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Abstract

Since the clear proof of the presence of tumor-associated genetic alterations in extracellular nucleic acids almost 20 years ago this field gained has attracted much interest. According to our current knowledge it seems as if all tumor-associated alterations found in tumor cells are also found in the extracellular environment. The isolation of extracellular nucleic acids from tumor patients and its genetic characterization with very sensitive and highly specific methods led to the concept of “liquid biopsy”. This means that for follow-up analysis of tumor patients, the physicians no longer depend exclusively on a single examination of tissue biopsies (usually at the time of diagnosis) but are able by longitudinally analyzing the extracellular nucleic acids to follow the reaction of a tumor to e.g. a given therapy, the development of resistance mechanisms. In this chapter we will discuss the detection and characterization of different genetic (e.g. mutation analysis and structural variations as seen in microsatellites), epigenetic (e.g. hypermethylation of selected sequences) and regulatory alterations (as in different miRNA expression patterns found in tumor patients). We will also touch on some confounding factors that have to be taken into consideration as well as the functional and biological aspects of extracellular nucleic acids.

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References

  1. Mukherjee S (2010) The emperor of all maladies. Scribner, New York

    Google Scholar 

  2. Anand P, Kunnumakkara AB, Sundaram C, Harikumar KB, Tharakan ST, Lai OS, Sung B, Aggarwal BB (2008) Cancer is a preventable disease that requires major lifestyle changes. Pharm Res 25(9):2097–2116

    Google Scholar 

  3. Salomon JA, Wang H, Freeman MK, Vos T, Flaxman AD, Lopez AD, Murray CJ (2012) Healthy life expectancy for 187 countries, 1990–2010: a systematic analysis for the Global Burden Disease Study 2010. Lancet 380(9859):2144–2162

    Google Scholar 

  4. Siegel R, Naishadham D, Jemal A (2012) Cancer statistics, 2012. CA Cancer J Clin 62(1):10–29

    Article  PubMed  Google Scholar 

  5. Kopans DB, Smith RA, Duffy SW (2011) Mammographic screening and “overdiagnosis”. Radiology 260(3):616–620

    Article  PubMed  Google Scholar 

  6. Fleischhacker M, Schmidt B (2007) Circulating nucleic acids (CNAs) and cancer – a survey. Biochim Biophys Acta 1775(1):181–232

    CAS  PubMed  Google Scholar 

  7. Jung K, Fleischhacker M, Rabien A (2010) Cell-free DNA in the blood as a solid tumor biomarker – a critical appraisal of the literature. Clin Chim Acta 411(21–22):1611–1624

    Article  CAS  PubMed  Google Scholar 

  8. Tzimagiorgis G, Michailidou EZ, Kritis A, Markopoulos AK, Kouidou S (2011) Recovering circulating extracellular or cell-free RNA from bodily fluids. Cancer Epidemiol 35(6):580–589

    Google Scholar 

  9. Weber JA, Baxter DH, Zhang S, Huang DY, Huang KH, Lee MJ, Galas DJ, Wang K (2010) The microRNA spectrum in 12 body fluids. Clin Chem 56(11):1733–1741

    Google Scholar 

  10. Kessler T, Hache H, Wierling C (2013) Integrative analysis of cancer-related signaling pathways. Front Physiol 4:124

    Article  PubMed Central  PubMed  Google Scholar 

  11. Leon SA, Shapiro B, Sklaroff DM, Yaros MJ (1977) Free DNA in the serum of cancer patients and the effect of therapy. Cancer Res 373:646–650

    Google Scholar 

  12. Chen XQ, Stroun M, Magnenat JL, Nicod LP, Kurt AM, Lyautey J, Lederrey C, Anker P (1996) Microsatellite alterations in plasma DNA of small cell lung cancer patients. Nat Med 2(9):1033–1035

    Google Scholar 

  13. Nawroz H, Koch W, Anker P, Stroun M, Sidransky D (1996) Microsatellite alterations in serum DNA of head and neck cancer patients. Nat Med 2(9):1035–1037

    Article  CAS  PubMed  Google Scholar 

  14. Jing RR, Wang HM, Cui M, Fang MK, Qiu XJ, Wu XH, Qi J, Wang YG, Zhang LR, Zhu JH, Ju SQ (2011) A sensitive method to quantify human cell-free circulating DNA in blood: relevance to myocardial infarction screening. Clin Biochem 44(13):1074–1079

    Google Scholar 

  15. Arnalich F, Menendez M, Lagos V, Ciria E, Quesada A, Codoceo R, Vazquez JJ, López-Collazo E, Montiel C (2010) Prognostic value of cell-free plasma DNA in patients with cardiac arrest outside the hospital: an observational cohort study. Crit Care 14(2):R47

    Google Scholar 

  16. Atamaniuk J, Stuhlmeier KM, Vidotto C, Tschan H, Dossenbach-Glaninger A, Mueller MM (2008) Effects of ultra-marathon on circulating DNA and mRNA expression of pro- and anti-apoptotic genes in mononuclear cells. Eur J Appl Physiol 104(4):711–717

    Google Scholar 

  17. Beiter T, Fragasso A, Hudemann J (2011) Short-term treadmill running as a model for studying cell-free DNA kinetics in vivo. Clin Chem 57(4):633–636

    Article  CAS  PubMed  Google Scholar 

  18. Breitbach S, Tug S, Simon P (2012) Circulating cell-free DNA: an up-coming molecular marker in exercise physiology. Sports Med 42(7):565–586

    Article  PubMed  Google Scholar 

  19. Atamaniuk J, Hsiao YY, Mustak M, Bernhard D, Erlacher L, Fodinger M, Tiran B, Stuhlmeier KM (2011) Analysing cell-free plasma DNA and SLE disease activity. Eur J Clin Invest 41(6):579–583

    Google Scholar 

  20. Jylhava J, Kotipelto T, Raitala A, Jylhä M, Hervonen A, Hurme M (2011) Aging is associated with quantitative and qualitative changes in circulating cell-free DNA: the vitality 90+ study. Mech Ageing Dev 132(1–2):20–26

    Google Scholar 

  21. Moreira VG, Prieto B, Rodriguez JS, Alvarez FV (2010) Usefulness of cell-free plasma DNA, procalcitonin and C-reactive protein as markers of infection in febrile patients. Ann Clin Biochem 47(Pt 3):253–258

    Article  CAS  PubMed  Google Scholar 

  22. Ozkaya O, Bek K, Bedir A, Acikgoz Y, Ozdemir T (2009) Plasma cell-free DNA levels in children on peritoneal dialysis. Nephron Clin Pract 113(4):c258–c261

    Article  CAS  PubMed  Google Scholar 

  23. Shin C, Kim JK, Kim JH, Jung KH, Cho KJ, Lee CK, Lee SG (2008) Increased cell-free DNA concentrations in patients with obstructive sleep apnea. Psychiatry Clin Neurosci 62(6):721–727

    Google Scholar 

  24. Korabecna M, Opatrna S, Wirth J, Rulcova K, Eiselt J, Sefrna F, Horinek A (2008) Cell-free plasma DNA during peritoneal dialysis and hemodialysis and in patients with chronic kidney disease. Ann NY Acad Sci 1137:296–301

    Google Scholar 

  25. Saukkonen K, Lakkisto P, Pettila V, Varpula M, Karlsson S, Ruokonen E, Pulkki K; Finnsepsis Study Group (2008) Cell-free plasma DNA as a predictor of outcome in severe sepsis and septic shock. Clin Chem 54(6):1000–1007

    Google Scholar 

  26. Campello YV, Ikuta N, Brondani da Rocha A, Lunge VR, Fett Schneider R, Kazantzi Fonseca AS, Grivicich I, Zanoni C, Regner A (2007) Role of plasma DNA as a predictive marker of fatal outcome following severe head injury in males. J Neurotrauma 24(7):1172–1181

    Google Scholar 

  27. Chiu TW, Young R, Chan LY, Burd A, Lo DY (2006) Plasma cell-free DNA as an indicator of severity of injury in burn patients. Clin Chem Lab Med 44(1):13–17

    Google Scholar 

  28. van der Drift MA, Prinsen CF, Hol BE (2008) Can free DNA be detected in sputum of lung cancer patients? Lung Cancer 61(3):385–390

    Article  PubMed  Google Scholar 

  29. Chiappetta C, Anile M, Leopizzi M, Venuta F, Della Rocca C (2013) Use of a new generation of capillary electrophoresis to quantify circulating free DNA in non-small cell lung cancer. Clin Chim Acta 425C:93–96

    Google Scholar 

  30. Ludovini V, Pistola L, Gregorc V, Floriani I, Rulli E, Piattoni S, Di CL, Semeraro A, Darwish S, Tofanetti FR, Stocchi L, Mihaylova Z, Bellezza G, Del SR, Daddi G, Crino L, Tonato M (2008) Plasma DNA, microsatellite alterations, and p53 tumor mutations are associated with disease-free survival in radically resected non-small cell lung cancer patients: a study of the perugia multidisciplinary team for thoracic oncology. J Thorac Oncol 3(4):365–373

    Article  PubMed  Google Scholar 

  31. Perego RA, Corizzato M, Brambilla P, Ferrero S, Bianchi C, Fasoli E, Signorini S, Torsello B, Invernizzi L, Bombelli S, Angeloni V, Pitto M, Battaglia C, Proserpio V, Magni F, Galasso G, Mocarelli P (2008) Concentration and microsatellite status of plasma DNA for monitoring patients with renal carcinoma. Eur J Cancer 44(7):1039–1047

    Google Scholar 

  32. Cheng C, Omura-Minamisawa M, Kang Y, Hara T, Koike I, Inoue T (2009) Quantification of circulating cell-free DNA in the plasma of cancer patients during radiation therapy. Cancer Sci 100(2):303–309

    Google Scholar 

  33. Garcia-Olmo DC, Picazo MG, Toboso I, Asensio AI, GarcÚa-Olmo D (2013) Quantitation of cell-free DNA and RNA in plasma during tumor progression in rats. Mol Cancer 12:8. doi:10.1186/1476-4598-12-8

  34. Wang BG, Huang HY, Chen YC, Bristow RE, Kassauei K, Cheng CC, Roden R, Sokoll LJ, Chan DW, Shih IM (2003) Increased plasma DNA integrity in cancer patients. Cancer Res 63(14):3966–3968

    Google Scholar 

  35. Lehner J, Stotzer OJ, Fersching D, Nagel D, Holdenrieder S (2013) Circulating plasma DNA and DNA integrity in breast cancer patients undergoing neoadjuvant chemotherapy. Clin Chim Acta 425C:206–211

    Google Scholar 

  36. Boddy JL, Gal S, Malone PR, Shaida N, Wainscoat JS, Harris AL (2006) The role of cell-free DNA size distribution in the management of prostate cancer. Oncol Res 16(1):35–41

    Google Scholar 

  37. Feng J, Gang F, Li X, Jin T, Houbao H, Yu C, Guorong L (2013) Plasma cell-free DNA and its DNA integrity as biomarker to distinguish prostate cancer from benign prostatic hyperplasia in patients with increased serum prostate-specific antigen. Int Urol Nephrol 45(4):1023–1028

    Google Scholar 

  38. Hanley R, Rieger-Christ KM, Canes D, Emara NR, Shuber AP, Boynton KA, Libertino JA, Summerhayes IC (2006) DNA integrity assay: a plasma-based screening tool for the detection of prostate cancer. Clin Cancer Res 12(15):4569–4574

    Google Scholar 

  39. Ellinger J, von RA, Bastian PJ, Müller SC (2010) Circulating cell-free serum DNA: significance as a new biomarker for urological malignancies. Urologe A 49(9):1131–1132, 1134

    Google Scholar 

  40. Hauser S, Zahalka T, Ellinger J, Fechner G, Heukamp LC, VON Ruecker A, Müller SC, Bastian PJ (2010) Cell-free circulating DNA: diagnostic value in patients with renal cell cancer. Anticancer Res 30(7):2785–2789

