Cell-free circulating tumor DNA in cancer

Chinese Journal of Cancer

Volumn 35, Issue 5, 2016, Pages

  Qin, Zhen ^a,b   Ljubimov, Vladimir A ^c   Zhou, Cuiqi ^a   Tong, Yunguang ^a,d   Liang, Jimin ^b  

^a UNIVERSITY OF CALIFORNIA   (United States)

^b XIDIAN UNIVERSITY   (China)

^c UNIVERSITY OF SOUTHERN CALIFORNIA   (United States)

^d XINXIANG MEDICAL UNIVERSITY   (China)

Author keywords

Cancer; Circulating tumor DNA; Liquid biopsy

Indexed keywords

CA 125 ANTIGEN; CA 19-9 ANTIGEN; CARCINOEMBRYONIC ANTIGEN; CELL FREE CIRCULATING TUMOR DNA; DNA; DNA FRAGMENT; K RAS PROTEIN; PROSTATE SPECIFIC ANTIGEN; TUMOR MARKER; UNCLASSIFIED DRUG;

CANCER RECURRENCE; CELL HETEROGENEITY; CIRCULATING TUMOR CELL; COPY NUMBER VARIATION; DNA ISOLATION; DNA METHYLATION; GENE MUTATION; GENETIC ASSOCIATION; GENOTYPE; GENOTYPING TECHNIQUE; HETEROZYGOSITY LOSS; HUMAN; KARYOTYPING; MICROSATELLITE INSTABILITY; MINIMAL RESIDUAL DISEASE; NEOPLASM; NEXT GENERATION SEQUENCING; ONCOGENE K RAS; ONCOGENE N RAS; PERSONALIZED MEDICINE; POLYMERASE CHAIN REACTION SYSTEM; REAL TIME POLYMERASE CHAIN REACTION; REVIEW; TREATMENT RESPONSE; TUMOR BIOPSY; TUMOR VOLUME;

EID: 84969926517     PISSN: None     EISSN: 1944446X     Source Type: Journal    
DOI: 10.1186/s40880-016-0092-4     Document Type: Review

References (121)

