Jaraba-Álvarez WV, Torres-Gómez IP, Manrique-Hernández RD, Gallo-Bonilla JE

Idioma: Español
Referencias bibliográficas: 137
Paginas: 551-564
Archivo PDF: 831.45 Kb.

RESUMEN

El diagnóstico y tamizaje prenatal, así como el diagnóstico y seguimiento de enfermedades en diversos campos de la medicina, se hace, en la actualidad, de manera más sencilla gracias al ADN libre en plasma. Este ADN representa una pequeña parte de la información genética de un tejido en particular o, en el caso de las mujeres en embarazo, una proporción del ADN fetal. En la oncología, por ejemplo, dada la heterogeneidad del cáncer, la aplicación del ADN libre en plasma ha sido difícil de implementar ya que solo existen algunos biomarcadores tumorales específicos para su uso en investigación. Metodologías como la reacción en cadena de la polimerasa (PCR) en tiempo real muestran una gran sensibilidad para detectar mutaciones que permitan establecer un correcto dignóstico y tratamiento de algunas enfermedades como las fetales o las tumorales, al mismo tiempo que disminuye costos. Lo anterior, no deja de ser una gran oportunidad para continuar los procesos de investigación y desarrollo de pruebas que permitan, en un futuro cercano, implementar el uso del ADN libre de células en el área clínica, con resultados confiables en el diagnóstico y tratamiento de enfermedades sin poner en riesgo la integridad del paciente.

REFERENCIAS (EN ESTE ARTÍCULO)

1. Mandel P, Metais P. Les acides nucléiques du plasma sanguin chez l’homme. C R Seances Soc Biol Fil 1948; 142: 241-243.

2. 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: 318-322.

3. Saller DN, Jr., Canick JA. Current methods of prenatal screening for Down syndrome and other fetal abnormalities. Clin Obstet Gynecol 2008; 51: 24-36.

4. Lo YM, Corbetta N, Chamberlain PF, Rai V, Sargent IL, Redman CW, et al. Presence of fetal DNA in maternal plasma and serum. Lancet 1997; 350: 485-487.

5. Bronkhorst AJ, Wentzel JF, Aucamp J, van Dyk E, du Plessis L, Pretorius PJ. Characterization of the cell-free DNA released by cultured cancer cells. Biochim Biophys Acta 2016; 1863: 157-165.

6. Agostini M, Enzo MV, Bedin C, Belardinelli V, Goldin E, Del Bianco P, et al. Circulating cell-free DNA: a promising marker of regional lymphonode metastasis in breast cancer patients. Cancer Biomark 2012; 11: 89- 98.

7. Gahan PB, Swaminathan R. Circulating nucleic acids in plasma and serum. Recent developments. Ann N Y Acad Sci 2008; 1137: 1-6.

8. Sozzi G, Conte D, Leon M, Ciricione R, Roz L, Ratcliffe C, et al. Quantification of free circulating DNA as a diagnostic marker in lung cancer. J Clin Oncol 2003; 21: 3902-3908.

9. Kim K, Shin DG, Park MK, Baik SH, Kim TH, Kim S, et al. Circulating cell-free DNA as a promising biomarker in patients with gastric cancer: diagnostic validity and significant reduction of cfDNA after surgical resection. Ann Surg Treat Res 2014; 86: 136-142.

10. Gahan PB. Circulating Nucleic Acids in Early Diagnosis, Prognosis and Treatment Monitoring: An Introduction. Dordrecht, Paises Bajos: Spinger; 2015.

11. University of Pittsburgh. Neurological surgery. Types of Brain Tumors. 2017. Disponible: http://www.neurosurgery. pitt.edu/centers-excellence/neurosurgical-oncology/ brain-and-brain-tumors/types-brain-tumors.

12. Schwarzenbach H, Hoon DS, Pantel K. Cell-free nucleic acids as biomarkers in cancer patients. Nat Rev Cancer 2011; 11: 426-437.

