmean/SUVmax ratio (r2 = −0.34, P = 0.02). A higher fraction of short cfDNA fragments was found in patients with liver and pleural lesions.

Conclusions

This study supports the hypothesis that cfDNA concentration and short cfDNA fragment size fraction reflect the tumour burden as well as metabolic activity in advanced NSCLC patients. This suggests their suitability as complementary tests for a more accurate diagnosis of tumour metabolic behaviour and to allow personalised therapies.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Data availability

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

References

  1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68:394–424.

    PubMed  Google Scholar 

  2. Inamura K. Lung cancer: understanding its molecular pathology and the 2015 WHO classification. Front Oncol. 2017;7:1–7.

    Article  Google Scholar 

  3. Pakkala S, Ramalingam SS. Personalized therapy for lung cancer: striking a moving target. JCI insight. 2018;3.

  4. Diaz LA, Bardelli A. Liquid biopsies: genotyping circulating tumor DNA. J Clin Oncol. 2014;32:579–86.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Wiener RS, Schwartz LM, Woloshin S, Welch HG. Population-based risk for complications after transthoracic needle lung biopsy of a pulmonary nodule: an analysis of discharge records. Ann Intern Med. 2011;155:137–44.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Valpione S, Gremel G, Mundra P, Middlehurst P, Galvani E, Girotti MR, et al. Plasma total cell-free DNA (cfDNA) is a surrogate biomarker for tumour burden and a prognostic biomarker for survival in metastatic melanoma patients. Eur J Cancer. 2018;88:1–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Tissot C, Toffart A-C, Villar S, Souquet P-J, Merle P, Moro-Sibilot D, et al. Circulating free DNA concentration is an independent prognostic biomarker in lung cancer. Eur Respir J. 2015;46:1773–80.

    Article  CAS  PubMed  Google Scholar 

  8. Spindler K-LG, Boysen AK, Pallisgård N, Johansen JS, Tabernero J, Sørensen MM, et al. Cell-free DNA in metastatic colorectal cancer: a systematic review and meta-analysis. Oncologist. 2017;22:1049–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Dawson S-J, Tsui DWY, Murtaza M, Biggs H, Rueda OM, Chin S-F, et al. Analysis of circulating tumor DNA to monitor metastatic breast cancer. N Engl J Med. 2013;368:1199–209.

    Article  CAS  PubMed  Google Scholar 

  10. Singh N, Gupta S, Pandey RM, Chauhan SS, Saraya A. High levels of cell-free circulating nucleic acids in pancreatic cancer are associated with vascular encasement. Metastasis Poor Surviv Cancer Invest. 2015;33:78–85.

    CAS  Google Scholar 

  11. Winther-Larsen A, Fledelius J, Demuth C, Bylov CM, Meldgaard P, Sorensen BS. Early change in FDG-PET signal and plasma cell-free DNA level predicts erlotinib response in EGFR wild-type NSCLC patients. Transl Oncol. 2016;9:505–11.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Szpechcinski A, Chorostowska-Wynimko J, Struniawski R, Kupis W, Rudzinski P, Langfort R, et al. Cell-free DNA levels in plasma of patients with non-small-cell lung cancer and inflammatory lung disease. Br J Cancer. 2015;113:476–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Weng J-L, Atyah M, Zhou C-H, Ren N. Progress in quantitative technique of circulating cell free DNA and its role in cancer diagnosis and prognosis. Cancer Gene Ther. 2019;239:75–84.

    Article  CAS  Google Scholar 

  14. Bronkhorst AJ, Ungerer V, Holdenrieder S. The emerging role of cell-free DNA as a molecular marker for cancer management. Biomol Detect Quantif. 2019;17:100087.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Underhill HR, Kitzman JO, Hellwig S, Welker NC, Daza R, Baker DN, et al. Fragment length of circulating tumor DNA. PLoS Genet. 2016;12:1–24.