    Google Scholar 

  41. Jiang WW, Zahurak M, Goldenberg D, Milman Y, Park HL, Westra WH, Koch W, Sidransky D, Califano J (2006) Increased plasma DNA integrity index in head and neck cancer patients. Int J Cancer 119(11):2673–2676

    Google Scholar 

  42. Sai S, Ichikawa D, Tomita H, Ikoma D, Tani N, Ikoma H, Kikuchi S, Fujiwara H, Ueda Y, Otsuji E (2007) Quantification of plasma cell-free DNA in patients with gastric cancer. Anticancer Res 27(4C):2747–2751

    Google Scholar 

  43. Holdenrieder S, Burges A, Reich O, Spelsberg FW, Stieber P (2008) DNA integrity in plasma and serum of patients with malignant and benign diseases. Ann NY Acad Sci 1137:162–170

    Google Scholar 

  44. Schmidt B, Weickmann S, Witt C, Fleischhacker M (2008) Integrity of cell-free plasma DNA in patients with lung cancer and nonmalignant lung disease. Ann NY Acad Sci 11(37):207–213

    Google Scholar 

  45. Delgado PO, Alves BC, Gehrke FS, Kuniyoshi RK, Wroclavski ML, Del Giglio A, Fonseca FL (2013) Characterization of cell-free circulating DNA in plasma in patients with prostate cancer. Tumour Biol 34(2):983–986

    Google Scholar 

  46. Dressman D, Yan H, Traverso G, Kinzler KW, Vogelstein B (2003) Transforming single DNA molecules into fluorescent magnetic particles for detection and enumeration of genetic variations. Proc Natl Acad Sci U S A 100(15):8817–8822

    Google Scholar 

  47. Kalinina O, Lebedeva I, Brown J, Silver J (1997) Nanoliter scale PCR with TaqMan detection. Nucleic Acids Res 25(10):1999–2004

    Google Scholar 

  48. Sykes PJ, Neoh SH, Brisco MJ, Hughes E, Condon J, Morley AA (1992) Quantitation of targets for PCR by use of limiting dilution. Biotechniques 13(3):444–449

    Google Scholar 

  49. Sakai K, Horiike A, Irwin DL, Kudo K, Fujita Y, Tanimoto A, Sakatani T, Saito R, Kaburaki K, Yanagitani N, Ohyanagi F, Nishio M, Nishio K (2013) Detection of epidermal growth factor receptor T790M mutation in plasma DNA from patients refractory to epidermal growth factor receptor tyrosine kinase inhibitor. Cancer Sci 104(9):1198–1204

    Google Scholar 

  50. Narayan A, Carriero NJ, Gettinger SN, Kluytenaar J, Kozak KR, Yock TI, Muscato NE, Ugarelli P, Decker RH, Patel AA (2012) Ultrasensitive measurement of hotspot mutations in tumor DNA in blood using error-suppressed multiplexed deep sequencing. Cancer Res 72(14):3492–3498

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  51. Liu X, Lu Y, Zhu G, Lei Y, Zheng L, Qin H, Tang C, Ellison G, McCormack R, Ji Q (2013) The diagnostic accuracy of pleural effusion and plasma samples versus tumour tissue for detection of EGFR mutation in patients with advanced non-small cell lung cancer: comparison of methodologies. J Clin Pathol 66:1065–1069

    Google Scholar 

  52. Hubers AJ, Heideman DA, Yatabe Y, Wood MD, Tull J, Tarón M, Molina MA, Mayo C, Bertran-Alamillo J, Herder GJ, Koning R, Sie D, Ylstra B, Meijer GA, Snijders PJ, Witte BI, Postmus PE, Smit EF, Thunnissen E (2013) EGFR mutation analysis in sputum of lung cancer patients: a multitechnique study. Lung Cancer 82(1):38–43. doi:10.1016/j.lungcan.2013.07.011

  53. Kuang Y, Rogers A, Yeap BY, Wang L, Makrigiorgos M, Vetrand K, Thiede S, Distel RJ, Jðnne PA (2009) Noninvasive detection of EGFR T790M in gefitinib or erlotinib resistant non-small cell lung cancer. Clin Cancer Res 15(8):2630–2636

    Google Scholar 

  54. Higgins MJ, Jelovac D, Barnathan E, Blair B, Slater S, Powers P, Zorzi J, Jeter SC, Oliver GR, Fetting J, Emens L, Riley C, Stearns V, Diehl F, Angenendt P, Huang P, Cope L, Argani P, Murphy KM, Bachman KE, Greshock J, Wolff AC, Park BH (2012) Detection of tumor PIK3CA status in metastatic breast cancer using peripheral blood. Clin Cancer Res 18(12):3462–3469

    Google Scholar 

  55. Jakupciak JP, Maragh S, Markowitz ME, Greenberg AK, Hoque MO, Maitra A, Barker PE, Wagner PD, Rom WN, Srivastava S, Sidransky D, O'Connell CD (2008) Performance of mitochondrial DNA mutations detecting early stage cancer. BMC Cancer 8:285. doi:10.1186/1471-2407-8-285

  56. Heitzer E, Auer M, Hoffmann EM, Pichler M, Gasch C, Ulz P, Lax S, Waldispuehl-Geigl J, Mauermann O, Mohan S, Pristauz G, Lackner C, H­fler G, Eisner F, Petru E, Sill H, Samonigg H, Pantel K, Riethdorf S, Bauernhofer T, Geigl JB, Speicher MR (2013) Establishment of tumor-specific copy number alterations from plasma DNA of patients with cancer. Int J Cancer 133(2):346–356

    Google Scholar 

  57. Leary RJ, Sausen M, Kinde I, Papadopoulos N, Carpten JD, Craig D, O'Shaughnessy J, Kinzler KW, Parmigiani G, Vogelstein B, Diaz LA Jr, Velculescu VE (2012) Detection of chromosomal alterations in the circulation of cancer patients with whole-genome sequencing. Sci Transl Med 4:162ra154

    Google Scholar 

  58. Liu Y, Liu B, Li XY, Li JJ, Qin HF, Tang CH, Guo WF, Hu HX, Li S, Chen CJ, Liu B, Gao HJ, Liu XQ (2011) A comparison of ARMS and direct sequencing for EGFR mutation analysis and tyrosine kinase inhibitors treatment prediction in body fluid samples of non-small-cell lung cancer patients. J Exp Clin Cancer Res 30:111

    Google Scholar 

  59. Beck J, Urnovitz HB, Mitchell WM, Schütz E (2010) Next generation sequencing of serum circulating nucleic acids from patients with invasive ductal breast cancer reveals differences to healthy and nonmalignant controls. Mol Cancer Res 8:335–342

    Google Scholar 

  60. Buttitta F, Felicioni L, Del Grammastro M, Filice G, Di Lorito A, Malatesta S, Viola P, Centi I, D'Antuono T, Zappacosta R, Rosini S, Cuccurullo F, Marchetti A (2013) Effective assessment of egfr mutation status in bronchoalveolar lavage and pleural fluids by next-generation sequencing. Clin Cancer Res 19:691–698

    Google Scholar 

  61. He J, Wu J, Jiao Y, Wagner-Johnston N, Ambinder RF, Diaz LA Jr, Kinzler KW, Vogelstein B, Papadopoulos N (2011) IgH gene rearrangements as plasma biomarkers in Non-Hodgkin’s lymphoma patients. Oncotarget 2:178–185

    Google Scholar 

  62. Gevensleben H, Garcia-Murillas I, Graeser MK, Schiavon G, Osin P, Parton M, Smith IE, Ashworth A, Turner NC (2013) Noninvasive detection of HER2 amplification with plasma DNA digital PCR. Clin Cancer Res 19(12):3276–3284

    Google Scholar 

  63. McBride DJ, Orpana AK, Sotiriou C, Joensuu H, Stephens PJ, Mudie LJ, Hðmðlðinen E, Stebbings LA, Andersson LC, Flanagan AM, Durbecq V, Ignatiadis M, Kallioniemi O, Heckman CA, Alitalo K, Edgren H, Futreal PA, Stratton MR, Campbell PJ (2010) Use of cancer-specific genomic rearrangements to quantify disease burden in plasma from patients with solid tumors. Genes Chromosomes Cancer 49:1062–1069

    Google Scholar 

  64. Forshew T, Murtaza M, Parkinson C, Gale D, Tsui DW, Kaper F, Dawson SJ, Piskorz AM, Jimenez-Linan M, Bentley D, Hadfield J, May AP, Caldas C, Brenton JD, Rosenfeld N (2012) Noninvasive identification and monitoring of cancer mutations by targeted deep sequencing of plasma DNA. Sci Transl Med 4:136ra68

    Google Scholar 

  65. Murtaza M, Dawson SJ, Tsui DW, Gale D, Forshew T, Piskorz AM, Parkinson C, Chin SF, Kingsbury Z, Wong AS, Marass F, Humphray S, Hadfield J, Bentley D, Chin TM, Brenton JD, Caldas C, Rosenfeld N (2013) Non-invasive analysis of acquired resistance to cancer therapy by sequencing of plasma DNA. Nature 497:108–112

    Article  CAS  PubMed  Google Scholar 

  66. Li M, Chen WD, Papadopoulos N, Goodman SN, Bjerregaard NC, Laurberg S, Levin B, Juhl H, Arber N, Moinova H, Durkee K, Schmidt K, He Y, Diehl F, Velculescu VE, Zhou S, Diaz LA Jr, Kinzler KW, Markowitz SD, Vogelstein B (2009) Sensitive digital quantification of DNA methylation in clinical samples. Nat Biotechnol 27(9):858–863

    Google Scholar 

  67. Weisenberger DJ, Trinh BN, Campan M, Sharma S, Long TI, Ananthnarayan S, Liang G, Esteva FJ, Hortobagyi GN, McCormick F, Jones PA, Laird PW (2008) DNA methylation analysis by digital bisulfite genomic sequencing and digital MethyLight. Nucleic Acids Res 36:4689–4698

    Google Scholar 

  68. Taly V, Pekin D, Benhaim L, Kotsopoulos SK, Le Corre D, Li X, Atochin I, Link DR, Griffiths AD, Pallier K, Blons H, BouchÕ O, Landi B, Hutchison JB, Laurent-Puig P (2013) Multiplex picodroplet digital PCR to detect KRAS mutations in circulating DNA from the plasma of colorectal cancer patients. Clin Chem. doi:10.1373/clinchem.2013.206359

  69. Yung TK, Chan KC, Mok TS, Tong J, To KF, Lo YM (2009) Single-molecule detection of epidermal growth factor receptor mutations in plasma by microfluidics digital PCR in non-small cell lung cancer patients. Clin Cancer Res 15(6):2076–2084

    Google Scholar 

  70. Hindson BJ, Ness KD, Masquelier DA, Belgrader P, Heredia NJ, Makarewicz AJ, Bright IJ, Lucero MY, Hiddessen AL, Legler TC, Kitano TK, Hodel MR, Petersen JF, Wyatt PW, Steenblock ER, Shah PH, Bousse LJ, Troup CB, Mellen JC, Wittmann DK, Erndt NG, Cauley TH, Koehler RT, So AP, Dube S, Rose KA, Montesclaros L, Wang S, Stumbo DP, Hodges SP, Romine S, Milanovich FP, White HE, Regan JF, Karlin-Neumann GA, Hindson CM, Saxonov S, Colston BW (2011) High-throughput droplet digital PCR system for absolute quantitation of DNA copy number. Anal Chem 83(22):8604–8610

    Google Scholar 

  71. Hindson CM, Chevillet JR, Briggs HA, Gallichotte EN, Ruf IK, Hindson BJ, Vessella RL, Tewari M (2013) Absolute quantification by droplet digital PCR versus analog real-time PCR. Nat Methods 10:1003–1005. doi:10.1038/nmeth.2633

