Potential clinical application of free-circulating DNA from blood in renal cancer

Early diagnosis of renal cancer carcinoma is a key determinant of patient survival. The asymptomatic disease course and lack of reliable diagnostic markers lead to the fact that more than 30 % renal cancer cases discovered at an advanced stage, when the prognosis is poor because kidney tumors are resistant to standard chemotherapy and radiation. More than 30 % of renal cancer carcinoma recur or metastasize after surgical treatment. Despite the implementation of novel targeted drugs and immune point inhibitors, the 5-year survival rate for metastatic renal cancer carcinoma remains dismal. Unsatisfactory result of renal cancer treatment may be caused by high inter- and intra-tumor heterogeneity and tumor evolution during therapy, as well as the lack of predictive and on-treatment monitoring biomarkers. Liquid biopsy test that utilizes free-circulating DNA (cfDNA) in the blood of patients, opens up new opportunities for managing patients with renal cancer. The diagnostic and predictive potential of these minimally invasive biomarkers has been demonstrated for various types of cancer. The use of highly sensitive methods of cfDNA analysis may allow early cancer detection and prediction of postoperative disease recurrence before dinical and radiographic progression. Serial cfDNA samples, that were collected before and during course of treatment, can provide information about the dynamic mutational changes in the volume of the entire tumor and metastases in real time, and the emergence of drug resistance during treatment. This information may be promising toolfor optimizing patient-specific therapeutic strategies. This review is focusing on the potential clinical application of cfDNA from blood in renal cancer.

1. Ferlay J., Colombet M., Soerjomataram I. et al. Estimating the global cancer incidence and mortality in 2018: GLOBOCAN sources and methods. Int J Cancer 2019;144(8):1941-53. DOI: 10.1002/ijc.31937.

2. Carril-Ajuria L., Santos M., Roldan-Romero J.M. et al. Prognostic and predictive value of PBRM1 in clear cell renal cell carcinoma. Cancers 2020;12(1):16. DOI: 10.3390/cancers1201001.

3. Hsieh J.J., Chen D., Wang P.I. et al. Genomic biomarkers of a randomized trial comparing first-line everolimus and sunitinib in patients with metastatic renal cell carcinoma. Eur Urol 2017;71(3):405-14. DOI: 10.1016/j.eururo.2016.10.007.

4. Gerlinger M., Rowan A.J., Horswell S. et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med 2012;366(10):883-92. DOI: 10.1056/NEJMoa1113205.

5. Turajlic S., Xu H., Litchfield К. et al. Tracking cancer evolution reveals constrained routes to metastases: TRACERx renal. Cell 2018;173(3):581-94.e12. DOI: 10.1016/j.cell.2018.03.057.

6. Mandel P., Metais P. Les acides nucleiques du plasma sanguine chez l'homme. C R Seances Soc Biol Fil 1948;142:241-3.

7. Thierry A.R., El Messaoudi S., Gahan P.B. et al. Origins, structures, and functions of circulating DNA in oncology. Cancer Metastasis Rev 2016;35(3):347-76. DOI: 10.1007/s10555-016-9629-x.

8. Leon S.A., Shapiro B., Sklaroff D.M., Yaros M.J. Free DNA in the serum of cancer patients and the effect of therapy. Cancer Res. 1977;37(3):646-50. PMID: 837366.

9. Vasioukhin V., Anker P., Maurice P. et al. Point mutations of the N-ras gene in the blood plasma DNA of patients with myelodysplastic syndrome or acute myelogenous leukaemia. Br J Haematol 1994;86(4):774-9. DOI: 10.1111/j.1365-2141.1994.tb04828.x.

10. Sorenson G.D., Pribish D.M., Valone F.H. et al. Soluble normal and mutated DNA sequences from single-copy genes in human blood. Cancer Epidemiol Biomarkers Prev 1994;3(1):67-71.

11. Chan K.C., Jiang P., Zheng Y.W. et al. Cancer genome scanning in plasma: detection of tumor-associated copy number aberrations, single-nucleotide variants, and tumoral heterogeneity by massively parallel sequencing. Clin Chem 2013;59(1):211-24. DOI: 10.1373/clinchem.2012.196014.

12. Murtaza M., Dawson S.J., Tsui D.W. et al. Non-invasive analysis of acquired resistance to cancer therapy by sequencing of plasma DNA. Nature 2013;497(7447):108-12. DOI: 10.1038/nature12065.

