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Gene Methylation in Circulating Cell-Free DNA from the Blood Plasma as Prognostic and Predictive Factor in Breast Cancer

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Abstract

Despite considerable progress in the early-stage diagnostics and treatment of breast cancer (BC), there is a high chance of recurrence. The existing methods for relapse detection are not suitable for early detection, since they require invasive procedures and are not able to promptly accompany treatment. A promising method is the so-called liquid biopsy based on the analysis of genetic material from peripheral blood, in particular, the fraction of circulating cell-free DNA (cfDNA) of blood plasma. Determination of mutations, copy number, and methylation of individual genes in cfDNA makes it possible to trace changes both in the tumor focus and in the pathological process as a whole. Moreover, the method is minimally invasive and characterized by good accuracy and promptness. The present review summarizes the published data on the prognostic and predictive value of epigenetic markers based on the analysis of gene methylation in plasma or serum cfDNA of BC patients. It was demonstrated that genes hypermethylated in cfDNA (RASSF1A, RARB, SOX17, WNT5A, etc.) can serve as effective markers of overall and tumor-specific survival and chemoresistance. An important advantage of methylation markers, in contrast to markers based on single nucleotide substitutions, microsatellites, and copy number variations, is universality, early manifestation, and clear association with the biology of the pathological process. DNA methylation analysis of the most effective markers can solve the problem of early detection of metastasis and recurrence of the disease and promptly monitor the response to neoadjuvant and postoperative chemotherapy, which is the basis for a personalized approach to the treatment of BC patients.

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REFERENCES

  1. Harbeck, N., Penault-Llorca, F., Cortes, J., et al., Breast cancer, Nat. Rev. Dis. Primers, 2019, vol. 5, no. 1. e66. https://doi.org/10.1038/s41572-019-0111-2

    Article  Google Scholar 

  2. Sørlie, T., Perou, C.M., Tibshirani, R., et al., Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications, Proc. Natl. Acad. Sci. U.S.A., 2001, vol. 98, no. 19, pp. 10869—10874. https://doi.org/10.1073/pnas.191367098

    Article  PubMed  PubMed Central  Google Scholar 

  3. Lehmann, B.D., Jovanović, B., Chen, X., et al., Refinement of triple-negative breast cancer molecular subtypes: implications for neoadjuvant chemotherapy selection, PLoS One, 2016, vol. 11, no. 6. e0157368. https://doi.org/10.1371/journal.pone.0157368

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Dawson, S.-J., Tsui, D.W.Y., Murtaza, M., et al., Analysis of circulating tumor DNA to monitor metastatic breast cancer, N. Engl. J. Med., 2013, vol. 368, no. 13, pp. 1199—1209. https://doi.org/10.1056/NEJMoa1213261

    Article  CAS  PubMed  Google Scholar 

  5. Siravegna, G., Marsoni, S., Siena, S., et al., Integrating liquid biopsies into the management of cancer, Nat. Rev. Clin. Oncol., 2017, vol. 14, no. 9, pp. 531—548. https://doi.org/10.1038/nrclinonc.2017.14

    Article  CAS  PubMed  Google Scholar 

  6. Nassar, F.J., Chamandi, G., Tfaily, M.A., et al., Peripheral blood-based biopsy for breast cancer risk prediction and early detection, Front. Med. (Lausanne), 2020, vol. 7. e28. https://doi.org/10.3389/fmed.2020.00028

    Article  Google Scholar 

  7. Wan, J.C.M., Massie, C., Garcia-Corbacho, J., et al., Liquid biopsies come of age: towards implementation of circulating tumour DNA, Nat. Rev. Cancer, 2017, vol. 17, no. 4, pp. 223—238. https://doi.org/10.1038/nrc.2017.7

    Article  CAS  PubMed  Google Scholar 

  8. Tzanikou, E. and Lianidou, E., The potential of ctDNA analysis in breast cancer, Crit. Rev. Clin. Lab. Sci., 2020, vol. 57, no. 1, pp. 54—72. https://doi.org/10.1080/10408363.2019.1670615