  72. Whale AS, Huggett JF, Cowen S, Speirs V, Shaw J, Ellison S, Foy CA, Scott DJ (2012) Comparison of microfluidic digital PCR and conventional quantitative PCR for measuring copy number variation. Nucleic Acids Res 40(11):e82

    Google Scholar 

  73. Diehl F, Schmidt K, Choti MA, Romans K, Goodman S, Li M, Thornton K, Agrawal N, Sokoll L, Szabo SA, Kinzler KW, Vogelstein B, Diaz LA Jr (2008) Circulating mutant DNA to assess tumor dynamics. Nat Med 14(9):985–990

    Google Scholar 

  74. Diehl F, Schmidt K, Durkee KH, Moore KJ, Goodman SN, Shuber AP, Kinzler KW, Vogelstein B (2008) Analysis of mutations in DNA isolated from plasma and stool of colorectal cancer patients. Gastroenterology 135(2):489–498

    Google Scholar 

  75. Chen WW, Balaj L, Liau LM, Samuels ML, Kotsopoulos SK, Maguire CA, Loguidice L, Soto H, Garrett M, Zhu LD, Sivaraman S, Chen C, Wong ET, Carter BS, Hochberg FH, Breakefield XO, Skog J (2013) BEAMing and droplet digital PCR analysis of mutant IDH1 mRNA in glioma patient serum and cerebrospinal fluid extracellular vesicles. Mol Ther Nucleic Acids 2:e109

    Google Scholar 

  76. Taniguchi K, Uchida J, Nishino K, Kumagai T, Okuyama T, Okami J, Higashiyama M, Kodama K, Imamura F, Kato K (2011) Quantitative detection of EGFR mutations in circulating tumor DNA derived from lung adenocarcinomas. Clin Cancer Res 17(24):7808–7815

    Google Scholar 

  77. Misale S, Yaeger R, Hobor S, Scala E, Janakiraman M, Liska D, Valtorta E, Schiavo R, Buscarino M, Siravegna G, Bencardino K, Cercek A, Chen CT, Veronese S, Zanon C, Sartore-Bianchi A, Gambacorta M, Gallicchio M, Vakiani E, Boscaro V, Medico E, Weiser M, Siena S, Di NF, Solit D, Bardelli A (2012) Emergence of KRAS mutations and acquired resistance to anti-EGFR therapy in colorectal cancer. Nature 486(7404):532–536

    CAS  PubMed Central  PubMed  Google Scholar 

  78. Dawson SJ, Tsui DW, Murtaza M, Biggs H, Rueda OM, Chin SF, Dunning MJ, Gale D, Forshew T, Mahler-Araujo B, Rajan S, Humphray S, Becq J, Halsall D, Wallis M, Bentley D, Caldas C, Rosenfeld (2013) Analysis of circulating tumor DNA to monitor metastatic breast cancer. N Engl J Med 368(13):1199–1209

    Google Scholar 

  79. Kim HR, Lee SY, Hyun DS, MK, Lee HK, Choi CM, Yang SH, Kim YC, Lee YC, Kim SY, Jang SH, Lee JC, Lee KY (2013) Detection of EGFR mutations in circulating free DNA by PNA-mediated PCR clamping. J Exp Clin Cancer Res 32(1):50. doi:10.1186/1756-9966-32-50

  80. Salvianti F, Pinzani P, Verderio P, Ciniselli CM, Massi D, De Giorgi V, Grazzini M, Pazzagli M, Orlando C (2012) Multiparametric analysis of cell-free DNA in melanoma patients. PLoS One 7(11):e49843

    Google Scholar 

  81. Ziai J, Hui P (2012) BRAF mutation testing in clinical practice. Expert Rev Mol Diagn 12(2):127–138

    Article  CAS  PubMed  Google Scholar 

  82. Nikiforov YE (2011) Molecular diagnostics of thyroid tumors. Arch Pathol Lab Med 135(5):569–577

    CAS  PubMed  Google Scholar 

  83. Bedeir A, Krasinskas AM (2011) Molecular diagnostics of colorectal cancer. Arch Pathol Lab Med 135(5):578–587

    CAS  PubMed  Google Scholar 

  84. Vang R, Shih I, Kurman RJ (2009) Ovarian low-grade and high-grade serous carcinoma: pathogenesis, clinicopathologic and molecular biologic features, and diagnostic problems. Adv Anat Pathol 16(5):267–282

    Article  PubMed Central  PubMed  Google Scholar 

  85. Lagos-Quintana M, Rauhut R, Lendeckel W, Tuschl T (2001) Identification of novel genes coding for small expressed RNAs. Science 294(5543):853–858

    Google Scholar 

  86. Jung M, Schaefer A, Steiner I, Kempkensteffen C, Stephan C, Erbersdobler A, Jung K (2010) Robust microRNA stability in degraded RNA preparations from human tissue and cell samples. Clin Chem 56(6):998–1006

    Google Scholar 

  87. Redova M, Sana J, Slaby O (2013) Circulating miRNAs as new blood-based biomarkers for solid cancers. Future Oncol 93:387–402

    Article  Google Scholar 

  88. Yun SJ, Jeong P, Kim WT, Kim TH, Lee YS, Song PH, Choi YH, Kim IY, Moon SK, Kim WJ (2012) Cell-free microRNAs in urine as diagnostic and prognostic biomarkers of bladder cancer. Int J Oncol 41(5):1871–1878

    Google Scholar 

  89. Koga Y, Yasunaga M, Moriya Y, Akasu T, Fujita S, Yamamoto S, Matsumura Y (2011) Exosome can prevent RNase from degrading microRNA in feces. J Gastrointest Oncol 2(4):215–222

    Google Scholar 

  90. Chen X, Ba Y, Ma L, Cai X, Yin Y, Wang K, Guo J, Zhang Y, Chen J, Guo X, Li Q, Li X, Wang W, Zhang Y, Wang J, Jiang X, Xiang Y, Xu C, Zheng P, Zhang J, Li R, Zhang H, Shang X, Gong T, Ning G, Wang J, Zen K, Zhang J, Zhang CY (2008) Characterization of microRNAs in serum: a novel class of biomarkers for diagnosis of cancer and other diseases. Cell Res 18(10):997–1006

    Google Scholar 

  91. Shen J, Todd NW, Zhang H, Yu L, Lingxiao X, Mei Y, Guarnera M, Liao J, Chou A, Lu CL, Jiang Z, Fang H, Katz RL, Jiang F (2011b) Plasma microRNAs as potential biomarkers for non-small-cell lung cancer. Lab Invest 91(4):579–587. doi:10.1038/labinvest.2010.194, Epub 2010 Nov 29

  92. Boeri M, Verri C, Conte D, Roz L, Modena P, Facchinetti F, Calabró E, Croce CM, Pastorino U, Sozzi G (2011) MicroRNA signatures in tissues and plasma predict development and prognosis of computed tomography detected lung cancer. Proc Natl Acad Sci U S A 108(9):3713–3718

    Google Scholar 

  93. Chen X, Hu Z, Wang W, Ba Y, Ma L, Zhang C, Wang C, Ren Z, Zhao Y, Wu S, Zhuang R, Zhang Y, Hu H, Liu C, Xu L, Wang J, Shen H, Zhang J, Zen K, Zhang CY (2012) Identification of ten serum microRNAs from a genome-wide serum microRNA expression profile as novel noninvasive biomarkers for nonsmall cell lung cancer diagnosis. Int J Cancer 130(7):1620–1628

    Google Scholar 

  94. Foss KM, Sima C, Ugolini D, Neri M, Allen KE, Weiss GJ (2011) miR-1254 and miR-574-5p: serum-based microRNA biomarkers for early-stage non-small cell lung cancer. J Thorac Oncol 6(3):482–488

    Google Scholar 

  95. Wei J, Gao W, Zhu CJ, Liu YQ, Mei Z, Cheng T, Shu YQ (2011) Identification of plasma microRNA-21 as a biomarker for early detection and chemosensitivity of non-small cell lung cancer. Chin J Cancer 30(6):407–414

    Google Scholar 

  96. Roth C, Stuckrath I, Pantel K, Izbicki JR, Tachezy M, Schwarzenbach H (2012) Low levels of cell-free circulating miR-361-3p and miR-625* as blood-based markers for discriminating malignant from benign lung tumors. PLoS One 7(6):e38248

    Google Scholar 

  97. Bianchi F, Nicassio F, Marzi M, Belloni E, Dall'olio V, Bernard L, Pelosi G, Maisonneuve P, Veronesi G, Di Fiore PP (2011) A serum circulating miRNA diagnostic test to identify asymptomatic high-risk individuals with early stage lung cancer. EMBO Mol Med 3(8):495–503

    Google Scholar 

  98. Hennessey PT, Sanford T, Choudhary A, Mydlarz WW, Brown D, Adai AT, Ochs MF, Ahrendt SA, Mambo E, Califano JA (2012) Serum microRNA biomarkers for detection of non-small cell lung cancer. PLoS One 7:e32307

    Google Scholar 

  99. Zheng D, Haddadin S, Wang Y, Gu LQ, Perry MC, Freter CE, Wang MX (2011) Plasma microRNAs as novel biomarkers for early detection of lung cancer. Int J Clin Exp Pathol 4:575–586

    Google Scholar 

  100. Shen J, Liu Z, Todd NW, Zhang H, Liao J, Yu L, Guarnera MA, Li R, Cai L, Zhan M, Jiang F (2011a) Diagnosis of lung cancer in individuals with solitary pulmonary nodules by plasma microRNA biomarkers. BMC Cancer 11:374. doi:10.1186/1471-2407-11-374

  101. Yuxia M, Zhennan T, Wei Z (2012) Circulating miR-125b is a novel biomarker for screening non-small-cell lung cancer and predicts poor prognosis. J Cancer Res Clin Oncol 138:2045–2050

    Article  PubMed  Google Scholar 

  102. Hu Z, Chen X, Zhao Y, Tian T, Jin G, Shu Y, Chen Y, Xu L, Zen K, Zhang C, Shen H (2010) Serum microRNA signatures identified in a genome-wide serum microRNA expression profiling predict survival of non-small-cell lung cancer. J Clin Oncol 28:1721–1726

    Google Scholar 

  103. Abd-El-Fattah AA, Sadik NA, Shaker OG, Aboulftouh ML (2013) Differential microRNAs expression in serum of patients with lung cancer, pulmonary tuberculosis, and pneumonia. Cell Biochem Biophys 67:875–884

    Google Scholar 

  104. Wang B, Zhang Q (2012) The expression and clinical significance of circulating microRNA-21 in serum of five solid tumors. J Cancer Res Clin Oncol 138:1659–1666

    Article  CAS  PubMed  Google Scholar 

  105. Xing L, Todd NW, Yu L, Fang H, Jiang F (2010) Early detection of squamous cell lung cancer in sputum by a panel of microRNA markers. Mod Pathol 23(8):1157–1164

    Google Scholar 

  106. Yu L, Todd NW, Xing L, Xie Y, Zhang H, Liu Z, Fang H, Zhang J, Katz RL, Jiang F (2010) Early detection of lung adenocarcinoma in sputum by a panel of microRNA markers. Int J Cancer 127(12):2870–2878

    Google Scholar 

  107. Xie Y, Todd NW, Liu Z, Zhan M, Fang H, Peng H, Alattar M, Deepak J, Stass SA, Jiang F (2010) Altered miRNA expression in sputum for diagnosis of non-small cell lung cancer. Lung Cancer 67:170–176

    Google Scholar 

  108. Roa WH, Kim JO, Razzak R, Du H, Guo L, Singh R, Gazala S, Ghosh S, Wong E, Joy AA, Xing JZ, Bedard EL (2012) Sputum microRNA profiling: a novel approach for the early detection of non-small cell lung cancer. Clin Invest Med 35(5):E271

    Google Scholar 

  109. Heegaard NH, Schetter AJ, Welsh JA, Yoneda M, Bowman ED, Harris CC (2012) Circulating micro-RNA expression profiles in early stage nonsmall cell lung cancer. Int J Cancer 130:1378–1386