1. Stewart BW, Wild C, International Agency for Research on Cancer, World Health Organization. World cancer report 2014. Lyon, Geneva: International Agency for Research on Cancer. WHO Press; 2014
2. Valastyan S, Weinberg RA. Tumor metastasis: molecular insights and evolving paradigms. Cell. 2011;147(2):275-92. doi:10.1016/j.cell.2011.09.024
3. Meric-Bernstam F, Mills GB. Overcoming implementation challenges of personalized cancer therapy. Nat Rev Clin Oncol. 2012;9(9):542-8. doi:10.1038/nrclinonc.2012.127
4. Vogelstein B, Papadopoulos N, Velculescu VE, Zhou S, Diaz LA Jr, Kinzler KW. Cancer genome landscapes. Science. 2013;339(6127):1546-58. doi:10.1126/science.1235122
5. Marusyk A, Polyak K. Tumor heterogeneity: causes and consequences. Biochim Biophys Acta. 2010;1805(1):105-17. doi:10.1016/j.bbcan.2009.11.002
6. Gerlinger M, Rowan AJ, Horswell S, Larkin J, Endesfelder D, Gronroos E, et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med. 2012;366(10):883-92. doi:10.1056/NEJMoa1113205
7. Yates LR, Campbell PJ. Evolution of the cancer genome. Nat Rev Genet. 2012;13(11):795-806. doi:10.1038/nrg3317
8. Aparicio S, Caldas C. The implications of clonal genome evolution for cancer medicine. N Engl J Med. 2013;368(9):842-51. doi:10.1056/NEJMra1204892
9. Heitzer E, Auer M, Gasch C, Pichler M, Ulz P, Hoffmann EM, et al. Complex tumor genomes inferred from single circulating tumor cells by array-CGH and next-generation sequencing. Cancer Res. 2013;73(10):2965-75. doi:10.1158/0008-5472.CAN-12-4140
10. Dawson SJ, Tsui DW, Murtaza M, Biggs H, Rueda OM, Chin SF, et al. Analysis of circulating tumor DNA to monitor metastatic breast cancer. N Engl J Med. 2013;368(13):1199-209. doi:10.1056/NEJMoa1213261
11. Mandel P, Metais P. Les acides nucleiques du plasma sanguin chez l’ homme. Seances Soc Biol Fil. 1948;142:241-3 (in French).
12. Stroun M, Anker P, Maurice P, Lyautey J, Lederrey C, Beljanski M. Neoplastic characteristics of the DNA found in the plasma of cancer patients. Oncology. 1989;46(5):318-22
13. Anker P, Mulcahy H, Chen XQ, Stroun M. Detection of circulating tumour DNA in the blood (plasma/serum) of cancer patients. Cancer Metastasis Rev. 1999;18(1):65-73
14. Gormally E, Caboux E, Vineis P, Hainaut P. Circulating free DNA in plasma or serum as biomarker of carcinogenesis: practical aspects and biological significance. Mutat Res. 2007;635(2-3):105-17. doi:10.1016/j.mrrev.2006.11.002
15. Fleischhacker M, Schmidt B. Circulating nucleic acids (CNAs) and cancer-a survey. Biochim Biophys Acta. 2007;1775(1):181-232. doi:10.1016/j.bbcan.2006.10.001
16. Schwarzenbach H, Stoehlmacher J, Pantel K, Goekkurt E. Detection and monitoring of cell-free DNA in blood of patients with colorectal cancer. Ann N Y Acad Sci. 2008;1137:190-6. doi:10.1196/annals.1448.025
17. Schwarzenbach H, Alix-Panabieres C, Muller I, Letang N, Vendrell JP, Rebillard X, et al. Cell-free tumor DNA in blood plasma as a marker for circulating tumor cells in prostate cancer. Clin Cancer Res. 2009;15(3):1032-8. doi:10.1158/1078-0432.CCR-08-1910
18. Schwarzenbach H, Muller V, Milde-Langosch K, Steinbach B, Pantel K. Evaluation of cell-free tumour DNA and RNA in patients with breast cancer and benign breast disease. Mol BioSyst. 2011;7(10):2848-54. doi:10.1039/c1mb05197k.
19. Salvianti F, Pinzani P, Verderio P, Ciniselli CM, Massi D, De Giorgi V, et al. Multiparametric analysis of cell-free DNA in melanoma patients. PLoS One. 2012;7(11):e49843. doi:10.1371/journal.pone.0049843