    Article  CAS  PubMed  Google Scholar 

  9. Constâncio, V., Nunes, S.P., Henrique, R., et al., DNA methylation-based testing in liquid biopsies as detection and prognostic biomarkers for the four major cancer types, Cells, 2020, vol. 9, no. 3. https://doi.org/10.3390/cells9030624

  10. Tamkovich, S.N., Vlassov, V.V., and Laktionov, P.P., Circulating DNA in the blood and its application in medical diagnosis, Mol. Biol. (Moscow), 2008, vol. 42, no. 1, pp. 9—19. https://doi.org/10.1134/S0026893308010020

    Article  CAS  Google Scholar 

  11. Rafi, I. and Chitty, L., Cell-free fetal DNA and non-invasive prenatal diagnosis, Br. J. Gen. Pract., 2009, vol. 59, no. 562, pp. e146—e148. https://doi.org/10.3399/bjgp09X420572

    Article  PubMed  PubMed Central  Google Scholar 

  12. Han, D., Li, R., Shi, J., et al., Liquid biopsy for infectious diseases: a focus on microbial cell-free DNA sequencing, Theranostics, 2020, vol. 10, no. 12, pp. 5501—5513. https://doi.org/10.7150/thno.45554

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Schwarzenbach, H. and Pantel, K., Circulating DNA as biomarker in breast cancer, Breast Cancer Res., 2015, vol. 17, no. 1. e136. https://doi.org/10.1186/s13058-015-0645-5

    Article  CAS  Google Scholar 

  14. Moss, J., Magenheim, J., Neiman, D., et al., Comprehensive human cell-type methylation atlas reveals origins of circulating cell-free DNA in health and disease, Nat. Commun., 2018, vol. 9, no. 1, p. 5068. https://doi.org/10.1038/s41467-018-07466-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Jahr, S., Hentze, H., Englisch, S., 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, vol. 61, no. 4, pp. 1659—1665. PMID: 11245480

    CAS  PubMed  Google Scholar 

  16. Roth, C., Pantel, K., Müller, V., et al., Apoptosis-related deregulation of proteolytic activities and high serum levels of circulating nucleosomes and DNA in blood correlate with breast cancer progression, BMC Cancer, 2011, vol. 11, p. 4. https://doi.org/10.1186/1471-2407-11-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Rykova, E.Y., Morozkin, E.S., Ponomaryova, A.A., et al., Cell-free and cell-bound circulating nucleic acid complexes: mechanisms of generation, concentration and content, Expert Opin. Biol. Ther., 2012, vol. 12, suppl. 1, pp. S141—S153. https://doi.org/10.1517/14712598.2012.673577

    Article  CAS  PubMed  Google Scholar 

  18. Rodrigues Filho, E.M., Ikuta, N., Simon, D., et al., Prognostic value of circulating DNA levels in critically ill and trauma patients, Rev. Bras. Ter. Intensiva, 2014, vol. 26, no. 3, pp. 305—312. https://doi.org/10.5935/0103-507X.20140043

    Article  PubMed  PubMed Central  Google Scholar 

  19. Vasilyeva, I.N., Low-molecular-weight DNA in blood plasma as an index of the influence of ionizing radiation, Ann. N.Y. Acad. Sci., 2001, vol. 945, pp. 221—228. https://doi.org/10.1111/j.1749-6632.2001.tb03889.x

    Article  CAS  PubMed  Google Scholar 

  20. Duvvuri, B. and Lood, C., Cell-free DNA as a biomarker in autoimmune rheumatic diseases, Front. Immunol., 2019, vol. 10, p. 502. https://doi.org/10.3389/fimmu.2019.00502

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Rohanizadegan, M., Analysis of circulating tumor DNA in breast cancer as a diagnostic and prognostic biomarker, Cancer Genet., 2018, vols. 228—229, pp. 159—168. https://doi.org/10.1016/j.cancergen.2018.02.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Delmonico, L., Alves, G., and Bines, J., Cell free DNA biology and its involvement in breast carcinogenesis, Adv. Clin. Chem., 2020, vol. 97, pp. 171—223. https://doi.org/10.1016/bs.acc.2019.12.006

    Article  CAS  PubMed  Google Scholar 

  23. 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, vol. 6, no. 224. e224ra24. https://doi.org/10.1126/scitranslmed.3007094