    Google Scholar 

  110. Krichevsky AM, Gabriely G (2009) miR-21: a small multi-faceted RNA. J Cell Mol Med 13(1):39–53

    Article  CAS  PubMed  Google Scholar 

  111. Faraoni I, Antonetti FR, Cardone J, Bonmassar E (2009) miR-155 gene: a typical multifunctional microRNA. Biochim Biophys Acta 1792(6):497–505

    Google Scholar 

  112. Fayyad-Kazan H, Bitar N, Najar M (2013) Circulating miR-150 and miR-342 in plasma are novel potential biomarkers for acute myeloid leukemia. J Transl Med 11:31

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  113. Tsujiura M, Ichikawa D, Komatsu S, Shiozaki A, Takeshita H, Kosuga T, Konishi H, Morimura R, Deguchi K, Fujiwara H, Okamoto K, Otsuji E (2010) Circulating microRNAs in plasma of patients with gastric cancers. Br J Cancer 102(7):1174–1179

    Google Scholar 

  114. Huang JJ, Yu J, Li JY, Liu YT, Zhong RQ (2012) Circulating microRNA expression is associated with genetic subtype and survival of multiple myeloma. Med Oncol 29(4):2402–2408

    Google Scholar 

  115. Kanaan Z, Rai SN, Eichenberger MR, Roberts H, Keskey B, Pan J, Galandiuk S (2012) Plasma miR-21: a potential diagnostic marker of colorectal cancer. Ann Surg 256(3):544–551

    Google Scholar 

  116. Kong X, Du Y, Wang G, Gao J, Gong Y, Li L, Zhang Z, Zhu J, Jing Q, Qin Y, Li Z (2011) Detection of differentially expressed microRNAs in serum of pancreatic ductal adenocarcinoma patients: miR-196a could be a potential marker for poor prognosis. Dig Dis Sci 56(2):602–609

    Google Scholar 

  117. Wong TS, Liu XB, Wong BY, Ng RW, Yuen AP, Wei WI (2008) Mature miR-184 as potential oncogenic microRNA of squamous cell carcinoma of tongue. Clin Cancer Res 14(9):2588–2592

    Google Scholar 

  118. Ouyang L, Liu P, Yang S, Ye S, Xu W, Liu X (2013) A three-plasma miRNA signature serves as novel biomarkers for osteosarcoma. Med Oncol 30(1):340

    Article  PubMed  Google Scholar 

  119. Bihrer V, Waidmann O, Friedrich-Rust M, Forestier N, Susser S, Haupenthal J, Welker M, Shi Y, Peveling-Oberhag J, Polta A, von Wagner M, Radeke HH, Sarrazin C, Trojan J, Zeuzem S, Kronenberger B, Piiper A (2011) Serum microRNA-21 as marker for necroinflammation in hepatitis C patients with and without hepatocellular carcinoma. PLoS One 6(10):e26971

    Google Scholar 

  120. Baggish AL, Hale A, Weiner RB, Lewis GD, Systrom D, Wang F, Wang TJ, Chan SY (2011) Dynamic regulation of circulating microRNA during acute exhaustive exercise and sustained aerobic exercise training. J Physiol 589(16):3983–3994

    Google Scholar 

  121. Lu Z, Ye Y, Jiao D, Qiao J, Cui S, Liu Z (2012) miR-155 and miR-31 are differentially expressed in breast cancer patients and are correlated with the estrogen receptor and progesterone receptor status. Oncol Lett 4(5):1027–1032

    Google Scholar 

  122. Liu GH, Zhou ZG, Chen R, Wang MJ, Zhou B, Li Y, Sun XF (2013) Serum miR-21 and miR-92a as biomarkers in the diagnosis and prognosis of colorectal cancer. Tumour Biol 34(4):2175–2181

    Google Scholar 

  123. Madhavan D, Zucknick M, Wallwiener M, Cuk K, Modugno C, Scharpff M, Schott S, Heil J, Turchinovich A, Yang R, Benner A, Riethdorf S, Trumpp A, Sohn C, Pantel K, Schneeweiss A, Burwinkel B (2012) Circulating miRNAs as surrogate markers for circulating tumor cells and prognostic markers in metastatic breast cancer. Clin Cancer Res 18:5972–5982

    Google Scholar 

  124. Wang Y, Gao X, Wei F, Zhang X, Yu J, Zhao H, Sun Q, Yan F, Yan C, Li H, Ren X (2014) Diagnostic and prognostic value of circulating miR-21 for cancer: a systematic review and meta-analysis. Gene 533(1):389–397

    Google Scholar 

  125. Kumarswamy R, Volkmann I, Thum T (2011) Regulation and function of miRNA-21 in health and disease. RNA Biol 8(5):706–713

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  126. Tili E, Michaille JJ, Croce CM (2013) MicroRNAs play a central role in molecular dysfunctions linking inflammation with cancer. Immunol Rev 253(1):167–184

    Article  PubMed  Google Scholar 

  127. Shen Y, Wang T, Yang T, Hu Q, Wan C, Chen L, Wen F (2013) Diagnostic value of circulating microRNAs for lung cancer: a meta-analysis. Genet Test Mol Biomarkers 17(5):359–366

    Google Scholar 

  128. Grady WM, Parkin RK, Mitchell PS (2008) Epigenetic silencing of the intronic microRNA hsa-miR-342 and its host gene EVL in colorectal cancer. Oncogene 27(27):3880–3888

    Article  CAS  PubMed  Google Scholar 

  129. Coskun E, Neumann M, Schlee C, Liebertz F, Heesch S, Goekbuget N, Hoelzer D, Baldus CD (2013) MicroRNA profiling reveals aberrant microRNA expression in adult ETP-ALL and functional studies implicate a role for miR-222 in acute leukemia. Leuk Res 37(6):647–656

    Google Scholar 

  130. Presneau N, Eskandarpour M, Shemais T, Henderson S, Halai D, Tirabosco R, Flanagan AM (2013) MicroRNA profiling of peripheral nerve sheath tumours identifies miR-29c as a tumour suppressor gene involved in tumour progression. Br J Cancer 108(4):964–972

    Google Scholar 

  131. Wang K, Yuan Y, Cho JH, McClarty S, Baxter D, Galas DJ (2012) Comparing the MicroRNA spectrum between serum and plasma. PLoS One 7(7):e41561

    Google Scholar 

  132. Zhao X, Yang Z, Li G, Li D, Zhao Y, Wu Y, Robson SC, He L, Xu Y, Miao R, Zhao H (2012) The role and clinical implications of microRNAs in hepatocellular carcinoma. Sci China Life Sci 55(10):906–919

    Google Scholar 

  133. Savad S, Mehdipour P, Miryounesi M, Shirkoohi R, Fereidooni F, Mansouri F, Modarressi MH (2012) Expression analysis of MiR-21, MiR-205, and MiR-342 in breast cancer in Iran. Asian Pac J Cancer Prev 13(3):873–877

    Google Scholar 

  134. Dacic S, Kelly L, Shuai Y, Nikiforova MN (2010) miRNA expression profiling of lung adenocarcinomas: correlation with mutational status. Mod Pathol 23(12):1577–1582

    Google Scholar 

  135. Kunz M (2013) MicroRNAs in melanoma biology. Adv Exp Med Biol 774:103–120

    Article  CAS  PubMed  Google Scholar 

  136. Narducci MG, Arcelli D, Picchio MC, Lazzeri C, Pagani E, Sampogna F, Scala E, Fadda P, Cristofoletti C, Facchiano A, Frontani M, Monopoli A, Ferracin M, Negrini M, Lombardo GA, Caprini E, Russo G (2011) MicroRNA profiling reveals that miR-21, miR486 and miR-214 are upregulated and involved in cell survival in Sezary syndrome. Cell Death Dis 2:e151

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  137. Ng EK, Chong WW, Jin H, Lam EK, Shin VY, Yu J, Poon TC, Ng SS, Sung JJ (2009) Differential expression of microRNAs in plasma of patients with colorectal cancer: a potential marker for colorectal cancer screening. Gut 58(10):1375–1381

    Article  CAS  PubMed  Google Scholar 

  138. Huang Z, Huang D, Ni S, Peng Z, Sheng W, Du X (2010) Plasma microRNAs are promising novel biomarkers for early detection of colorectal cancer. Int J Cancer 127(1):118–126

    Google Scholar 

  139. Taylor DD, Gercel-Taylor C (2008) MicroRNA signatures of tumor-derived exosomes as diagnostic biomarkers of ovarian cancer. Gynecol Oncol 110(1):13–21

    Article  CAS  PubMed  Google Scholar 

  140. Resnick KE, Alder H, Hagan JP, Richardson DL, Croce CM, Cohn DE (2009) The detection of differentially expressed microRNAs from the serum of ovarian cancer patients using a novel real-time PCR platform. Gynecol Oncol 112(1):55–59

    Google Scholar 

  141. Hsu CM, Lin PM, Wang YM, Chen ZJ, Lin SF, Yang MY (2012) Circulating miRNA is a novel marker for head and neck squamous cell carcinoma. Tumour Biol 33(6):1933–1942

    Google Scholar 

  142. Le HB, Zhu WY, Chen DD, He JY, Huang YY, Liu XG, Zhang YK (2012) Evaluation of dynamic change of serum miR-21 and miR-24 in pre- and post-operative lung carcinoma patients. Med Oncol 29(5):3190–3197

    Google Scholar 

  143. Sanfiorenzo C, Ilie MI, Belaid A, BarlÕsi F, Mouroux J, Marquette CH, Brest P, Hofman P (2013) Two panels of plasma microRNAs as non-invasive biomarkers for prediction of recurrence in resectable NSCLC. PLoS One 8(1):e54596

    Google Scholar 

  144. Silva J, Garcia V, Zaballos ê, Provencio M, LombardÚa L, Almonacid L, GarcÚa JM, DomÚnguez G, Peþa C, Diaz R, Herrera M, Varela A, Bonilla F (2011) Vesicle-related microRNAs in plasma of nonsmall cell lung cancer patients and correlation with survival. Eur Respir J 37(3):617–623

    Google Scholar 

  145. Koberle V, Kronenberger B, T, Trojan J, Imelmann E, Peveling-Oberhag J, Welker MW, Elhendawy M, Zeuzem S, Piiper A, Waidmann O (2013) Serum microRNA-1 and microRNA-122 are prognostic markers in patients with hepatocellular carcinoma. Eur J Cancer 49(16):3442–3449

    Google Scholar 

  146. Selth LA, Townley SL, Bert AG, Stricker PD, Sutherland PD, Horvath LG, Goodall GJ, Butler LM, Tilley WD (2013) Circulating microRNAs predict biochemical recurrence in prostate cancer patients. Br J Cancer 109:641–650

    Google Scholar 

  147. Brase JC, Johannes M, Schlomm T, Fðlth M, Haese A, Steuber T, Beissbarth T, Kuner R, Sültmann H (2011) Circulating miRNAs are correlated with tumor progression in prostate cancer. Int J Cancer 128(3):608–616

    Google Scholar 

  148. Gonzales JC, Fink LM, Goodman OB Jr (2011) Comparison of circulating MicroRNA 141 to circulating tumor cells, lactate dehydrogenase, and prostate-specific antigen for determining treatment response in patients with metastatic prostate cancer. Clin Genitourin Cancer 9(1):39–45

    Article  PubMed  Google Scholar 

  149. Huang Z, Hua D, Hu Y, Cheng Z, Zhou X, Xie Q, Wang Q, Wang F, Du X, Zeng Y (2012) Quantitation of plasma circulating DNA using quantitative PCR for the detection of hepatocellular carcinoma. Pathol Oncol Res 18(2):271–276

    Google Scholar 

  150. Williams Z, Ben-Dov IZ, Elias R, Mihailovic A, Brown M, Rosenwaks Z, Tuschl T (2013) Comprehensive profiling of circulating microRNA via small RNA sequencing of cDNA libraries reveals biomarker potential and limitations. Proc Natl Acad Sci U S A 110(11):4255–4260