20. Park JL, Kim HJ, Choi BY, Lee HC, Jang HR, Song KS, et al. Quantitative analysis of cell-free DNA in the plasma of gastric cancer patients. Oncol Lett. 2012;3(4):921-6. doi:10.3892/ol.2012.592
21. Delgado PO, Alves BC, Gehrke Fde S, Kuniyoshi RK, Wroclavski ML, Del Giglio A, et al. Characterization of cell-free circulating DNA in plasma in patients with prostate cancer. Tumour Biol. 2013;34(2):983-6. doi:10.1007/s13277-012-0634-6
22. Friel AM, Corcoran C, Crown J, O’Driscoll L. Relevance of circulating tumor cells, extracellular nucleic acids, and exosomes in breast cancer. Breast Cancer Res Treat. 2010;123(3):613-25. doi:10.1007/s10549-010-0980-2
23. Ashworth TR. A case of cancer in which cells similar to those in the tumors were seen in the blood after death. Aus Med J. 1869;14:146-7
24. Pantel K, Brakenhoff RH, Brandt B. Detection, clinical relevance and specific biological properties of disseminating tumour cells. Nat Rev Cancer. 2008;8(5):329-40. doi:10.1038/nrc2375
25. Alix-Panabieres C, Pantel K. Circulating tumor cells: liquid biopsy of cancer. Clin Chem. 2013;59(1):110-8. doi:10.1373/clinchem.2012.194258
26. Pantel K, Alix-Panabieres C. Circulating tumour cells in cancer patients: challenges and perspectives. Trends Mol Med. 2010;16(9):398-406. doi:10.1016/j.molmed.2010.07.001
27. Alix-Panabieres C, Pantel K. Technologies for detection of circulating tumor cells: facts and vision. Lab Chip. 2014;14(1):57-62. doi:10.1039/c3lc50644d.
28. Ilie M, Hofman V, Long E, Bordone O, Selva E, Washetine K, et al. Current challenges for detection of circulating tumor cells and cell-free circulating nucleic acids, and their characterization in non-small cell lung carcinoma patients. What is the best blood substrate for personalized medicine? Ann Transl Med. 2014;2(11):107. doi:10.3978/j.issn.2305-5839.2014.08.11
29. Stroun M, Lyautey J, Lederrey C, Olson-Sand A, Anker P. About the possible origin and mechanism of circulating DNA apoptosis and active DNA release. Clin Chim Acta. 2001;313(1-2):139-42
30. Jahr S, Hentze H, Englisch S, Hardt D, Fackelmayer FO, Hesch RD, 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(4):1659-65
31. Chan KC, Zhang J, Hui AB, Wong N, Lau TK, Leung TN, et al. Size distributions of maternal and fetal DNA in maternal plasma. Clin Chem. 2004;50(1):88-92. doi:10.1373/clinchem.2003.024893
32. Mouliere F, Robert B, Arnau Peyrotte E, Del Rio M, Ychou M, Molina F, et al. High fragmentation characterizes tumour-derived circulating DNA. PLoS One. 2011;6(9):e23418. doi:10.1371/journal.pone.0023418
33. Diehl F, Li M, Dressman D, He Y, Shen D, Szabo S, et al. Detection and quantification of mutations in the plasma of patients with colorectal tumors. Proc Natl Acad Sci USA. 2005;102(45):16368-73. doi:10.1073/pnas.0507904102
34. Diehl F, Schmidt K, Choti MA, Romans K, Goodman S, Li M, et al. Circulating mutant DNA to assess tumor dynamics. Nat Med. 2008;14(9):985-90. doi:10.1038/nm.1789
35. Roninson IB, Broude EV, Chang BD. If not apoptosis, then what? Treatment-induced senescence and mitotic catastrophe in tumor cells. Drug Resist Updat. 2001;4(5):303-13. doi:10.1054/drup.2001.0213
36. Wang BG, Huang HY, Chen YC, Bristow RE, Kassauei K, Cheng CC, et al. Increased plasma DNA integrity in cancer patients. Cancer Res. 2003;63(14):3966-8
37. Anker P, Stroun M, Maurice PA. Spontaneous release of DNA by human blood lymphocytes as shown in an in vitro system. Cancer Res. 1975;35(9):2375-82