    Article  Google Scholar 

  16. Jiang P, Chan CWM, Chan KCA, Cheng SH, Wong J, Wong VWS, et al. Lengthening and shortening of plasma DNA in hepatocellular carcinoma patients. Proc Natl Acad Sci U S A. 2015;112:E1317–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Mouliere F, Robert B, Peyrotte E, Del Rio M, Ychou M, Molina F, et al. High fragmentation characterizes tumour-derived circulating DNA. PLoS One. 2011;6(9):e23418.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Yamamoto Y, Uemura M, Nakano K, Hayashi Y, Wang C, Ishizuya Y, et al. Increased level and fragmentation of plasma circulating cell-free DNA are diagnostic and prognostic markers for renal cell carcinoma. Oncotarget. 2018;9:20467–75.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Lapin M, Oltedal S, Tjensvoll K, Buhl T, Smaaland R, Garresori H, et al. Fragment size and level of cell-free DNA provide prognostic information in patients with advanced pancreatic cancer. J Transl Med. 2018;16:1–10.

    Article  Google Scholar 

  20. Soliman SES, Alhanafy AM, Habib MSE, Hagag M, Ibrahem RAL. Serum circulating cell free DNA as potential diagnostic and prognostic biomarker in non small cell lung cancer. Biochem Biophys Reports. 2018;15:45–51.

    Article  Google Scholar 

  21. Lin J, Xie G, Liao G, Wang B, Yan M, Li H, et al. Prognostic value of 18F-FDG-PET/CT in patients with nasopharyngeal carcinoma: a systematic review and meta-analysis. Oncotarget. 2017;8:33884–96.

    Article  PubMed  Google Scholar 

  22. Infante JR, Cabrera J, Rayo JI, Cruz C, Serrano J, Moreno A, et al. 18F-FDG PET/CT quantitative parameters as prognostic factor in localized and inoperable lung cancer. Rev Esp Med Nucl Imagen Mol. 2020;39:353–9.

    CAS  PubMed  Google Scholar 

  23. Zhu D, Wang L, Zhang H, Chen J, Wang Y, Byanju S, et al. Prognostic value of 18F-FDG-PET/CT parameters in patients with pancreatic carcinoma: a systematic review and meta-analysis. Medicine. 2017;96:e7813.

    Article  PubMed  PubMed Central  Google Scholar 

  24. McEvoy AC, Warburton L, Al-Ogaili Z, Celliers L, Calapre L, Pereira MR, et al. Correlation between circulating tumour DNA and metabolic tumour burden in metastatic melanoma patients. BMC Cancer. 2018;18:1–8.

    Article  Google Scholar 

  25. Woff E, Kehagias P, Vandeputte C, Ameye L, Guiot T, Paesmans M, et al. Combining 18F-FDG PET/CT-based metabolically active tumor volume and circulating cell-free DNA significantly improves outcome prediction in chemorefractory metastatic colorectal cancer. J Nucl Med. 2019;60:1366–72.

    Article  CAS  PubMed  Google Scholar 

  26. Vizza E, Corrado G, De Angeli M, Carosi M, Mancini E, Baiocco E, et al. Serum DNA integrity index as a potential molecular biomarker in endometrial cancer. J Exp Clin Cancer Res. 2018;37:16.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Çelik F, Tan YZ, Özdemir S, Sılan F. Comparison of SUVmax values obtained from F-18 FDG PET/CT and cell-free DNA levels measured from plasma in oncology patients. Mol Imaging Radionucl Ther. 2019;28:46–52.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Winther-Larsen A, Demuth C, Fledelius J, Madsen AT, Hjorthaug K, Meldgaard P, et al. Correlation between circulating mutant DNA and metabolic tumour burden in advanced non-small cell lung cancer patients. Br J Cancer. 2017;117:704–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Morbelli S, Alama A, Ferrarazzo G, Coco S, Genova C, Rijavec E, et al. Circulating tumor DNA reflects tumor metabolism rather than tumor burden in chemotherapy-naive patients with advanced non–small cell lung cancer:18F-FDG PET/CT study. J Nucl Med. 2017;58:1764–9.