    Google Scholar 

  151. Song MY, Pan KF, Su HJ, Zhang L, Ma JL, Li JY, Yuasa Y, Kang D, Kim YS, You WC (2012) Identification of serum microRNAs as novel non-invasive biomarkers for early detection of gastric cancer. PLoS One 7(3):e33608

    Google Scholar 

  152. Shiotani A, Murao T, Kimura Y, Matsumoto H, Kamada T, Kusunoki H, Inoue K, Uedo N, Iishi H, Haruma K (2013) Identification of serum miRNAs as novel non-invasive biomarkers for detection of high risk for early gastric cancer. Br J Cancer 109(9):2323–2330

    Google Scholar 

  153. Cookson VJ, Bentley MA, Hogan BV, Horgan K, Hayward BE, Hazelwood LD, Hughes TA (2012) Circulating microRNA profiles reflect the presence of breast tumours but not the profiles of microRNAs within the tumours. Cell Oncol (Dordr) 35(4):301–308

    Google Scholar 

  154. Leidner RS, Li L, Thompson CL (2013) Dampening enthusiasm for circulating microRNA in breast cancer. PLoS One 8(3):e57841

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  155. Kanaan Z, Roberts H, Eichenberger MR, Billeter A, Ocheretner G, Pan J, Rai SN, Jorden J, Williford A, Galandiuk S (2013) A plasma MicroRNA panel for detection of colorectal adenomas: a step toward more precise screening for colorectal cancer. Ann Surg 258(3):400–408

    Google Scholar 

  156. Huang Y, Hu Q, Deng Z, Hang Y, Wang J, Wang K (2013) MicroRNAs in body fluids as biomarkers for non-small cell lung cancer: a systematic review. Technol Cancer Res Treat. doi:10.7785/tcrt.2012.500377

  157. Hu Z, Dong J, Wang LE, Ma H, Liu J, Zhao Y, Tang J, Chen X, Dai J, Wei Q, Zhang C, Shen H (2012) Serum microRNA profiling and breast cancer risk: the use of miR-484/191 as endogenous controls. Carcinogenesis 33(4):828–834

    Google Scholar 

  158. Wu Q, Wang C, Lu Z, Guo L, Ge Q (2012) Analysis of serum genome-wide microRNAs for breast cancer detection. Clin Chim Acta 413(13–14):1058–1065

    Google Scholar 

  159. Hooten NN, Fitzpatrick M, Wood WH 3rd, De S, Ejiogu N, Zhang Y, Mattison JA, Becker KG, Zonderman AB, Evans MK (2013) Age-related changes in microRNA levels in serum. Aging (Albany, NY) 5(10):725–740

    Google Scholar 

  160. De Guire V, Robitaille R, Tetreault N, GuÕrin R, MÕnard C, Bambace N, Sapieha P (2013) Circulating miRNAs as sensitive and specific biomarkers for the diagnosis and monitoring of human diseases: promises and challenges. Clin Biochem 46(10–11):846–860

    Google Scholar 

  161. Bourke MJ (2009) Making every colonoscopy count: ensuring quality in endoscopy. J Gastroenterol Hepatol 24(Suppl 3):S43–S50

    Article  PubMed  Google Scholar 

  162. Imperiale TF (2012) Noninvasive screening tests for colorectal cancer. Dig Dis 30(Suppl 2):16–26

    Article  PubMed  Google Scholar 

  163. Kisiel JB, Ahlquist DA (2013) Stool DNA testing for cancer surveillance in inflammatory bowel disease: an early view. Therap Adv Gastroenterol 6(5):371–380

    Article  PubMed Central  PubMed  Google Scholar 

  164. Miller S, Steele S (2012) Novel molecular screening approaches in colorectal cancer. J Surg Oncol 105(5):459–467

    Article  CAS  PubMed  Google Scholar 

  165. Hong L, Ahuja N (2013) DNA methylation biomarkers of stool and blood for early detection of colon cancer. Genet Test Mol Biomarkers 17(5):401–406

    Article  CAS  PubMed  Google Scholar 

  166. Sidransky D, Tokino T, Hamilton SR, Kinzler KW, Levin B, Frost P, Vogelstein B (1992) Identification of ras oncogene mutations in the stool of patients with curable colorectal tumors. Science 256(5053):102–105

    Google Scholar 

  167. Ahlquist DA, Skoletsky JE, Boynton KA, Harrington JJ, Mahoney DW, Pierceall WE, Thibodeau SN, Shuber AP (2000) Colorectal cancer screening by detection of altered human DNA in stool: feasibility of a multitarget assay panel. Gastroenterology 119(5):1219–1227

    Google Scholar 

  168. Muller HM, Oberwalder M, Fiegl H, Morandell M, Goebel G, Zitt M, Muhlthaler M, Ofner D, Margreiter R, Widschwendter M (2004) Methylation changes in faecal DNA: a marker for colorectal cancer screening? Lancet 363(9417):1283–1285

    Article  PubMed  Google Scholar 

  169. Oberwalder M, Zitt M, Wontner C, Fiegl H, Goebel G, Zitt M, Kohle O, Muhlmann G, Ofner D, Margreiter R, Muller HM (2008) SFRP2 methylation in fecal DNA – a marker for colorectal polyps. Int J Colorectal Dis 23(1):15–19

    Article  PubMed  Google Scholar 

  170. Yamazaki N, Koga Y, Yamamoto S, Kakugawa Y, Otake Y, Hayashi R, Saito N, Matsumura Y (2013) Application of the fecal microRNA test to the residuum from the fecal occult blood test. Jpn J Clin Oncol 43(7):726–733

    Google Scholar 

  171. Leung WK, To KF, Man EP, Chan MW, Hui AJ, Ng SS, Lau JY, Sung JJ (2007) Detection of hypermethylated DNA or cyclooxygenase-2 messenger RNA in fecal samples of patients with colorectal cancer or polyps. Am J Gastroenterol 102(5):1070–1076

    Google Scholar 

  172. Elliott GO, Johnson IT, Scarll J, Dainty J, Williams EA, Garg D, Coupe A, Bradburn DM, Mathers JC, Belshaw NJ (2013) Quantitative profiling of CpG island methylation in human stool for colorectal cancer detection. Int J Colorectal Dis 28(1):35–42

    Google Scholar 

  173. Carmona FJ, Azuara D, Berenguer-Llergo A, Fernández AF, Biondo S, de Oca J, Rodriguez-Moranta F, Salazar R, Villanueva A, Fraga MF, Guardiola J, Capellá G, Esteller M, Moreno V (2013) DNA methylation biomarkers for noninvasive diagnosis of colorectal cancer. Cancer Prev Res (Phila) 6(7):656–665

    Google Scholar 

  174. Lind GE, Raiborg C, Danielsen SA, Rognum TO, Thiis-Evensen E, Hoff G, Nesbakken A, Stenmark H, Lothe RA (2011) SPG20, a novel biomarker for early detection of colorectal cancer, encodes a regulator of cytokinesis. Oncogene 30(37):3967–3978

    Google Scholar 

  175. Zhang H, Song YC, Dang CX (2013) Detection of hypermethylated spastic paraplegia-20 in stool samples of patients with colorectal cancer. Int J Med Sci 10(3):230–234

    Article  PubMed Central  PubMed  Google Scholar 

  176. Goh L, Murphy SK, Muhkerjee S, Furey TS (2007) Genomic sweeping for hypermethylated genes. Bioinformatics 23(3):281–288

    Google Scholar 

  177. Kron K, Pethe V, Briollais L, Sadikovic B, Ozcelik H, Sunderji A, Venkateswaran V, Pinthus J, Fleshner N, van der Kwast T, Bapat B (2009) Discovery of novel hypermethylated genes in prostate cancer using genomic CpG island microarray. PLoS One 4(3):e4830

    Google Scholar 

  178. Ausch C, Kim YH, Tsuchiya KD, Dzieciatkowski S, Washington MK, Paraskeva C, Radich J, Grady WM (2009) Comparative analysis of PCR-based biomarker assay methods for colorectal polyp detection from fecal DNA. Clin Chem 55(8):1559–1563

    Google Scholar 

  179. Uhm KO, Lee JO, Lee YM, Lee ES, Kim HS, Park SH (2010) Aberrant DNA methylation of integrin alpha4: a potential novel role for metastasis of cholangiocarcinoma. J Cancer Res Clin Oncol 136(2):187–194

    Google Scholar 

  180. Kisiel JB, Yab TC, Nazer Hussain FT, Taylor WR, Garrity-Park MM, Sandborn WJ, Loftus EV, Wolff BG, Smyrk TC, Itzkowitz SH, Rubin DT, Zou H, Mahoney DW, Ahlquist DA (2013) Stool DNA testing for the detection of colorectal neoplasia in patients with inflammatory bowel disease. Aliment Pharmacol Ther 37(5):546–554

    Google Scholar 

  181. Kalimutho M, Di Cecilia S, Del Vecchio Blanco G, Roviello F, Sileri P, Cretella M, Formosa A, Corso G, Marrelli D, Pallone F, Federici G, Bernardini S (2011) Epigenetically silenced miR-34b/c as a novel faecal-based screening marker for colorectal cancer. Br J Cancer 104(11):1770–1778

    Google Scholar 

  182. Zhang J, Yang S, Xie Y, Chen X, Zhao Y, He D, Li J (2012) Detection of methylated tissue factor pathway inhibitor 2 and human long DNA in fecal samples of patients with colorectal cancer in China. Cancer Epidemiol 36(1):73–77

    Google Scholar 

  183. Ahlquist DA, Taylor WR, Mahoney DW, Zou H, Domanico M, Thibodeau SN, Boardman LA, Berger BM, Lidgard GP (2012) The stool DNA test is more accurate than the plasma septin 9 test in detecting colorectal neoplasia. Clin Gastroenterol Hepatol 10(3):272–277

    Google Scholar 

  184. Ahlquist DA, Zou H, Domanico M, Mahoney DW, Yab TC, Taylor WR, Butz ML, Thibodeau SN, Rabeneck L, Paszat LF, Kinzler KW, Vogelstein B, Bjerregaard NC, Laurberg S, S½rensen HT, Berger BM, Lidgard GP (2012) Next-generation stool DNA test accurately detects colorectal cancer and large adenomas. Gastroenterology 142(2):248–256

    Google Scholar 

  185. Kisiel JB, Yab TC, Taylor WR, Chari ST, Petersen GM, Mahoney DW, Ahlquist DA (2012) Stool DNA testing for the detection of pancreatic cancer: assessment of methylation marker candidates. Cancer 118(10):2623–2631

    Google Scholar 

  186. Gormally E, Vineis P, Matullo G, Veglia F, Caboux E, Le Roux E, Peluso M, Garte S, Guarrera S, Munnia A, Airoldi L, Autrup H, Malaveille C, Dunning A, Overvad K, Tj½nneland A, Lund E, Clavel-Chapelon F, Boeing H, Trichopoulou A, Palli D, Krogh V, Tumino R, Panico S, Bueno-de-Mesquita HB, Peeters PH, Pera G, Martinez C, Dorronsoro M, Barricarte A, Navarro C, Quirós JR, Hallmans G, Day NE, Key TJ, Saracci R, Kaaks R, Riboli E, Hainaut P (2006) TP53 and KRAS2 mutations in plasma DNA of healthy subjects and subsequent cancer occurrence: a prospective study. Cancer Res 66(13):6871–6876

    Google Scholar 

  187. Itzkowitz SH (2009) Incremental advances in excremental cancer detection tests. J Natl Cancer Inst 101(18):1225–1227

    Article  PubMed  Google Scholar 

  188. Eisenberger CF, Schoenberg M, Enger C, Hortopan S, Shah S, Chow NH, Marshall FF, Sidransky D (1999) Diagnosis of renal cancer by molecular urinalysis. J Natl Cancer Inst 91(23):2028–2032