38. Stroun M, Maurice P, Vasioukhin V, Lyautey J, Lederrey C, Lefort F, et al. The origin and mechanism of circulating DNA. Ann N Y Acad Sci. 2000;906:161-8
39. Stroun M, Lyautey J, Lederrey C, Mulcahy HE, Anker P. Alu repeat sequences are present in increased proportions compared to a unique gene in plasma/serum DNA: evidence for a preferential release from viable cells? Ann N Y Acad Sci. 2001;945:258-64
40. Rogers JC, Boldt D, Kornfeld S, Skinner A, Valeri CR. Excretion of deoxyribonucleic acid by lymphocytes stimulated with phytohemagglutinin or antigen. Proc Natl Acad Sci USA. 1972;69(7):1685-9
41. Rogers JC. Identification of an intracellular precursor to DNA excreted by human lymphocytes. Proc Natl Acad Sci USA. 1976;73(9):3211-5
42. Kohler C, Barekati Z, Radpour R, Zhong XY. Cell-free DNA in the circulation as a potential cancer biomarker. Anticancer Res. 2011;31(8):2623-8
43. Chan KC, Jiang P, Chan CW, Sun K, Wong J, Hui EP, et al. Noninvasive detection of cancer-associated genome-wide hypomethylation and copy number aberrations by plasma DNA bisulfite sequencing. Proc Natl Acad Sci USA. 2013;110(47):18761-8. doi:10.1073/pnas.1313995110
44. Yu SC, Lee SW, Jiang P, Leung TY, Chan KC, Chiu RW, et al. High-resolution profiling of fetal DNA clearance from maternal plasma by massively parallel sequencing. Clin Chem. 2013;59(8):1228-37. doi:10.1373/clinchem.2013.203679
45. Lo YM, Zhang J, Leung TN, Lau TK, Chang AM, Hjelm NM. Rapid clearance of fetal DNA from maternal plasma. Am J Hum Genet. 1999;64(1):218-24. doi:10.1086/302205
46. Lo YM, Leung SF, Chan LY, Chan AT, Lo KW, Johnson PJ, et al. Kinetics of plasma Epstein-Barr virus DNA during radiation therapy for nasopharyngeal carcinoma. Cancer Res. 2000;60(9):2351-5
47. To EW, Chan KC, Leung SF, Chan LY, To KF, Chan AT, et al. Rapid clearance of plasma Epstein-Barr virus DNA after surgical treatment of nasopharyngeal carcinoma. Clin Cancer Res. 2003;9(9):3254-9
48. Chan KC. Plasma Epstein-Barr virus DNA as a biomarker for nasopharyngeal carcinoma. Chin J Cancer. 2014;33(12):598-603. doi:10.5732/cjc.014.10192
49. Marzese DM, Hirose H, Hoon DS. Diagnostic and prognostic value of circulating tumor-related DNA in cancer patients. Expert Rev Mol Diagn. 2013;13(8):827-44. doi:10.1586/14737159.2013.845088
50. Jung M, Klotzek S, Lewandowski M, Fleischhacker M, Jung K. Changes in concentration of DNA in serum and plasma during storage of blood samples. Clin Chem. 2003;49(6 Pt 1):1028-9
51. Bjorkman L, Reich CF, Pisetsky DS. The use of fluorometric assays to assess the immune response to DNA in murine systemic lupus erythematosus. Scand J Immunol. 2003;57(6):525-33
52. Tuaeva NO, Abramova ZI, Sofronov VV. The origin of elevated levels of circulating DNA in blood plasma of premature neonates. Ann N Y Acad Sci. 2008;1137:27-30. doi:10.1196/annals.1448.043
53. Chen Z, Feng J, Buzin CH, Liu Q, Weiss L, Kernstine K, et al. Analysis of cancer mutation signatures in blood by a novel ultra-sensitive assay: monitoring of therapy or recurrence in non-metastatic breast cancer. PLoS One. 2009;4(9):e7220. doi:10.1371/journal.pone.0007220
54. Vogelstein B, Kinzler KW. Digital PCR. Proc Natl Acad Sci USA. 1999;96(16):9236-41
55. Hindson BJ, Ness KD, Masquelier DA, Belgrader P, Heredia NJ, Makarewicz AJ, et al. High-throughput droplet digital PCR system for absolute quantitation of DNA copy number. Anal Chem. 2011;83(22):8604-10. doi:10.1021/ac202028g.
56. Pekin D, Skhiri Y, Baret JC, Le Corre D, Mazutis L, Salem CB, et al. Quantitative and sensitive detection of rare mutations using droplet-based microfluidics. Lab Chip. 2011;11(13):2156-66. doi:10.1039/c1lc20128j.