13. Bettegowda C., Sausen M., Leary R.J. et al. Detection of circulating tumor DNA in early-and late-stage human malignancies. Sci Transl Med 2014;6(224):224ra24. DOI: 10.1126/scitranslmed.3007094.

14. Heitzer E., Haque I.S., Roberts C.E., Speicher M.R. Current and future perspectives of liquid biopsies in genomics-driven oncology. Nat Rev Genet 2019;20(2):71-88. DOI: 10.1038/s41576-018-0071-5.

15. Barlebo Ahlborn L., 0strup O. Toward liquid biopsies in cancer treatment: application of circulating tumor DNA. APMIS 2019;127(5):329-36. DOI: 10.1111/apm.12912.

16. Roy D., Tiirikainen M. Diagnostic power of DNA methylation classifiers for early detection of cancer. Trends Cancer 2020;6(2):78-81. DOI: 10.1016/j.trecan.2019.12.006.

17. Von Knobloch R., Hegele A., Brandt H. et al. High frequency of serum DNA alterations in renal cell carcinoma detected by fluorescent microsatellite analysis. Int J Cancer 2002;98(6):889-94. DOI: 10.1002/ijc.10263.

18. Skrypkina I., Tsyba L., Onyshchenko K. et al. Concentration and methylation of cell-free DNA from blood plasma as diagnostic markers of renal cancer. Dis Markers 2016;2016:3693096 DOI: 10.1155/2016/3693096.

19. Perego R.A., Corizzato M., Brambilla P. et al. Concentration and microsatellite status of plasma DNA for monitoring patients with renal carcinoma. Eur J Cancer 2008;44(7):1039-47. DOI: 10.1016/j.ejca.2008.03.008.

20. Hauser S., Zahalka T., Ellinger J. et al. Cell-free circulating DNA: diagnostic value in patients with renal cell cancer. Anticancer Res 2010;30(7):2785-9.

21. Ellinger J., Muller D.C., Muller S.C. et al. Circulating mitochondrial DNA in serum: a universal diagnostic biomarker for patients with urological malignancies. Urol Oncol 2012;30(4):509-15. DOI: 10.1016/j.urolonc.2010.03.004.

22. Wan J., Zhu L., Jiang Z., Cheng K. Monitoring of plasma cell-free DNA in predicting postoperative recurrence of clear cell renal cell carcinoma. Urol Int 2013;91(3):273-8. DOI: 10.1159/000351409.

23. Lu H., Busch J., Jung M. et al. Diagnostic and prognostic potential of circulating cell-free genomic and mitochondrial DNA fragments in clear cell renal cell carcinoma patients. Clin Chim Acta 2016;452:109-19. DOI: 10.1016/j.cca.2015.11.009.

24. Yamamoto Y., Uemura M., Nakano K. et al. Increased level and fragmentation of plasma circulating cell-free DNA are diagnostic and prognostic markers for renal cell carcinoma. Oncotarget 2018;9(29):20467-75. DOI: 10.18632/oncotarget.24943.

25. de Martino M., Klatte T., Haitel A., Marberger M. Serum cell-free DNA in renal cell carcinoma: a diagnostic and prognostic marker. Cancer 2012;118(1):82-90. DOI: 10.1002/cncr.26254.

26. Gang F., Guorong L., An Z. et al. Prediction of clear cell renal cell carcinoma by integrity of cell-free DNA in serum. Urology 2010;75(2):262-5. DOI: 10.1016/j.urology.2009.06.048.

27. Hauser S., Zahalka T., Fechner G. et al. Serum DNA hypermethylation in patients with kidney cancer: results of a prospective study. Anticancer Res 2013;33(10):4651-6.

28. Feng G., Ye X., Fang F. et al. Quantification of plasma cell-free DNA1 in predicting therapeutic efficacy of sorafenib on metastatic clear cell renal cell carcinoma. Dis Markers 2013;34(2):105-11. DOI: 10.3233/DMA-120950.

29. Lin Y.L., Wang Y.P., Li H.Z., Zhan X. Aberrant promoter methylation of PCDH17 (Protocadherin 17) in serum and its clinical significance in renal cell carcinoma. Med Sci Monit 2017;23:3318-23. DOI: 10.12659/msm.902077.