  24. Diehl, F., Schmidt, K., Choti, M.A., et al., Circulating mutant DNA to assess tumor dynamics, Nat. Med., 2007, vol. 14, no. 9, pp. 985—990. https://doi.org/10.1038/nm.1789

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Stewart, C.M., Kothari, P.D., Mouliere, F., et al., The value of cell-free DNA for molecular pathology, J. Pathol., 2018, vol. 244, no. 5, pp. 616—627.https://doi.org/10.1002/path.5048

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Li, L., Choi, J.-Y., Lee, K.-M., et al., DNA methylation in peripheral blood: a potential biomarker for cancer molecular epidemiology, J. Epidemiol., 2012, vol. 22, no. 5, pp. 384—394. https://doi.org/10.2188/jea.JE20120003

    Article  PubMed  PubMed Central  Google Scholar 

  27. Kang, S., Li, Q., Chen, Q., et al., CancerLocator: non-invasive cancer diagnosis and tissue-of-origin prediction using methylation profiles of cell-free DNA, Genome Biol., 2017, vol. 18, no. 1, p. 53. https://doi.org/10.1186/s13059-017-1191-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Huang, Z.H., Li, L.H., and Hua, D., Quantitative analysis of plasma circulating DNA at diagnosis and during follow-up of breast cancer patients, Cancer Lett., 2006, vol. 243, no. 1, pp. 64—70. https://doi.org/10.1016/j.canlet.2005.11.027

    Article  CAS  PubMed  Google Scholar 

  29. Zanetti-Dällenbach, R., Wight, E., Fan, A.X.-C., et al., Positive correlation of cell-free DNA in plasma/serum in patients with malignant and benign breast disease, Anticancer Res., 2008, vol. 28, no. 2A, pp. 921—925

    PubMed  Google Scholar 

  30. Gong, B., Xue, J., Yu, J., et al., Cell-free DNA in blood is a potential diagnostic biomarker of breast cancer, Oncol. Lett., 2012, vol. 3, no. 4, pp. 897—900. https://doi.org/10.3892/ol.2012.576

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Catarino, R., Ferreira, M.M., Rodrigues, H., et al., Quantification of free circulating tumor DNA as a diagnostic marker for breast cancer, DNA Cell Biol., 2008, vol. 27, no. 8, pp. 415—421. https://doi.org/10.1089/dna.2008.0744

    Article  CAS  PubMed  Google Scholar 

  32. Agassi, R., Czeiger, D., Shaked, G., et al., Measurement of circulating cell-free DNA levels by a simple fluorescent test in patients with breast cancer, Am. J. Clin. Pathol., 2015, vol. 143, no. 1, pp. 18—24. https://doi.org/10.1309/AJCPI5YHG0OGFAHM

    Article  CAS  PubMed  Google Scholar 

  33. Tangvarasittichai, O., Jaiwang, W., and Tangvarasittichai, S., The plasma DNA concentration as a potential breast cancer screening marker, Indian J. Clin. Biochem., 2015, vol. 30, no. 1, pp. 55—58. https://doi.org/10.1007/s12291-013-0407-z

    Article  CAS  PubMed  Google Scholar 

  34. Leary, R.J., Sausen, M., Kinde, I., et al., Detection of chromosomal alterations in the circulation of cancer patients with whole-genome sequencing, Sci. Transl. Med., 2012, vol. 4, no. 162. e162ra154. https://doi.org/10.1126/scitranslmed.3004742

  35. Wang, J., Han, X., and Sun, Y., DNA methylation signatures in circulating cell-free DNA as biomarkers for the early detection of cancer, Sci. China Life Sci., 2017, vol. 60, no. 4, pp. 356—362. https://doi.org/10.1007/s11427-016-0253-7

    Article  CAS  PubMed  Google Scholar 

  36. Warton, K. and Samimi, G., Methylation of cell-free circulating DNA in the diagnosis of cancer, Front. Mol. Biosci., 2015, vol. 2, p. 13. https://doi.org/10.3389/fmolb.2015.00013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Issa, J.P., DNA methylation as a clinical marker in oncology, J. Clin. Oncol., 2012, vol. 30, no. 20, pp. 2566—2568. https://doi.org/10.1200/jco.2012.42.1016