57. Forshew T, Murtaza M, Parkinson C, Gale D, Tsui DW, Kaper F, et al. Noninvasive identification and monitoring of cancer mutations by targeted deep sequencing of plasma DNA. Sci Transl Med. 2012;4(136):136ra68. doi:10.1126/scitranslmed.3003726
58. Wang J, Ramakrishnan R, Tang Z, Fan W, Kluge A, Dowlati A, et al. Quantifying EGFR alterations in the lung cancer genome with nanofluidic digital PCR arrays. Clin Chem. 2010;56(4):623-32. doi:10.1373/clinchem.2009.134973
59. Dressman D, Yan H, Traverso G, Kinzler KW, Vogelstein B. Transforming single DNA molecules into fluorescent magnetic particles for detection and enumeration of genetic variations. Proc Natl Acad Sci USA. 2003;100(15):8817-22. doi:10.1073/pnas.1133470100
60. Higgins MJ, Jelovac D, Barnathan E, Blair B, Slater S, Powers P, et al. Detection of tumor PIK3CA status in metastatic breast cancer using peripheral blood. Clin Cancer Res. 2012;18(12):3462-9. doi:10.1158/1078-0432.CCR-11-2696
61. Ignatiadis M, Dawson SJ. Circulating tumor cells and circulating tumor DNA for precision medicine: dream or reality? Ann Oncol. 2014;25(12):2304-13. doi:10.1093/annonc/mdu480
62. Haber DA, Velculescu VE. Blood-based analyses of cancer: circulating tumor cells and circulating tumor DNA. Cancer Discov. 2014;4(6):650-61. doi:10.1158/2159-8290.CD-13-1014
63. Lanman RB, Mortimer SA, Zill OA, Sebisanovic D, Lopez R, Blau S, et al. Analytical and clinical validation of a digital sequencing panel for quantitative, highly accurate evaluation of cell-free circulating tumor DNA. PLoS One. 2015;10(10):e0140712. doi:10.1371/journal.pone.0140712
64. Kinde I, Wu J, Papadopoulos N, Kinzler KW, Vogelstein B. Detection and quantification of rare mutations with massively parallel sequencing. Proc Natl Acad Sci USA. 2011;108(23):9530-5. doi:10.1073/pnas.1105422108
65. Bettegowda C, Sausen M, Leary RJ, Kinde I, Wang Y, Agrawal N, 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
66. Rothe F, Laes JF, Lambrechts D, Smeets D, Vincent D, Maetens M, et al. Plasma circulating tumor DNA as an alternative to metastatic biopsies for mutational analysis in breast cancer. Ann Oncol. 2014;25(10):1959-65. doi:10.1093/annonc/mdu288
67. Carreira S, Romanel A, Goodall J, Grist E, Ferraldeschi R, Miranda S, et al. Tumor clone dynamics in lethal prostate cancer. Sci Transl Med. 2014;6(254):254ra125. doi:10.1126/scitranslmed.3009448
68. Newman AM, Bratman SV, To J, Wynne JF, Eclov NC, Modlin LA, et al. An ultrasensitive method for quantitating circulating tumor DNA with broad patient coverage. Nat Med. 2014;20(5):548-54. doi:10.1038/nm.3519
69. Murtaza M, Dawson SJ, Tsui DW, Gale D, Forshew T, Piskorz AM, 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
70. McBride DJ, Orpana AK, Sotiriou C, Joensuu H, Stephens PJ, Mudie LJ, et al. Use of cancer-specific genomic rearrangements to quantify disease burden in plasma from patients with solid tumors. Genes Chromosomes Cancer. 2010;49(11):1062-9. doi:10.1002/gcc.20815
71. Shaw JA, Page K, Blighe K, Hava N, Guttery D, Ward B, et al. Genomic analysis of circulating cell-free DNA infers breast cancer dormancy. Genome Res. 2012;22(2):220-31. doi:10.1101/gr.123497.111
72. Leary RJ, Kinde I, Diehl F, Schmidt K, Clouser C, Duncan C, et al. Development of personalized tumor biomarkers using massively parallel sequencing. Sci Transl Med. 2010;2(20):20ra14. doi:10.1126/scitranslmed.3000702