    Google Scholar 

  189. Szarvas T, Kovalszky I, Bedi K, Szendroi A, Majoros A, Riesz P, Füle T, László V, Kiss A, Romics I (2007) Deletion analysis of tumor and urinary DNA to detect bladder cancer: urine supernatant versus urine sediment. Oncol Rep 18(2):405–409

    Google Scholar 

  190. Utting M, Muller G, Werner W, Schubert J, Junker K (2000) Detection of tumor genetic alterations of bladder carcinomas in body fluids depends on sample treatment before DNA isolation. Ann NY Acad Sci 906:67–71

    Google Scholar 

  191. Chang HW, Tsui KH, Shen LC, Huang HW, Wang SN, Chang PL (2007) Urinary cell-free DNA as a potential tumor marker for bladder cancer. Int J Biol Markers 22(4):287–294

    Google Scholar 

  192. Bryzgunova OE, Skvortsova TE, Kolesnikova EV, Starikov AV, Rykova EY, Vlassov VV, Laktionov PP (2006) Isolation and comparative study of cell-free nucleic acids from human urine. Ann N Y Acad Sci 1075:334–340

    Google Scholar 

  193. Casadio V, Calistri D, Salvi S, Gunelli R, Carretta E, Amadori D, Silvestrini R, Zoli W (2013) Urine cell-free DNA integrity as a marker for early prostate cancer diagnosis: a pilot study. Biomed Res Int 2013:270457

    Google Scholar 

  194. Casadio V, Calistri D, Tebaldi M, Bravaccini S, Gunelli R, Martorana G, Bertaccini A, Serra L, Scarpi E, Amadori D, Silvestrini R, Zoli W (2013) Urine Cell-Free DNA integrity as a marker for early bladder cancer diagnosis: preliminary data. Urol Oncol 31:1744–1750

    Google Scholar 

  195. Duffy MJ, van Rossum LG, van Turenhout ST, Malminiemi O, Sturgeon C, Lamerz R, Nicolini A, Haglund C, Holubec L, Fraser CG, Halloran SP (2011) Use of faecal markers in screening for colorectal neoplasia: a European group on tumor markers position paper. Int J Cancer 128(1):3–11

    Google Scholar 

  196. Rex DK, Johnson DA, Anderson JC (2009) American College of Gastroenterology guidelines for colorectal cancer screening 2009 [corrected]. Am J Gastroenterol 104(3):739–750

    Article  PubMed  Google Scholar 

  197. Luo YX, Chen DK, Song SX, Wang L, Wang JP (2011) Aberrant methylation of genes in stool samples as diagnostic biomarkers for colorectal cancer or adenomas: a meta-analysis. Int J Clin Pract 65(12):1313–1320

    Google Scholar 

  198. Bosch LJ, Carvalho B, Fijneman RJ, Jimenez CR, Pinedo HM, van Engeland M, Meijer GA (2011) Molecular tests for colorectal cancer screening. Clin Colorectal Cancer 10(1):8–23

    Google Scholar 

  199. Lin JS, Webber EM, Beil TL, Goddard KA, Whitlock EP (2012) Fecal DNA testing in screening for colorectal cancer in average-risk adults [Internet]. AHRQ Comp Effect Rev 52 http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0041016/

  200. Schwarzenbach H, Eichelser C, Kropidlowski J, Janni W, Rack B, Pantel K (2012) Loss of heterozygosity at tumor suppressor genes detectable on fractionated circulating cell-free tumor DNA as indicator of breast cancer progression. Clin Cancer Res 18(20):5719–5730

    Google Scholar 

  201. Schwarzenbach H, Alix-Panabieres C, Muller I, Letang N, Vendrell JP, Rebillard X, Pantel K (2009) Cell free tumor DNA in blood plasma as a marker for circulating tumor cells in prostate cancer. Clin Cancer Res 15(3):1032–1038

    Google Scholar 

  202. Schwarzenbach H, Chun FK, Muller I, Seidel C, Urban K, Erbersdobler A, Huland H, Pantel K, Friedrich MG (2008) Microsatellite analysis of allelic imbalance in tumour and blood from patients with prostate cancer. BJU Int 102(2):253–258

    Google Scholar 

  203. Field JK, Liloglou T, Xinarianos G, Prime W, Fielding P, Walshaw MJ, Turnbull L (1999) Genetic alterations in bronchial lavage as a potential marker for individuals with a high risk of developing lung cancer. Cancer Res 59(11):2690–2695

    Google Scholar 

  204. Stevenson J, Prendergast BJ (2013) Reversible DNA methylation regulates seasonal photoperiodic time measurement. Proc Natl Acad Sci U S A. doi:10.1073/pnas.1310643110

    Google Scholar 

  205. Mathers JC, Strathdee G, Relton CL (2010) Induction of epigenetic alterations by dietary and other environmental factors. Adv Genet 71:3–39

    Article  PubMed  Google Scholar 

  206. Bergman Y, Cedar H (2013) DNA methylation dynamics in health and disease. Nat Struct Mol Biol 20(3):274–281

    Article  CAS  PubMed  Google Scholar 

  207. Johansson A, Enroth S, Gyllensten U (2013) Continuous aging of the human DNA methylome throughout the human lifespan. PLoS One 8(6):e67378

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  208. Kristensen LS, Raynor M, Candiloro I, Dobrovic A (2012) Methylation profiling of normal individuals reveals mosaic promoter methylation of cancer-associated genes. Oncotarget 3(4):450–461

    Google Scholar 

  209. Fleischhacker M, Dietrich D, Liebenberg V, Field JK, Schmidt B (2013) The role of DNA methylation as biomarkers in the clinical management of lung cancer. Expert Rev Respir Med 7(4):363–383

    Google Scholar 

  210. Hauser S, Kogej M, Fechner G, VON Pezold J, Vorreuther R, Lümmen G, Müller SC, Ellinger J (2013) Serum DNA hypermethylation in patients with bladder cancer: results of a prospective multicenter study. Anticancer Res 33(3):779–784

    Google Scholar 

  211. Liloglou T, Bediaga NG, Brown BR, Field JK, Davies MP (2014) Epigenetic biomarkers in lung cancer. Cancer Lett 342(2):200–212

    Google Scholar 

  212. Chimonidou M, Tzitzira A, Strati A, Sotiropoulou G, Sfikas C, Malamos N, Georgoulias V, Lianidou E (2013) CST6 promoter methylation in circulating cell-free DNA of breast cancer patients. Clin Biochem 46(3):235–240

    Google Scholar 

  213. Deligezer U, Yaman F, Darendeliler E (2010) Post-treatment circulating plasma BMP6 mRNA and H3K27 methylation levels discriminate metastatic prostate cancer from localized disease. Clin Chim Acta 411(19–20):1452–1456

    Article  CAS  PubMed  Google Scholar 

  214. Lo NC, Wang H, McHugh A, Lattanzio L, Matin R, Harwood C, Syed N, Hatzimichael E, Briasoulis E, Merlano M, Evans A, Thompson A, Leigh I, Fleming C, Inman GJ, Proby C, Crook T (2013) Methylated tissue factor pathway inhibitor 2 (TFPI2) DNA in serum is a biomarker of metastatic melanoma. J Invest Dermatol 133(5):1278–1285

    Article  Google Scholar 

  215. Salazar F, Molina MA, Sanchez-Ronco M, Moran T, Ramirez JL, Sanchez JM, Stahel R, Garrido P, Cobo M, Isla D, Bertran-Alamillo J, Massuti B, Cardenal F, Manegold C, Lianes P, Trigo JM, Sanchez JJ, Taron M, Rosell R (2011) First-line therapy and methylation status of CHFR in serum influence outcome to chemotherapy versus EGFR tyrosine kinase inhibitors as second-line therapy in stage IV non-small-cell lung cancer patients. Lung Cancer 72(1):84–91

    Google Scholar 

  216. Colotta F, Allavena P, Sica A, Garlanda C, Mantovani A (2009) Cancer-related inflammation, the seventh hallmark of cancer: links to genetic instability. Carcinogenesis 30(7):1073–1081

    Google Scholar 

  217. Allavena P, Garlanda C, Borrello MG, Sica A, Mantovani A (2008) Pathways connecting inflammation and cancer. Curr Opin Genet Dev 18(1):3–10

    Google Scholar 

  218. Candido J, Hagemann T (2013) Cancer-related inflammation. J Clin Immunol 33(Suppl 1):S79–S84

    Article  PubMed  Google Scholar 

  219. Coussens LM, Zitvogel L, Palucka AK (2013) Neutralizing tumor-promoting chronic inflammation: a magic bullet? Science 339(6117):286–291

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  220. Heikkila K, Ebrahim S, Lawlor DA (2007) A systematic review of the association between circulating concentrations of C reactive protein and cancer. J Epidemiol Community Health 61(9):824–833

    Article  PubMed Central  PubMed  Google Scholar 

  221. Wang CS, Sun CF (2009) C-reactive protein and malignancy: clinico-pathological association and therapeutic implication. Chang Gung Med J 32(5):471–482

    PubMed  Google Scholar 

  222. Moore MM, Chua W, Charles KA, Clarke SJ (2010) Inflammation and cancer: causes and consequences. Clin Pharmacol Ther 87:504–508

    Google Scholar 

  223. Grivennikov SI (2013) Inflammation and colorectal cancer: colitis-associated neoplasia. Semin Immunopathol 35(2):229–244

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  224. Okayama H, Schetter AJ, Harris CC (2012) MicroRNAs and inflammation in the pathogenesis and progression of colon cancer. Dig Dis 30(Suppl 2):9–15

    Article  PubMed  Google Scholar 

  225. Rogler G (2012) Inflammatory bowel disease cancer risk, detection and surveillance. Dig Dis 30(Suppl 2):48–54

    Article  PubMed  Google Scholar 

  226. Touati E (2010) When bacteria become mutagenic and carcinogenic: lessons from H. pylori. Mutat Res 703(1):66–70

    Article  CAS  PubMed  Google Scholar 

  227. Miyashita T, Shah FA, Miwa K, Sasaki S, Nishijima K, Oyama K, Ninomiya I, Fushida S, Fujimura T, Hattori T, Harmon JW, Ohta T (2013) Impact of inflammation-metaplasia-adenocarcinoma sequence and prevention in surgical rat models. Digestion 87(1):6–11

    Article  CAS  PubMed  Google Scholar 

  228. Gukovsky I, Li N, Todoric J, Gukovskaya A, Karin M (2013) Inflammation, autophagy, and obesity: common features in the pathogenesis of pancreatitis and pancreatic cancer. Gastroenterology 144(6):1199–1209

    Google Scholar 

  229. Momi N, Kaur S, Krishn SR, Batra SK (2012) Discovering the route from inflammation to pancreatic cancer. Minerva Gastroenterol Dietol 58(4):283–297

    CAS  PubMed Central  PubMed  Google Scholar 

  230. Steele CW, Jamieson NB, Evans TR, McKay CJ, Sansom OJ, Morton JP, Carter CR (2013) Exploiting inflammation for therapeutic gain in pancreatic cancer. Br J Cancer 108(5):997–1003

    Google Scholar 

  231. Jafri SH, Shi R, Mills G (2013) Advance lung cancer inflammation index (ALI) at diagnosis is a prognostic marker in patients with metastatic non-small cell lung cancer (NSCLC): a retrospective review. BMC Cancer 13:158. doi:10.1186/1471-2407-13-158

    Article  PubMed Central  PubMed  Google Scholar 

  232. Mossman BT, Shukla A, Heintz NH, Verschraegen CF, Thomas A, Hassan R (2013) New insights into understanding the mechanisms, pathogenesis, and management of malignant mesotheliomas. Am J Pathol 182(4):1065–1077

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  233. Michaud DS (2007) Chronic inflammation and bladder cancer. Urol Oncol 25(3):260–268