    Article  CAS  PubMed  Google Scholar 

  38. Bryzgunova, O.E. and Laktionov, P.P., Current methods of extracellular DNA methylation analysis, Mol. Biol. (Moscow), 2017, vol. 51, no. 2, pp. 167—183. https://doi.org/10.1134/S0026893317010071

    Article  CAS  Google Scholar 

  39. Parpart-Li, S., Bartlett, B., Popoli, M., et al., The effect of preservative and temperature on the analysis of circulating tumor DNA, Clin. Cancer Res., 2017, vol. 23, no. 10, pp. 2471—2477. https://doi.org/10.1158/1078-0432.ccr-16-1691

    Article  CAS  PubMed  Google Scholar 

  40. Sherwood, J.L., Corcoran, C., Brown, H., et al., Optimized pre-analytical methods improve KRAS mutation detection in circulating tumour DNA (ctDNA) from patients with non-small cell lung cancer (NSCLC), PLoS One, 2016, vol. 11, no. 2. e0150197. https://doi.org/10.1371/journal.pone.0150197

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Liggett, T.E., Melnikov, A., Yi, Q., et al., Distinctive DNA methylation patterns of cell-free plasma DNA in women with malignant ovarian tumors, Gynecol. Oncol., 2011, vol. 120, no. 1, pp. 113—120. https://doi.org/10.1016/j.ygyno.2010.09.019

    Article  CAS  PubMed  Google Scholar 

  42. Darst, R.P., Pardo, C.E., Ai, L., et al., Bisulfite sequencing of DNA, Curr. Protoc. Mol. Biol., 2010, vol. 91, pp. 7.9.1—7.9.17. https://doi.org/10.1002/0471142727.mb0709s91

  43. Tanaka, K. and Okamoto, A., Degradation of DNA by bisulfite treatment, Bioorg. Med. Chem. Lett., 2007, vol. 17, no. 7, pp. 1912—1915. https://doi.org/10.1016/j.bmcl.2007.01.040

    Article  CAS  PubMed  Google Scholar 

  44. Yi, S., Long, F., Cheng, J., et al., An optimized rapid bisulfite conversion method with high recovery of cell-free DNA, BMC Mol. Biol., 2017, vol. 18, no. 1, p. 24. https://doi.org/10.1186/s12867-017-0101-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Yamamoto, N., Nakayama, T., Kajita, M., et al., Detection of aberrant promoter methylation of GSTP1, RASSF1A, and RARβ2 in serum DNA of patients with breast cancer by a newly established one-step methylation-specific PCR assay, Breast Cancer Res. Treat., 2012, vol. 132, no. 1, pp. 165—173.https://doi.org/10.1007/s10549-011-1575-2

    Article  CAS  PubMed  Google Scholar 

  46. Herman, J.G., Graff, J.R., Myöhänen, S., et al., Methylation-specific PCR: a novel PCR assay for methylation status of CpG islands, Proc. Natl. Acad. Sci. U.S.A., 1996, vol. 93, no. 18, pp. 9821—9826. https://doi.org/10.1073/pnas.93.18.9821

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Delpu, Y., Cordelier, P., Cho, W.C., et al., DNA methylation and cancer diagnosis, Int. J. Mol. Sci., 2013, vol. 14, no. 7, pp. 15029—15058. https://doi.org/10.3390/ijms140715029

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Eads, C.A., Danenberg, K.D., Kawakami, K., et al., MethyLight: a high-throughput assay to measure DNA methylation, Nucleic Acids Res., 2000, vol. 28, no. 8. e32. https://doi.org/10.1093/nar/28.8.e32

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Wojdacz, T.K., Dobrovic, A., and Hansen, L.L., Methylation-sensitive high-resolution melting, Nat. Protoc., 2008, vol. 3, no. 12, pp. 1903—1908. https://doi.org/10.1038/nprot.2008.191

    Article  CAS  PubMed  Google Scholar 

  50. Yu, M., Heinzerling, T.J., and Grady, W.M., DNA methylation analysis using droplet digital PCR, Methods Mol. Biol., 2018, vol. 1768, pp. 363—383. https://doi.org/10.1007/978-1-4939-7778-9_21