73. Wang TL, Maierhofer C, Speicher MR, Lengauer C, Vogelstein B, Kinzler KW, et al. Digital karyotyping. Proc Natl Acad Sci USA. 2002;99(25):16156-61. doi:10.1073/pnas.202610899
74. Leary RJ, Sausen M, Kinde I, Papadopoulos N, Carpten JD, Craig D, et al. Detection of chromosomal alterations in the circulation of cancer patients with whole-genome sequencing. Sci Transl Med. 2012;4(162):162ra54. doi:10.1126/scitranslmed.3004742
75. Wang TL, Diaz LA Jr, Romans K, Bardelli A, Saha S, Galizia G, et al. Digital karyotyping identifies thymidylate synthase amplification as a mechanism of resistance to 5-fluorouracil in metastatic colorectal cancer patients. Proc Natl Acad Sci USA. 2004;101(9):3089-94. doi:10.1073/pnas.0308716101
76. Duncan CG, Leary RJ, Lin JC, Cummins J, Di C, Schaefer CF, et al. Identification of microbial DNA in human cancer. BMC Med Genomics. 2009;2:22. doi:10.1186/1755-8794-2-22
77. Chan KC, Jiang P, Zheng YW, Liao GJ, Sun H, Wong J, 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
78. Heitzer E, Ulz P, Belic J, Gutschi S, Quehenberger F, Fischereder K, et al. Tumor-associated copy number changes in the circulation of patients with prostate cancer identified through whole-genome sequencing. Genome Med. 2013;5(4):30. doi:10.1186/gm434
79. Giacona MB, Ruben GC, Iczkowski KA, Roos TB, Porter DM, Sorenson GD. Cell-free DNA in human blood plasma: length measurements in patients with pancreatic cancer and healthy controls. Pancreas. 1998;17(1):89-97
80. Umetani N, Kim J, Hiramatsu S, Reber HA, Hines OJ, Bilchik AJ, 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
81. Umetani N, Giuliano AE, Hiramatsu SH, Amersi F, Nakagawa T, Martino S, et al. Prediction of breast tumor progression by integrity of free circulating DNA in serum. J Clin Oncol. 2006;24(26):4270-6. doi:10.1200/JCO.2006.05.9493
82. Leon SA, Shapiro B, Sklaroff DM, Yaros MJ. Free DNA in the serum of cancer patients and the effect of therapy. Cancer Res. 1977;37(3):646-50
83. Tomita H, Ichikawa D, Ikoma D, Sai S, Tani N, Ikoma H, et al. Quantification of circulating plasma DNA fragments as tumor markers in patients with esophageal cancer. Anticancer Res. 2007;27(4C):2737-41
84. Nawroz H, Koch W, Anker P, Stroun M, Sidransky D. Microsatellite alterations in serum DNA of head and neck cancer patients. Nat Med. 1996;2(9):1035-7
85. Gang F, Guorong L, An Z, Anne GP, Christian G, Jacques T. 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
86. Pinzani P, Salvianti F, Zaccara S, Massi D, De Giorgi V, Pazzagli M, et al. Circulating cell-free DNA in plasma of melanoma patients: qualitative and quantitative considerations. Clin Chim Acta. 2011;412(23-24):2141-5. doi:10.1016/j.cca.2011.07.027
87. Hanley R, Rieger-Christ KM, Canes D, Emara NR, Shuber AP, Boynton KA, et al. DNA integrity assay: a plasma-based screening tool for the detection of prostate cancer. Clin Cancer Res. 2006;12(15):4569-74. doi:10.1158/1078-0432.CCR-06-0130
88. Elshimali YI, Khaddour H, Sarkissyan M, Wu Y, Vadgama JV. The clinical utilization of circulating cell free DNA (CCFDNA) in blood of cancer patients. Int J Mol Sci. 2013;14(9):18925-58. doi:10.3390/ijms140918925
89. Sorenson GD, Pribish DM, Valone FH, Memoli VA, Bzik DJ, Yao SL. Soluble normal and mutated DNA sequences from singlecopy genes in human blood. Cancer Epidemiol Biomarkers Prev. 1994;3(1):67-71
90. Vasioukhin V, Anker P, Maurice P, Lyautey J, Lederrey C, Stroun M. 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