    Article  CAS  PubMed  Google Scholar 

  30. Nygaard AD, Holdgaard PC, Spindler KLG, Pallisgaard N, Jakobsen A. The correlation between cell-free DNA and tumour burden was estimated by PET/CT in patients with advanced NSCLC. Br J Cancer. 2014;110:363–8.

    Article  CAS  PubMed  Google Scholar 

  31. Hu Z, Chen H, Long Y, Li P, Gu Y. The main sources of circulating cell-free DNA: apoptosis, necrosis and active secretion. Crit Rev Oncol Hematol. 2021;157:103166.

    Article  PubMed  Google Scholar 

  32. Giroux DJ, Rami-Porta R, Chansky K, Crowley JJ, Groome PA, Postmus PE, et al. The IASLC Lung Cancer Staging Project: data elements for the prospective project. J Thorac Oncol. 2009;4:679–83.

  33. Vesselle H, Salskov A, Turcotte E, Wiens L, Schmidt R, Jordan CD, et al. Relationship between non-small cell lung cancer FDG uptake at PET, tumor histology, and Ki-67 proliferation index. J Thorac Oncol. 2008;3:971–8.

    Article  PubMed  Google Scholar 

  34. Cappabianca S, Porto A, Petrillo M, Greco B, Reginelli A, Ronza F, et al. Preliminary study on the correlation between grading and histology of solitary pulmonary nodules and contrast enhancement and [18F]fluorodeoxyglucose standardised uptake value after evaluation by dynamic multiphase CT and PET/CT. J Clin Pathol. 2011;64:114–9.

    Article  PubMed  Google Scholar 

  35. Chiu C-H, Yeh Y-C, Lin K-H, Wu Y-C, Lee Y-C, Chou T-Y, et al. Histological subtypes of lung adenocarcinoma have differential 18F-fluorodeoxyglucose uptakes on the positron emission tomography/computed tomography scan. J Thorac Oncol. 2011;6:1697–703.

    Article  PubMed  Google Scholar 

  36. Stewart CM, Tsui DWY. Circulating cell-free DNA for non-invasive cancer management. Cancer Gene Ther. 2018;228–229:169–79.

    Article  Google Scholar 

  37. Sorber L, Zwaenepoel K, Jacobs J, De Winne K, Goethals S, Reclusa P, et al. Circulating cell-free DNA and RNA analysis as liquid biopsy: optimal centrifugation protocol. Cancers (Basel). 2019;11:458.

    Article  CAS  Google Scholar 

  38. Bronkhorst AJ, Aucamp J, Pretorius PJ. Cell-free DNA: Preanalytical variables. Clin Chim Acta. 2015;450:243–53.

    Article  CAS  PubMed  Google Scholar 

  39. Shi J, Zhang R, Li J, Zhang R. Size profile of cell-free DNA: a beacon guiding the practice and innovation of clinical testing. Theranostics. 2020;10:4737–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Dooms C, van Baardwijk A, Verbeken E, van Suylen RJ, Stroobants S, De Ruysscher D, et al. Association between 18F-fluoro-2-deoxy-D-glucose uptake values and tumor vitality: prognostic value of positron emission tomography in early-stage non-small cell lung cancer. J Thorac Oncol. 2009;4:822–8.

    Article  PubMed  Google Scholar 

  41. Wang R-A, Li Q-L, Li Z-S, Zheng P-J, Zhang H-Z, Huang X-F, et al. Apoptosis drives cancer cells proliferate and metastasize. J Cell Mol Med. 2013;17:205–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Jahr S, Hentze H, Englisch S, Hardt D, Fackelmayer FO, Hesch R-D, et al. DNA fragments in the blood plasma of cancer patients: quantitations and evidence for their origin from apoptotic and necrotic cells. Cancer Res. 2001;61:1659–65.

    CAS  PubMed  Google Scholar 

  43. Kaira K, Okumura T, Ohde Y, Takahashi T, Murakami H, Oriuchi N, et al. Correlation between 18F-FDG uptake on PET and molecular biology in metastatic pulmonary tumors. J Nucl Med. 2011;52:705–11.