    Article  CAS  PubMed  Google Scholar 

  234. Stauffer JK, Scarzello AJ, Jiang Q, Wiltrout RH (2012) Chronic inflammation, immune escape, and oncogenesis in the liver: a unique neighborhood for novel intersections. Hepatology 56(4):1567–1574

    Google Scholar 

  235. Moss SF, Blaser MJ (2005) Mechanisms of disease: inflammation and the origins of cancer. Nat Clin Pract Oncol 2(2):90–97

    Article  CAS  PubMed  Google Scholar 

  236. Shan W, Liu J (2009) Inflammation: a hidden path to breaking the spell of ovarian cancer. Cell Cycle 8:3107–3111

    Article  CAS  PubMed  Google Scholar 

  237. Riva G, Barozzi P, Torelli G, Luppi M (2010) Immunological and inflammatory features of Kaposi’s sarcoma and other Kaposi’s sarcoma-associated herpesvirus/human herpesvirus 8-associated neoplasias. AIDS Rev 12(1):40–51

    Google Scholar 

  238. Hasselbalch HC (2013) Chronic inflammation as a promotor of mutagenesis in essential thrombocythemia, polycythemia vera and myelofibrosis. A human inflammation model for cancer development? Leuk Res 37(2):214–220

    Article  CAS  PubMed  Google Scholar 

  239. Demopoulos K, Arvanitis DA, Vassilakis DA (2002) MYCL1, FHIT, SPARC, p16(INK4) and TP53 genes associated to lung cancer in idiopathic pulmonary fibrosis. J Cell Mol Med 6(2):215–222

    Article  CAS  PubMed  Google Scholar 

  240. Samara KD, Tzortzaki EG, Neofytou E, Karatzanis AD, Lambiri I, Tzanakis N, Siafakas NM (2010) Somatic DNA alterations in lung epithelial barrier cells in COPD patients. Pulm Pharmacol Ther 23(3):208–214

    Google Scholar 

  241. Brentnall TA, Crispin DA, Bronner MP, Cherian SP, Hueffed M, Rabinovitch PS, Rubin CE, Haggitt RC, Boland CR (1996) Microsatellite instability in nonneoplastic mucosa from patients with chronic ulcerative colitis. Cancer Res 56(6):1237–1240

    Google Scholar 

  242. Rauh P, Rickes S, Fleischhacker M (2003) Microsatellite alterations in free-circulating serum DNA in patients with ulcerative colitis. Dig Dis 21(4):363–366

    Article  PubMed  Google Scholar 

  243. Ranjha R, Paul J (2013) Micro-RNAs in inflammatory diseases and as a link between inflammation and cancer. Inflamm Res 62(4):343–355

    Article  CAS  PubMed  Google Scholar 

  244. Link A, Balaguer F, Shen Y, Nagasaka T, Lozano JJ, Boland CR, Goel A (2010) Fecal MicroRNAs as novel biomarkers for colon cancer screening. Cancer Epidemiol Biomarkers Prev 19(7):1766–1774

    Google Scholar 

  245. Shen J, Liu Z, Todd NW, Zhang H, Liao J, Yu L, Guarnera MA, Li R, Cai L, Zhan M, Jiang F (2011) Diagnosis of lung cancer in individuals with solitary pulmonary nodules by plasma microRNA biomarkers. BMC Cancer 11:374

    Google Scholar 

  246. Kowalewska M, Nowak R, Chechlinska M (2010) Implications of cancer-associated systemic inflammation for biomarker studies. Biochim Biophys Acta 1806(2):163–171

    CAS  PubMed  Google Scholar 

  247. Ohshima K, Inoue K, Fujiwara A, Hatakeyama K, Kanto K, Watanabe Y, Muramatsu K, Fukuda Y, Ogura S, Yamaguchi K, Mochizuki T (2010) Let-7 microRNA family is selectively secreted into the extracellular environment via exosomes in a metastatic gastric cancer cell line. PLoS One 5(10):e13247

    Article  PubMed Central  PubMed  Google Scholar 

  248. Turchinovich A, Samatov TR, Tonevitsky AG et al (2013) Circulating miRNAs: cell-cell communication function. Front Genet 4:119

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  249. Turchinovich A, Weiz L, Langheinz A, Burwinkel B (2011) Characterization of extracellular circulating microRNA. Nucleic Acids Res 39(16):7223–7233

    Google Scholar 

  250. Garcia JM, Garcia V, Pena C, DomÚnguez G, Silva J, Diaz R, Espinosa P, Citores MJ, Collado M, Bonilla F (2008) Extracellular plasma RNA from colon cancer patients is confined in a vesicle-like structure and is mRNA-enriched. RNA 14(7):1424–1432

    Google Scholar 

  251. Fischer S, Gesierich S, Griemert B (2013) Extracellular RNA liberates tumor necrosis factor-alpha to promote tumor cell trafficking and progression. Cancer Res 73(16):5080–5089. doi:10.1158/0008-5472.CAN-12-4657

    Article  CAS  PubMed  Google Scholar 

  252. Mittelbrunn M, Gutierrez-Vazquez C, Villarroya-Beltri C, Gonzalez S, Sanchez-Cabo F, Gonzalez MA, Bernad A, Sanchez-Madrid F (2011) Unidirectional transfer of microRNA-loaded exosomes from T cells to antigen-presenting cells. Nat Commun 2:282

    Article  PubMed Central  PubMed  Google Scholar 

  253. Kosaka N, Iguchi H, Ochiya T (2010) Circulating microRNA in body fluid: a new potential biomarker for cancer diagnosis and prognosis. Cancer Sci 101(10):2087–2092

    Article  CAS  PubMed  Google Scholar 

  254. Martins VR, Dias MS, Hainaut P (2013) Tumor-cell-derived microvesicles as carriers of molecular information in cancer. Curr Opin Oncol 25(1):66–75

    Article  CAS  PubMed  Google Scholar 

  255. Peinado H, Aleckovic M, Lavotshkin S, Matei I, Costa-Silva B, Moreno-Bueno G, Hergueta-Redondo M, Williams C, GarcÚa-Santos G, Ghajar C, Nitadori-Hoshino A, Hoffman C, Badal K, Garcia BA, Callahan MK, Yuan J, Martins VR, Skog J, Kaplan RN, Brady MS, Wolchok JD, Chapman PB, Kang Y, Bromberg J, Lyden D (2012) Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET. Nat Med 18(6):883–891

    Google Scholar 

  256. Vickers KC, Remaley AT (2012) Lipid-based carriers of microRNAs and intercellular communication. Curr Opin Lipidol 23(2):91–97

    Article  CAS  PubMed  Google Scholar 

  257. Roccaro AM, Sacco A, Maiso P, Azab AK, Tai YT, Reagan M, Azab F, Flores LM, Campigotto F, Weller E, Anderson KC, Scadden DT, Ghobrial IM (2013) BM mesenchymal stromal cell-derived exosomes facilitate multiple myeloma progression. J Clin Invest 123(4):1542–1555

    Google Scholar 

  258. Lee TH, Montalvo L, Chrebtow V, Busch MP (2001) Quantitation of genomic DNA in plasma and serum samples: higher concentrations of genomic DNA found in serum than in plasma. Transfusion 41:276–282

    Google Scholar 

  259. Vallee A, Marcq M, Bizieux A, Kouri CE, Lacroix H, Bennouna J, Douillard JY, Denis MG (2013) Plasma is a better source of tumor-derived circulating cell-free DNA than serum for the detection of EGFR alterations in lung tumor patients. Lung Cancer 82(2):373–374. doi:10.1016/j.lungcan.2013.08.014

  260. Kroh EM, Parkin RK, Mitchell PS, Tewari M (2010) Analysis of circulating microRNA biomarkers in plasma and serum using quantitative reverse transcription-PCR (qRT-PCR). Methods 50(4):298–301

    Google Scholar 

  261. Bryzgunova OE, Morozkin ES, Yarmoschuk SV, Vlassov VV, Laktionov PP (2008) Methylation-specific sequencing of GSTP1 gene promoter in circulating/extracellular DNA from blood and urine of healthy donors and prostate cancer patients. Ann N Y Acad Sci 1137:222–225

    Google Scholar 

  262. Molina-Pinelo S, Suarez R, Pastor MD, Nogal A, Marquez-Martin E, Martin-Juan J, Carnero A, Paz-Ares L (2012) Association between the miRNA signatures in plasma and bronchoalveolar fluid in respiratory pathologies. Dis Markers 32(4):221–230

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  263. Payne SR, Serth J, Schostak M, Kamradt J, Strauss A, Thelen P, Model F, Day JK, Liebenberg V, Morotti A, Yamamura S, Lograsso J, Sledziewski A, Semjonow A (2009) DNA methylation biomarkers of prostate cancer: confirmation of candidates and evidence urine is the most sensitive body fluid for non-invasive detection. Prostate 69(12):1257–1269

    Google Scholar 

  264. Chan KC, Yeung SW, Lui WB, Rainer TH, Lo YM (2005) Effects of preanalytical factors on the molecular size of cell-free DNA in blood. Clin Chem 51(4):781–784

    Google Scholar 

  265. El Messaoudi S, Rolet F, Mouliere F, Thierry AR (2013) Circulating cell free DNA: preanalytical considerations. Clin Chim Acta 424:222–230

    Google Scholar 

  266. Jung M, Klotzek S, Lewandowski M, Fleischhacker M, Jung K (2003) Changes in concentration of DNA in serum and plasma during storage of blood samples. Clin Chem 49:1028–1029

    Google Scholar 

  267. Fernando MR, Chen K, Norton S, Krzyzanowski G, Bourne D, Hunsley B, Ryan WL, Bassett C (2010) A new methodology to preserve the original proportion and integrity of cell-free fetal DNA in maternal plasma during sample processing and storage. Prenat Diagn 30:418–424

    Google Scholar 

  268. Hidestrand M, Stokowski R, Song K, Oliphant A, Deavers J, Goetsch M, Simpson P, Kuhlman R, Ames M, Mitchell M, Tomita-Mitchell A (2012) Influence of temperature during transportation on cell-free DNA analysis. Fetal Diagn Ther 31(2):122–128

    Google Scholar 

  269. Schatz P, Tetzner R, Weiss G, K­nig T, Frischmann I, Weizenegger M, Bartel J (2011) Preservation of cell-free DNA in stored blood samples for the analysis of the mSEPT9 colorectal cancer screeing marker enables sample shipment by mail. Clin Chem Lab Med 49:S613

    Google Scholar 

  270. Madisen L, Hoar DI, Holroyd CD, Crisp M, Hodes ME (1987) DNA banking: the effects of storage of blood and isolated DNA on the integrity of DNA. Am J Med Genet 27(2):379–390

    Google Scholar 

  271. Holdenrieder S, von Pawel J, Nagel D, Stieber P (2010) Long-term stability of circulating nucleosomes in serum. Anticancer Res 30(5):1613–1615

    Google Scholar 

  272. Boddy JL, Gal S, Malone PR, Harris AL, Wainscoat JS (2005) Prospective study of quantitation of plasma DNA levels in the diagnosis of malignant versus benign prostate disease. Clin Cancer Res 11(4):1394–1399

    Google Scholar 

  273. Cheng HH, Yi HS, Kim Y, Kroh EM, Chien JW, Eaton KD, Goodman MT, Tait JF, Tewari M, Pritchard CC (2013) Plasma processing conditions substantially influence circulating microRNA biomarker levels. PLoS One 8(6):e64795

    Google Scholar 

  274. Duttagupta R, Jiang R, Gollub J, Getts RC, Jones KW (2011) Impact of cellular miRNAs on circulating miRNA biomarker signatures. PLoS One 6(6):e20769

    Google Scholar 

  275. Muller I, Beeger C, Alix-Panabieres C, Rebillard X, Pantel K, Schwarzenbach H (2008) Identification of loss of heterozygosity on circulating free DNA in peripheral blood of prostate cancer patients: potential and technical improvements. Clin Chem 54(4):688–696