    Article  CAS  PubMed  Google Scholar 

  51. Fackler, M.J., Lopez Bujanda, Z., Umbricht, C., et al., Novel methylated biomarkers and a robust assay to detect circulating tumor DNA in metastatic breast cancer, Cancer Res., 2014, vol. 74, no. 8, pp. 2160—2170. https://doi.org/10.1158/0008-5472.CAN-13-3392

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Beck, S. and Rakyan, V.K., The methylome: approaches for global DNA methylation profiling, Trends Genet., 2008, vol. 24, no. 5, pp. 231—237. https://doi.org/10.1016/j.tig.2008.01.006

    Article  CAS  PubMed  Google Scholar 

  53. Legendre, C., Gooden, G.C., Johnson, K., et al., Whole-genome bisulfite sequencing of cell-free DNA identifies signature associated with metastatic breast cancer, Clin. Epigenet., 2015, vol. 7, p. 100. https://doi.org/10.1186/s13148-015-0135-8

    Article  CAS  Google Scholar 

  54. Samorodnitsky, E., Datta, J., Jewell, B.M., et al., Comparison of custom capture for targeted next-generation DNA sequencing, J. Mol. Diagn., 2015, vol. 17, no. 1, pp. 64—75. https://doi.org/10.1016/j.jmoldx.2014.09.009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Widschwendter, M., Evans, I., Jones, A., et al., Methylation patterns in serum DNA for early identification of disseminated breast cancer, Genome Med., 2017, vol. 9, no. 1, p. 115. https://doi.org/10.1186/s13073-017-0499-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Pasha, H.A., Rezk, N.A., and Riad, M.A., Circulating cell free nuclear DNA, mitochondrial DNA and global DNA methylation: potential noninvasive biomarkers for breast cancer diagnosis, Cancer Invest., 2019, vol. 37, no. 9, pp. 432—439. https://doi.org/10.1080/07357907.2019.1663864

    Article  CAS  PubMed  Google Scholar 

  57. Severi, G., Southey, M.C., English, D.R., et al., Epigenome-wide methylation in DNA from peripheral blood as a marker of risk for breast cancer, Breast Cancer Res. Treat., 2014, vol. 148, no. 3, pp. 665—673. https://doi.org/10.1007/s10549-014-3209-y

    Article  CAS  PubMed  Google Scholar 

  58. van Veldhoven, K., Polidoro, S., Baglietto, L., et al., Epigenome-wide association study reveals decreased average methylation levels years before breast cancer diagnosis, Clin. Epigenet., 2015, vol. 7, no. 1, p. 67. https://doi.org/10.1186/s13148-015-0104-2

    Article  CAS  Google Scholar 

  59. Wu, H.-C., Delgado-Cruzata, L., Flom, J.D., et al., Repetitive element DNA methylation levels in white blood cell DNA from sisters discordant for breast cancer from the New York site of the breast cancer family registry, Carcinogenesis, 2012, vol. 33, no. 10, pp. 1946—1952. https://doi.org/10.1093/carcin/bgs201

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Choi, J.-Y., James, S.R., Link, P.A., et al., Association between global DNA hypomethylation in leukocytes and risk of breast cancer, Carcinogenesis, 2009, vol. 30, no. 11, pp. 1889—1897. https://doi.org/10.1093/carcin/bgp143

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Kuchiba, A., Iwasaki, M., Ono, H., et al., Global methylation levels in peripheral blood leukocyte DNA by LUMA and breast cancer: a case-control study in Japanese women, Br. J. Cancer, 2014, vol. 110, no. 11, pp. 2765—2771. https://doi.org/10.1038/bjc.2014.223

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Tang, Q., Cheng, J., Cao, X., et al., Blood-based DNA methylation as biomarker for breast cancer: a systematic review, Clin. Epigenet., 2016, vol. 8. e115. https://doi.org/10.1186/s13148-016-0282-6

    Article  CAS  Google Scholar 

  63. Müller, H.M., Widschwendter, A., Fiegl, H., et al., DNA methylation in serum of breast cancer patients: an independent prognostic marker, Cancer Res., 2003, vol. 63, no. 22, pp. 7641—7645.