91. Schwarzenbach H, Eichelser C, Kropidlowski J, Janni W, Rack B, Pantel K. Loss of heterozygosity at tumor suppressor genes detectable on fractionated circulating cell-free tumor DNA as indicator of breast cancer progression. Clin Cancer Res. 2012;18(20):5719-30. doi:10.1158/1078-0432.CCR-12-0142
92. Heyn H, Esteller M. DNA methylation profiling in the clinic: applications and challenges. Nat Rev Genet. 2012;13(10):679-92. doi:10.1038/nrg3270
93. Esteller M, Sanchez-Cespedes M, Rosell R, Sidransky D, Baylin SB, Herman JG. Detection of aberrant promoter hypermethylation of tumor suppressor genes in serum DNA from non-small cell lung cancer patients. Cancer Res. 1999;59(1):67-70
94. Silva JM, Dominguez G, Villanueva MJ, Gonzalez R, Garcia JM, Corbacho C, et al. Aberrant DNA methylation of the p16INK4a gene in plasma DNA of breast cancer patients. Br J Cancer. 1999;80(8):1262-4. doi:10.1038/sj.bjc.6690495
95. Wong IH, Lo YM, Zhang J, Liew CT, Ng MH, Wong N, et al. Detection of aberrant p16 methylation in the plasma and serum of liver cancer patients. Cancer Res. 1999;59(1):71-3
96. Kawakami K, Brabender J, Lord RV, Groshen S, Greenwald BD, Krasna MJ, et al. Hypermethylated APC DNA in plasma and prognosis of patients with esophageal adenocarcinoma. J Natl Cancer Inst. 2000;92(22):1805-11
97. Lecomte T, Berger A, Zinzindohoue F, Micard S, Landi B, Blons H, et al. Detection of free-circulating tumor-associated DNA in plasma of colorectal cancer patients and its association with prognosis. Int J Cancer. 2002;100(5):542-8. doi:10.1002/ijc.10526
98. Warton K, Samimi G. Methylation of cell-free circulating DNA in the diagnosis of cancer. Front Mol Biosci. 2015;2:13. doi:10.3389/fmolb.2015.00013
99. Zhai R, Zhao Y, Su L, Cassidy L, Liu G, Christiani DC. Genome-wide DNA methylation profiling of cell-free serum DNA in esophageal adenocarcinoma and Barrett esophagus. Neoplasia. 2012;14(1):29-33
100. Diaz LA Jr, Bardelli A. Liquid biopsies: genotyping circulating tumor DNA. J Clin Oncol. 2014;32(6):579-86. doi:10.1200/JCO.2012.45.2011
101. Lipson EJ, Velculescu VE, Pritchard TS, Sausen M, Pardoll DM, Topalian SL, et al. Circulating tumor DNA analysis as a real-time method for monitoring tumor burden in melanoma patients undergoing treatment with immune checkpoint blockade. J Immunother Cancer. 2014;2(1):42. doi:10.1186/s40425-014-0042-0
102. Yoshimasu T, Maebeya S, Suzuma T, Bessho T, Tanino H, Arimoto J, et al. Disappearance curves for tumor markers after resection of intrathoracic malignancies. Int J Biol Markers. 1999;14(2):99-105
103. Ito K, Hibi K, Ando H, Hidemura K, Yamazaki T, Akiyama S, et al. Usefulness of analytical CEA doubling time and half-life time for overlooked synchronous metastases in colorectal carcinoma. Jpn J Clin Oncol. 2002;32(2):54-8
104. Shinozaki M, O’Day SJ, Kitago M, Amersi F, Kuo C, Kim J, et al. Utility of circulating B-RAF DNA mutation in serum for monitoring melanoma patients receiving biochemotherapy. Clin Cancer Res. 2007;13(7):2068-74. doi:10.1158/1078-0432.CCR-06-2120
105. Bidard FC, Madic J, Mariani P, Piperno-Neumann S, Rampanou A, Servois V, et al. Detection rate and prognostic value of circulating tumor cells and circulating tumor DNA in metastatic uveal melanoma. Int J Cancer. 2014;134(5):1207-13. doi:10.1002/ijc.28436
106. Tie J, Kinde I, Wang Y, Wong HL, Roebert J, Christie M, et al. Circulating tumor DNA as an early marker of therapeutic response in patients with metastatic colorectal cancer. Ann Oncol. 2015;26(8):1715-22. doi:10.1093/annonc/mdv177