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

The authors would like to dedicate this manuscript to Dr. Rafael Molina, who recently passed away. His dedication and passion to the field of cancer diagnosis were an inspiration to all of us. The authors thank the patients for their participation in the study and the study staff who were involved in collecting specimen material at the study sites. The authors would like to express our gratitude to Dr. James Hugall for providing language assistance for the manuscript.

Funding

Hoffman-La Roche Ltd. supplied the reagent cobas® cfDNA Sample Preparation Kit for cfDNA extraction.

Author information

Author notes

  1. P. Paredes and JA. Puig-Butillé contributed equally to this manuscript

Authors and Affiliations

  1. Biochemistry and Molecular Genetics Department, Hospital Clínic, Barcelona, Spain

    JM. González de Aledo-Castillo

  2. Nuclear Medicine Department, Hospital Clínic, Barcelona, Spain

    S. Casanueva-Eliceiry, D. Fuster & P. Paredes

  3. Radiology Department, Hospital Clínic, Barcelona, Spain

    A. Soler-Perromat & I. Vollmer

  4. Thoracic Oncology Unit, Hospital Clínic, Barcelona, Spain

    D. Fuster, N. Reguart, I. Vollmer, P. Paredes & JA. Puig-Butillé

  5. Medical Oncology Department, Hospital Clínic, Barcelona, Spain

    N. Reguart, N. Viñolas & R. Reyes

  6. August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain

    D. Fuster, N. Reguart, P. Paredes & JA. Puig-Butillé

  7. Faculty of Medicine, University of Barcelona, Barcelona, Spain

    D. Fuster & P. Paredes

  8. Molecular Biology CORE, Hospital Clínic, Villarroel 170, 08036, Barcelona, Spain

    V. Pastor & JA. Puig-Butillé

Authors
  1. JM. González de Aledo-Castillo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S. Casanueva-Eliceiry
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A. Soler-Perromat
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. D. Fuster
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. V. Pastor
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. N. Reguart
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. N. Viñolas
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. R. Reyes
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. I. Vollmer
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. P. Paredes
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. JA. Puig-Butillé
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Conceptualisation: JM. González de Aledo-Castillo, I. Vollmer, P. Paredes, JA. Puig-Butillé; data curation: JM. González de Aledo-Castillo, S. Casanueva-Eliceiry, A. Soler, V. Pastor, N. Reguart, N. Viñolas, R. Reyes, I. Vollmer, P. Paredes, JA. Puig-Butillé; formal analysis: JM. González de Aledo-Castillo; investigation: JM. González de Aledo-Castillo, I. Vollmer, P. Paredes, JA. Puig-Butillé; methodology: JM. González de Aledo-Castillo, JA. Puig-Butillé; project administration: P. Paredes, JA. Puig-Butillé; resources: P. Paredes, I. Vollmer, D. Fuster, N. Reguart, JA. Puig-Butillé; supervision: P. Paredes, JA. Puig-Butillé; visualisation: JM. González de Aledo-Castillo, I. Vollmer, P. Paredes, JA. Puig-Butillé; writing – original draft: JM. González de Aledo-Castillo: writing – review and editing: JM. González de Aledo-Castillo, I. Vollmer, P. Paredes, N. Reguart, JA. Puig-Butillé. All authors read and approved the final manuscript.

Corresponding author

Correspondence to JA. Puig-Butillé.

Ethics declarations

Ethics approval and consent to participate

This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of Hospital Clinic de Barcelona (approval registration number HCB/2016/0889).

Consent to participate

Not applicable.

Consent for publication

Not applicable.

Conflict of interest

The authors declare no competing interests.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This article is part of the Topical Collection on Oncology - Chest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

González de Aledo-Castillo, J., Casanueva-Eliceiry, S., Soler-Perromat, A. et al. Cell-free DNA concentration and fragment size fraction correlate with FDG PET/CT-derived parameters in NSCLC patients. Eur J Nucl Med Mol Imaging 48, 3631–3642 (2021). https://doi.org/10.1007/s00259-021-05306-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00259-021-05306-2

Keywords

Search

Navigation