    PubMed  Google Scholar 

  64. Sharma, G., Mirza, S., Parshad, R., et al., Clinical significance of promoter hypermethylation of DNA repair genes in tumor and serum DNA in invasive ductal breast carcinoma patients, Life Sci., 2010, vol. 87, nos. 3—4, pp. 83—91. https://doi.org/10.1016/j.lfs.2010.05.001

    Article  CAS  PubMed  Google Scholar 

  65. Göbel, G., Auer, D., Gaugg, I., et al., Prognostic significance of methylated RASSF1A and PITX2 genes in blood- and bone marrow plasma of breast cancer patients, Breast Cancer Res. Treat., 2011, vol. 130, no. 1, pp. 109—117. https://doi.org/10.1007/s10549-010-1335-8

    Article  CAS  PubMed  Google Scholar 

  66. Fujita, N., Nakayama, T., Yamamoto, N., et al., Methylated DNA and total DNA in serum detected by one-step methylation-specific PCR is predictive of poor prognosis for breast cancer patients, Oncology, 2012, vol. 83, no. 5, pp. 273—282. https://doi.org/10.1159/000342083

    Article  CAS  PubMed  Google Scholar 

  67. Mirza, S., Sharma, G., Parshad, R., et al., Clinical significance of promoter hypermethylation of ERβ and RARβ2 in tumor and serum DNA in Indian breast cancer patients, Ann. Surg. Oncol., 2012, vol. 19, no. 9, pp. 3107—3115. https://doi.org/10.1245/s10434-012-2323-5

    Article  PubMed  Google Scholar 

  68. Fu, D., Ren, C., Tan, H., et al., Sox17 promoter methylation in plasma DNA is associated with poor survival and can be used as a prognostic factor in breast cancer, Medicine (Baltimore), 2015, vol. 94, no. 11. e637. https://doi.org/10.1097/MD.0000000000000637

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Matsui, S., Kagara, N., Mishima, C., et al., Methylation of the SEPT9_v2 promoter as a novel marker for the detection of circulating tumor DNA in breast cancer patients, Oncol. Rep., 2016, vol. 36, no. 4, pp. 2225—2235. https://doi.org/10.3892/or.2016.5004

    Article  CAS  PubMed  Google Scholar 

  70. Visvanathan, K., Fackler, M.S., Zhang, Z., et al., Monitoring of serum DNA methylation as an early independent marker of response and survival in metastatic breast cancer: TBCRC 005 prospective biomarker study, J. Clin. Oncol., 2017, vol. 35, no. 7, pp. 751—758. https://doi.org/10.1200/JCO.2015.66.2080

    Article  CAS  PubMed  Google Scholar 

  71. Panagopoulou, M., Karaglani, M., Balgkouranidou, I., et al., Circulating cell-free DNA in breast cancer: size profiling, levels, and methylation patterns lead to prognostic and predictive classifiers, Oncogene, 2019, vol. 38, no. 18, pp. 3387—3401. https://doi.org/10.1038/s41388-018-0660-y

    Article  CAS  PubMed  Google Scholar 

  72. van der Auwera, I., Elst, H.J., van Laere, S.J., et al., The presence of circulating total DNA and methylated genes is associated with circulating tumour cells in blood from breast cancer patients, Br. J. Cancer, 2009, vol. 100, no. 8, pp. 1277—1286. https://doi.org/10.1038/sj.bjc.6605013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Matuschek, C., Bölke, E., Lammering, G., et al., Methylated APC and GSTP1 genes in serum DNA correlate with the presence of circulating blood tumor cells and are associated with a more aggressive and advanced breast cancer disease, Eur. J. Med. Res., 2010, vol. 15, no. 7, pp. 277—286. https://doi.org/10.1186/2047-783x-15-7-277

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Chimonidou, M., Strati, A., Malamos, N., et al., SOX17 promoter methylation in circulating tumor cells and matched cell-free DNA isolated from plasma of patients with breast cancer, Clin. Chem., 2013, vol. 59, no. 1, pp. 270—279. https://doi.org/10.1373/clinchem.2012.191551