30. Maia M.C., Bergerot P.G., Dizman N. et al. Association of circulating tumor DNA (ctDNA) detection in metastatic renal cell carcinoma (mRCC) with tumor burden. Kidney Cancer 2017;1(1):65-70. DOI: 10.3233/KCA-170007.

31. Dizman N., Bergerot P., Bergerot C. et al. Exceptional response to nivolumab rechallenge in metastatic renal cell carcinoma with parallel changes in genomic profile. Eur Urol 2018;73(2):308-10. DOI: 10.1016/j.eururo.2017.08.006.

32. Pal S.K., Sonpavde G., Agarwal N. et al. Evolution of circulating tumor DNA profile from first-line to subsequent therapy in metastatic renal cell carcinoma. Eur Urol 2017;72(4):557-64. DOI: 10.1016/j.eururo.2017.03.046.

33. Yamamoto Y., Uemura M., Fujita M. et al. Clinical significance of the mutational landscape and fragmentation of circulating tumor DNA in renal cell carcinoma. Cancer Sci 2019;110(2):617-28. DOI: 10.1111/cas.13906.

34. Jung M., Ellinger J., Gevensleben H. et al. Cell-free SHOX2 DNA methylation in blood as a molecular staging parameter for risk stratification in renal cell carcinoma patients: a prospective observational cohort study. Clin Chem 2019;65(4):559-68. DOI: 10.1373/clinchem.2018.297549.

35. Smith C.G., Moser T., Mouliere F. et al. Comprehensive characterization of cell-free tumor DNA in plasma and urine of patients with renal tumors. Genome Med 2020;12(1):23. DOI: 10.1186/s13073-020-00723-8

36. Wang B.G., Huang H.Y., Chen Y.C. et al. Increased plasma DNA integrity in cancer patients. Cancer Res 2003;63(14):3966—8.

37. Jiang W.W., Zahurak M., Goldenberg D. et al. Increased plasma DNA integrity index in head and neck cancer patients. Int J Cancer 2006;119(11):2673-6. DOI: 10.1002/ijc.22250.

38. Umetani N., Kim J., Hiramatsu S. et al. Increased integrity of free circulating DNA in sera of patients with colorectal or periampullary cancer: direct quantitative PCR for ALU repeats. Clin Chem 2006;52(6):1062-9. DOI: 10.1373/clinchem.2006.068577.

39. Madhavan D., Wallwiener M., Bents K. et al. Plasma DNA integrity as a biomarker for primary and metastatic breast cancer and potential marker for early diagnosis. Brest Cancer Res Treat 2014;146(1):163-74. DOI: 10.1007/s10549-014-2946-2.

40. Fiala C., Diamandis E.P. Utility of orculating tumor DNA in cancer diagnostics with emphasis on early detection. BMC Med 2018;16(1):166. DOI: 10.1186/s12916-018-1157-9.

41. Merker J.D., Oxnard G.R., Compton C. et al. Circulating tumor DNA analysis in patients with cancer: American Society of Clinical Oncology and College of American Pathologists Joint Review. J Clin Oncol 2018;36(16):1631—41. DOI: 10.1200/JCO.2017.76.8671.

42. Ralla B., Stephan C., Meller S. et al. Nucleic acid-based biomarkers in body fluids of patients with urologic malignancies. Crit Rev Clin Lab Sci 2014;51(4):200-31.

43. Wei T., Zhang Q., Li X. et al. Monitoring tumor burden in response to FOLFIRINOX chemotherapy via profiling circulating cell-free DNA in pancreatic cancer. Mol Cancer Ther 2019;18(1):196-203. DOI: 10.1158/1535-7163.MCT-17-1298. DOI: 10.3109/10408363.2014.914888.

44. Reinert T., Sch0ler L.V., Thomsen R. et al. Analysis of circulating tumour DNA to monitor disease burden following colorectal cancer surgery. Gut 2016;65(4):625-34. DOI: 10.1136/gutjnl-2014-308859.

45. Shen S.Y., Singhania R., Fehringer G. et al. Sensitive tumour detection and classification using plasma cell-free DNA methylomes. Nature 2018;563(7732):579—83. DOI: 10.1038/s41586-018-0703-0.

46. Lasseter K., Nassar A.H., Hamieh L. et al. Plasma cell-free DNA variant analysis compared with methylated DNA analysis in renal cell carcinoma. Genet Med 2020;22(8):1366-73. DOI: 10.1038/s41436-020-0801-x.