    Article  PubMed  Google Scholar 

  276. Page K, Powles T, Slade MJ, DE Bella MT, Walker RA, Coombes RC, Shaw JA (2006) The importance of careful blood processing in isolation of cell-free DNA. Ann NY Acad Sci 1075:313–317

    Google Scholar 

  277. Kirschner MB, Kao SC, Edelman JJ, Armstrong NJ, Vallely MP, van Zandwijk N, Reid G (2011) Haemolysis during sample preparation alters microRNA content of plasma. PLoS One 69:e24145

    Google Scholar 

  278. Leidinger P, Keller A, Borries A, Huwer H, Rohling M, Huebers J, Lenhof HP, Meese E (2011) Specific peripheral miRNA profiles for distinguishing lung cancer from COPD. Lung Cancer 74(1):41–47

    Google Scholar 

  279. Ulivi P, Foschi G, Mengozzi M, Scarpi E, Silvestrini R, Amadori D, Zoli W (2013) Peripheral blood miR-328 expression as a potential biomarker for the early diagnosis of NSCLC. Int J Mol Sci 14(5):10332–10342

    Google Scholar 

  280. Pritchard CC, Kroh E, Wood B, Arroyo JD, Dougherty KJ, Miyaji MM, Tait JF, Tewari M (2012) Blood cell origin of circulating microRNAs: a cautionary note for cancer biomarker studies. Cancer Prev Res (Phila) 5(3):492–497

    Google Scholar 

  281. Kirschner MB, Edelman JJ, Kao SC, Vallely MP, van Zandwijk N, Reid G (2013) The impact of hemolysis on cell-free microRNA biomarkers. Front Genet 4:94. doi:10.3389/fgene.2013.00094

  282. Danese E, Minicozzi AM, Benati M, Montagnana M, Paviati E, Salvagno GL, Gusella M, Pasini F, Guidi GC, Lippi G (2013) Epigenetic alteration: new insights moving from tissue to plasma – the example of PCDH10 promoter methylation in colorectal cancer. Br J Cancer 109:807–813

    Google Scholar 

  283. Zhao X, Han RB, Zhao J, Wang J, Yang F, Zhong W, Zhang L, Li LY, Wang MZ (2013) Comparison of epidermal growth factor receptor mutation statuses in tissue and plasma in stage I-IV non-small cell lung cancer patients. Respiration 85(2):119–125

    Google Scholar 

  284. Git A, Dvinge H, Salmon-Divon M, Osborne M, Kutter C, Hadfield J, Bertone P, Caldas C (2010) Systematic comparison of microarray profiling, real-time PCR, and next-generation sequencing technologies for measuring differential microRNA expression. RNA 16(5):991–1006

    Google Scholar 

  285. Koshiol J, Wang E, Zhao Y, Marincola F, Landi MT (2010) Strengths and limitations of laboratory procedures for microRNA detection. Cancer Epidemiol Biomarkers Prev 19(4):907–911

    Google Scholar 

  286. Nelson PT, Wang WX, Wilfred BR, Tang G (2008) Technical variables in high-throughput miRNA expression profiling: much work remains to be done. Biochim Biophys Acta 1779(11):758–765

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  287. Willenbrock H, Salomon J, Sokilde R, Barken KB, Hansen TN, Nielsen FC, M½ller S, Litman T (2009) Quantitative miRNA expression analysis: comparing microarrays with next-generation sequencing. RNA 15(11):2028–2034

    Google Scholar 

  288. Burgos KL, Javaherian A, Bomprezzi R, Ghaffari L, Rhodes S, Courtright A, Tembe W, Kim S, Metpally R, Van Keuren-Jensen K (2013) Identification of extracellular miRNA in human cerebrospinal fluid by next-generation sequencing. RNA 19(5):712–722

    Google Scholar 

  289. Yuan H, Zhu ZZ, Lu Y, Liu F, Zhang W, Huang G, Zhu G, Jiang B (2012) A modified extraction method of circulating free DNA for epidermal growth factor receptor mutation analysis. Yonsei Med J 53(1):132–137

    Google Scholar 

  290. Keeley B, Stark A, Pisanic TR 2nd, Kwak R, Zhang Y, Wrangle J, Baylin S, Herman J, Ahuja N, Brock MV, Wang TH (2013) Extraction and processing of circulating DNA from large sample volumes using methylation on beads for the detection of rare epigenetic events. Clin Chim Acta 425C:169–175

    Google Scholar 

  291. Kim DJ, Linnstaedt S, Palma J, Park JC, Ntrivalas E, Kwak-Kim JY, Gilman-Sachs A, Beaman K, Hastings ML, Martin JN, Duelli DM (2012) Plasma components affect accuracy of circulating cancer-related microRNA quantitation. J Mol Diagn 14(1):71–80

    Google Scholar 

  292. Ho AS, Huang X, Cao H, Christman-Skieller C, Bennewith K, Le QT, Koong AC (2010) Circulating miR-210 as a novel hypoxia marker in pancreatic cancer. Transl Oncol 3(2):109–113

    Google Scholar 

  293. Kumar SV, Hurteau GJ, Spivack SD (2006) Validity of messenger RNA expression analyses of human saliva. Clin Cancer Res 12(17):5033–5039

    Article  CAS  PubMed  Google Scholar 

  294. Mouliere F, El MS, Gongora C, Guedj AS, Robert B, Del RM, Molina F, Lamy PJ, Lopez-Crapez E, Mathonnet M, Ychou M, Pezet D, Thierry AR (2013) Circulating cell-free DNA from colorectal cancer patients may reveal high KRAS or BRAF mutation load. Transl Oncol 6(3):319–328

    Article  PubMed Central  PubMed  Google Scholar 

  295. Pinzani P, Salvianti F, Zaccara S, Massi D, De Giorgi V, Pazzagli M, Orlando C (2011) Circulating cell-free DNA in plasma of melanoma patients: qualitative and quantitative considerations. Clin Chim Acta 412(23–24):2141–2145

    Google Scholar 

  296. Sikora A, Zimmermann BG, Rusterholz C, Birri D, Kolla V, Lapaire O, Hoesli I, Kiefer V, Jackson L, Hahn S (2010) Detection of increased amounts of cell-free fetal DNA with short PCR amplicons. Clin Chem 56(1):136–138

    Google Scholar 

  297. Dingle TC, Sedlak RH, Cook L, Jerome KR (2013) Tolerance of droplet-digital PCR vs real-time quantitative PCR to inhibitory substances. Clin Chem 59(11):1670–1672

    Google Scholar 

  298. Cuk K, Zucknick M, Heil J, Madhavan D, Schott S, Turchinovich A, Arlt D, Rath M, Sohn C, Benner A, Junkermann H, Schneeweiss A, Burwinkel B (2013) Circulating microRNAs in plasma as early detection markers for breast cancer. Int J Cancer 132(7):1602–1612

    Google Scholar 

  299. Kan CW, Hahn MA, Gard GB, Maidens J, Huh JY, Marsh DJ, Howell VM (2012) Elevated levels of circulating microRNA-200 family members correlate with serous epithelial ovarian cancer. BMC Cancer 12:627

    Google Scholar 

  300. Perhavec A, Cerkovnik P, Novakovic S, Zgajnar J (2008) The hTERT mRNA in plasma samples of early breast cancer patients, non-cancer patients and healthy individuals. Neoplasma 55(6):549–554

    Google Scholar 

  301. Schwarzenbach H, Milde-Langosch K, Steinbach B, Müller V, Pantel K (2012) Diagnostic potential of PTEN-targeting miR-214 in the blood of breast cancer patients. Breast Cancer Res Treat 134(3):933–941

    Google Scholar 

  302. Zhang X, Wang C, Wang L, Du L, Wang S, Zheng G, Li W, Zhuang X, Zhang X, Dong Z (2012) Detection of circulating Bmi-1 mRNA in plasma and its potential diagnostic and prognostic value for uterine cervical cancer. Int J Cancer 131(1):165–172

    Google Scholar 

  303. Giraldez MD, Lozano JJ, Ramirez G, Hijona E, Bujanda L, Castells A, Gironella M (2013) Circulating microRNAs as biomarkers of colorectal cancer: results from a genome-wide profiling and validation study. Clin Gastroenterol Hepatol 11(6):681–688.e3

    Google Scholar 

  304. Wang J, Chen J, Chang P, LeBlanc A, Li D, Abbruzzesse JL, Frazier ML, Killary AM, Sen S (2009) MicroRNAs in plasma of pancreatic ductal adenocarcinoma patients as novel blood-based biomarkers of disease. Cancer Prev Res (Phila) 2(9):807–813

    Google Scholar 

  305. Saccomanno G, Archer VE, Auerbach O, Saunders RP, Brennan LM (1974) Development of carcinoma of the lung as reflected in exfoliated cells. Cancer 33(1):256–270

    Google Scholar 

  306. Hirsch FR, Franklin WA, Gazdar AF, Bunn PA Jr (2001) Early detection of lung cancer: clinical perspectives of recent advances in biology and radiology. Clin Cancer Res 7(1):5–22

    Google Scholar 

  307. Carozzi FM, Bisanzi S, Falini P, Sani C, Venturini G, Lopes Pegna A, Bianchi R, Ronchi C, Picozzi G, Mascalchi M, Carrozzi L, Baliva F, Pistelli F, Tavanti L, Falaschi F, Grazzini M, Innocenti F, Paci E; ITALUNG Study Research group (2010) Molecular profile in body fluids in subjects enrolled in a randomised trial for lung cancer screening: perspectives of integrated strategies for early diagnosis. Lung Cancer 6(2):216–221

    Google Scholar 

  308. Diehl F, Li M, Dressman D, He Y, Shen D, Szabo S, Diaz LA Jr, Goodman SN, David KA, Juhl H, Kinzler KW, Vogelstein B (2005) Detection and quantification of mutations in the plasma of patients with colorectal tumors. Proc Natl Acad Sci U S A 102(45):16368–16373

    Google Scholar 

  309. Berger BM, Ahlquist DA (2012) Stool DNA screening for colorectal neoplasia: biological and technical basis for high detection rates. Pathology 44(2):80–88

    Article  CAS  PubMed  Google Scholar 

  310. Tang D, Liu J, Wang DR, Yu HF, Li YK, Zhang JQ (2011) Diagnostic and prognostic value of the methylation status of secreted frizzled-related protein 2 in colorectal cancer. Clin Invest Med 34(2):E88–E95

    Google Scholar 

  311. Garcia-Olmo DC, Samos J, Picazo MG, Asensio AI, Toboso I, Garcia-Olmo D (2008) Release of cell-free DNA into the bloodstream leads to high levels of non-tumor plasma DNA during tumor progression in rats. Cancer Lett 272(1):133–140

    Google Scholar 

  312. Gorges TM, Schiller J, Schmitz A, Schuetzmann D, Schatz C, Zollner TM, Krahn T, von Ahsen O (2012) Cancer therapy monitoring in xenografts by quantitative analysis of circulating tumor DNA. Biomarkers 17(6):498–506

    Google Scholar 

  313. McShane LM, Altman DG, Sauerbrei W, Taube SE, Gion M, Clark GM (2005) REporting recommendations for tumor MARKer prognostic studies (REMARK). Nat Clin Pract Oncol 2(8):416–422

    Article  CAS  PubMed  Google Scholar 

  314. Kidess E, Jeffrey SS (2013) Circulating tumor cells versus tumor-derived cell-free DNA: rivals or partners in cancer care in the era of single-cell analysis? Genome Med 5(8):70

    Article  PubMed Central  PubMed  Google Scholar 

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Fleischhacker, M., Schmidt, B. (2015). Extracellular Nucleic Acids and Cancer. In: Gahan, P. (eds) Circulating Nucleic Acids in Early Diagnosis, Prognosis and Treatment Monitoring. Advances in Predictive, Preventive and Personalised Medicine, vol 5. Springer, Dordrecht. https://doi.org/10.1007/978-94-017-9168-7_10

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