    Article  CAS  PubMed  Google Scholar 

  75. Mirza, S., Sharma, G., Parshad, R., et al., Clinical significance of Stratifin, ERalpha and PR promoter methylation in tumor and serum DNA in Indian breast cancer patients, Clin. Biochem., 2010, vol. 43, nos. 4—5, pp. 380—386. https://doi.org/10.1016/j.clinbiochem.2009.11.016

    Article  CAS  PubMed  Google Scholar 

  76. Martínez-Galán, J., Torres-Torres, B., Núñez, M.I., et al., ESR1 gene promoter region methylation in free circulating DNA and its correlation with estrogen receptor protein expression in tumor tissue in breast cancer patients, BMC Cancer, 2014, vol. 14, p. 59. https://doi.org/10.1186/1471-2407-14-59

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Hagrass, H.A., Pasha, H.F., and Ali, A.M., Estrogen receptor alpha (ERα) promoter methylation status in tumor and serum DNA in Egyptian breast cancer patients, Gene, 2014, vol. 552, no. 1, pp. 81—86. https://doi.org/10.1016/j.gene.2014.09.016

    Article  CAS  PubMed  Google Scholar 

  78. Liu, X.-R., Zhang, R.-Y., Gong, H., et al., Methylome variation predicts exemestane resistance in advanced ER+ breast cancer, Technol. Cancer Res. Treat., 2020, vol. 19. e1533033819896331. https://doi.org/10.1177/1533033819896331

    Article  CAS  Google Scholar 

  79. Garufi, G., Palazzo, A., Paris, I., et al., Neoadjuvant therapy for triple-negative breast cancer: potential predictive biomarkers of activity and efficacy of platinum chemotherapy, PARP- and immune-checkpoint-inhibitors, Expert Opin. Pharmacother., 2020, vol. 21, no. 6, pp. 687—699. https://doi.org/10.1080/14656566.2020.1724957

    Article  CAS  PubMed  Google Scholar 

  80. Ades, F., Zardavas, D., Bozovic-Spasojevic, I., et al., Luminal B breast cancer: molecular characterization, clinical management, and future perspectives, J. Clin. Oncol., 2014, vol. 32, no. 25, pp. 2794—2803. https://doi.org/10.1200/JCO.2013.54.1870

    Article  PubMed  Google Scholar 

  81. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG), Long-term outcomes for neoadjuvant versus adjuvant chemotherapy in early breast cancer: meta-analysis of individual patient data from ten randomised trials, Lancet Oncol., 2018, vol. 19, no. 1, pp. 27—39. https://doi.org/10.1016/S1470-2045(17)30777-5

    Article  Google Scholar 

  82. Caparica, R., Lambertini, M., Pondé, N., et al., Post-neoadjuvant treatment and the management of residual disease in breast cancer: state of the art and perspectives, Ther. Adv. Med. Oncol., 2019, vol. 11. e1758835919827714. https://doi.org/10.1177/1758835919827714

    Article  Google Scholar 

  83. Avraham, A., Uhlmann, R., Shperber, A., et al., Serum DNA methylation for monitoring response to neoadjuvant chemotherapy in breast cancer patients, Int. J. Cancer, 2012, vol. 131, no. 7, pp. e1166—e1172. https://doi.org/10.1002/ijc.27526

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Sharma, G., Mirza, S., Parshad, R., et al., DNA methylation of circulating DNA: a marker for monitoring efficacy of neoadjuvant chemotherapy in breast cancer patients, Tumour Biol., 2012, vol. 33, no. 6, pp. 1837—1843. https://doi.org/10.1007/s13277-012-0443-y

    Article  CAS  PubMed  Google Scholar 

  85. Takahashi, H., Kagara, N., Tanei, T., et al., Correlation of methylated circulating tumor DNA with response to neoadjuvant chemotherapy in breast cancer patients, Clin. Breast Cancer, 2017, vol. 17, no. 1, pp. 61—69. e3. https://doi.org/10.1016/j.clbc.2016.06.006

  86. Sigin, V.O., Kalinkin, A.I., Kuznetsova, E.B., et al., DNA methylation markers panel can improve prediction of response to neoadjuvant chemotherapy in luminal B breast cancer, Sci. Rep., 2020, vol. 10, no. 1, p. 9239. https://doi.org/10.1038/s41598-020-66197-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Kekeeva T.V., Zhinzhilo T.A., Nenakhova Yu.N., et al., ADCY8 gene methylation in plasma as a predictive marker of breast cancer neoadjuvant chemotherapy, Med. Genet., 2018, vol. 17, no. 10, pp. 38—41. https://doi.org/10.25557/2073-7998.2018.10.38-41