107. Pathak AK, Bhutani M, Kumar S, Mohan A, Guleria R. Circulating cell-free DNA in plasma/serum of lung cancer patients as a potential screening and prognostic tool. Clin Chem. 2006;52(10):1833-42. doi:10.1373/clinchem.2005.062893
108. Nygaard AD, Garm Spindler KL, Pallisgaard N, Andersen RF, Jakobsen A. The prognostic value of KRAS mutated plasma DNA in advanced nonsmall cell lung cancer. Lung Cancer. 2013;79(3):312-7. doi:10.1016/j.lungcan.2012.11.016
109. Olsson E, Winter C, George A, Chen Y, Howlin J, Tang MH, et al. Serial monitoring of circulating tumor DNA in patients with primary breast cancer for detection of occult metastatic disease. EMBO Mol Med. 2015;7(8):1034-47. doi:10.15252/emmm.201404913
110. Diaz LA Jr, Williams RT, Wu J, Kinde I, Hecht JR, Berlin J, et al. The molecular evolution of acquired resistance to targeted EGFR blockade in colorectal cancers. Nature. 2012;486(7404):537-40. doi:10.1038/nature11219
111. Misale S, Yaeger R, Hobor S, Scala E, Janakiraman M, Liska D, et al. Emergence of KRAS mutations and acquired resistance to anti-EGFR therapy in colorectal cancer. Nature. 2012;486(7404):532-6. doi:10.1038/nature11156
112. Misale S, Arena S, Lamba S, Siravegna G, Lallo A, Hobor S, et al. Blockade of EGFR and MEK intercepts heterogeneous mechanisms of acquired resistance to anti-EGFR therapies in colorectal cancer. Sci Transl Med. 2014;6(224):224ra26. doi:10.1126/scitranslmed.3007947
113. Bardelli A, Corso S, Bertotti A, Hobor S, Valtorta E, Siravegna G, et al. Amplification of the MET receptor drives resistance to anti-EGFR therapies in colorectal cancer. Cancer Discov. 2013;3(6):658-73. doi:10.1158/2159-8290.CD-12-0558
114. De Mattos-Arruda L, Cortes J, Santarpia L, Vivancos A, Tabernero J, Reis-Filho JS, et al. Circulating tumour cells and cell-free DNA as tools for managing breast cancer. Nat Rev Clin Oncol. 2013;10(7):377-89. doi:10.1038/nrclinonc.2013.80
115. Siravegna G, Bardelli A. Genotyping cell-free tumor DNA in the blood to detect residual disease and drug resistance. Genome Biol. 2014;15(8):449. doi:10.1186/s13059-014-0449-4
116. Board RE, Wardley AM, Dixon JM, Armstrong AC, Howell S, Renshaw L, et al. Detection of PIK3CA mutations in circulating free DNA in patients with breast cancer. Breast Cancer Res Treat. 2010;120(2):461-7. doi:10.1007/s10549-010-0747-9
117. Wang JY, Hsieh JS, Chang MY, Huang TJ, Chen FM, Cheng TL, et al. Molecular detection of APC, K-ras, and p53 mutations in the serum of colorectal cancer patients as circulating biomarkers. World J Surg. 2004;28(7):721-6. doi:10.1007/s00268-004-7366-8
118. Yamada T, Nakamori S, Ohzato H, Oshima S, Aoki T, Higaki N, et al. Detection of K-ras gene mutations in plasma DNA of patients with pancreatic adenocarcinoma: correlation with clinicopathological features. Clin Cancer Res. 1998;4(6):1527-32
119. Perkins G, Yap TA, Pope L, Cassidy AM, Dukes JP, Riisnaes R, et al. Multipurpose utility of circulating plasma DNA testing in patients with advanced cancers. PLoS One. 2012;7(11):e47020. doi:10.1371/journal.pone.0047020
120. Shi J, Liu Q, Sommer SS. Detection of ultrarare somatic mutation in the human TP53 gene by bidirectional pyrophosphorolysisactivated polymerization allele-specific amplification. Hum Mutat. 2007;28(2):131-6. doi:10.1002/humu.20423
121. Thompson JD, Shibahara G, Rajan S, Pel J, Marziali A. Winnowing DNA for rare sequences: highly specific sequence and methylation based enrichment. PLoS One. 2012;7(2):e31597. doi:10.1371/journal.pone.0031597.