    Article  Google Scholar 

  88. Moss, J., Zick, A., Grinshpun, A., et al., Circulating breast-derived DNA allows universal detection and monitoring of localized breast cancer, Ann. Oncol., 2020, vol. 31, no. 3, pp. 395—403. https://doi.org/10.1016/j.annonc.2019.11.014

    Article  CAS  PubMed  Google Scholar 

  89. Fiegl, H., Millinger, S., Mueller-Holzner, E., et al., Circulating tumor-specific DNA: a marker for monitoring efficacy of adjuvant therapy in cancer patients, Cancer Res., 2005, vol. 65, no. 4, pp. 1141—1145. https://doi.org/10.1158/0008-5472.CAN-04-2438

    Article  CAS  PubMed  Google Scholar 

  90. Gil, E.Y., Jo, U.H., Jeong, H., et al., Promoter methylation of RASSF1A modulates the effect of the microtubule-targeting agent docetaxel in breast cancer, Int. J. Oncol., 2012, vol. 41, pp. 611—620. https://doi.org/10.3892/ijo.2012.1470

    Article  CAS  PubMed  Google Scholar 

  91. Kajabova, V., Smolkova, B., Zmetakova, I., et al., RASSF1A promoter methylation levels positively correlate with estrogen receptor expression in breast cancer patients, Transl. Oncol., 2013, vol. 6, pp. 297—304. https://doi.org/10.1593/tlo.13244

    Article  PubMed  PubMed Central  Google Scholar 

  92. Liggett, T.E., Melnikov, A.A., Marks, J.R., et al., Methylation patterns in cell-free plasma DNA reflect removal of the primary tumor and drug treatment of breast cancer patients, Int. J. Cancer, 2011, vol. 128, no. 2, pp. 492—499. https://doi.org/10.1002/ijc.25363

    Article  CAS  PubMed  Google Scholar 

  93. Mastoraki, S., Strati, A., Tzanikou, E., et al., ESR1 methylation: a liquid biopsy-based epigenetic assay for the follow-up of patients with metastatic breast cancer receiving endocrine treatment, Clin. Cancer Res., 2018, vol. 24, no. 6, pp. 1500—1510. https://doi.org/10.1158/1078-0432.CCR-17-1181

    Article  CAS  PubMed  Google Scholar 

  94. Zurita, M., Lara, P.C., Del Moral, R., et al., Hypermethylated 14-3-3-sigma and ESR1 gene promoters in serum as candidate biomarkers for the diagnosis and treatment efficacy of breast cancer metastasis, BMC Cancer, 2010, vol. 10, p. 217. https://doi.org/10.1186/1471-2407-10-217

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Funding

The study was carried out within the framework of the state contract with the Ministry of Education and Science of the Russian Federation with the support of the applied research program (PNI) 0403-2020-0002 for 2020–2022.

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Authors and Affiliations

  1. Institute of General Pathology and Pathophysiology, 125315, Moscow, Russia

    S. V. Rykov, E. A. Filippova, V. I. Loginov & E. A. Braga

  2. National Research Center Kurchatov Institute–GosNIIgenetika, Kurchatov Genomic Center, 117545, Moscow, Russia

    S. V. Rykov

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  1. S. V. Rykov
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  2. E. A. Filippova
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  3. V. I. Loginov
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  4. E. A. Braga
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Correspondence to S. V. Rykov or E. A. Braga.

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The authors declare that they have no conflict of interests. This article does not contain any studies involving animals or human participants performed by any of the authors.

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Translated by N. Maleeva

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Rykov, S.V., Filippova, E.A., Loginov, V.I. et al. Gene Methylation in Circulating Cell-Free DNA from the Blood Plasma as Prognostic and Predictive Factor in Breast Cancer. Russ J Genet 57, 1239–1252 (2021). https://doi.org/10.1134/S1022795421110120

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  • DOI: https://doi.org/10.1134/S1022795421110120

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