13. Kuo YB, Chen JS, Fan CW, Li YS, Chan EC. Comparison of KRAS mutation analysis of primary tumors and matched circulating cell-free DNA in plasmas of patients with colorectal cancer. Clin Chim Acta 2014; 433: 284- 289.

14. Kim MY, Oskarsson T, Acharyya S, Nguyen DX, Zhang XH, Norton L, et al. Tumor self-seeding by circulating cancer cells. Cell 2009; 139: 1315-1326.

15. Alix-Panabieres C, Pantel K. Circulating tumor cells: liquid biopsy of cancer. Clin Chem 2013; 59: 110-118.

16. 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: 1207-1213.

17. Chen X, Bonnefoi H, Diebold-Berger S, Lyautey J, Lederrey C, Faltin-Traub E, et al. Detecting tumor-related alterations in plasma or serum DNA of patients diagnosed with breast cancer. Clin Cancer Res 1999; 5: 2297- 2303.

18. Sozzi G, Conte D, Mariani L, Lo Vullo S, Roz L, Lombardo C, et al. Analysis of circulating tumor DNA in plasma at diagnosis and during follow-up of lung cancer patients. Cancer Res 2001; 61: 4675-4678.

19. Madhavan D, Wallwiener M, Bents K, Zucknick M, Nees J, Schott S, et al. Plasma DNA integrity as a biomarker for primary and metastatic breast cancer and potential marker for early diagnosis. Breast Cancer Res Treat 2014; 146: 163-174.

20. Frattini M, Gallino G, Signoroni S, Balestra D, Lusa L, Battaglia L, et al. Quantitative and qualitative characterization of plasma DNA identifies primary and recurrent colorectal cancer. Cancer Lett 2008; 263: 170- 181.

21. Gerlinger M, Rowan AJ, Horswell S, Math M, Larkin J, Endesfelder D, et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med 2012; 366: 883-892.

22. 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: 211-224.

23. 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 U S A 2013; 110: 18761-18768.

24. 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: 162ra154.

25. Howell JA, Khan SA, Knapp S, Thursz MR, Sharma R. The clinical role of circulating free tumor DNA in gastrointestinal malignancy. Transl Res 2017; 183: 137- 154.

26. Spindler KL, Pallisgaard N, Andersen RF, Brandslund I, Jakobsen A. Circulating free DNA as biomarker and source for mutation detection in metastatic colorectal cancer. PLoS One 2015; 10: e0108247.

27. Castells A, Puig P, Mora J, Boadas J, Boix L, Urgell E, et al. K-ras mutations in DNA extracted from the plasma of patients with pancreatic carcinoma: diagnostic utility and prognostic significance. J Clin Oncol 1999; 17: 578-584.

28. Dianxu F, Shengdao Z, Tianquan H, Yu J, Ruoqing L, Zurong Y, et al. A prospective study of detection of pancreatic carcinoma by combined plasma K-ras mutations and serum CA19-9 analysis. Pancreas 2002; 25: 336-341.

29. 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: 2068- 2074.

30. Egger G, Liang G, Aparicio A, Jones PA. Epigenetics in human disease and prospects for epigenetic therapy. Nature 2004; 429: 457-463.

31. Wu T, Giovannucci E, Welge J, Mallick P, Tang WY, Ho SM. Measurement of GSTP1 promoter methylation in body fluids may complement PSA screening: a metaanalysis. Br J Cancer 2011; 105: 65-73.

32. Dumache R, Puiu M, Motoc M, Vernic C, Dumitrascu V. Prostate cancer molecular detection in plasma samples by glutathione S-transferase P1 (GSTP1) methylation analysis. Clin Lab 2014; 60: 847-852.

33. Church TR, Wandell M, Lofton-Day C, Mongin SJ, Burger M, Payne SR, et al. Prospective evaluation of methylated SEPT9 in plasma for detection of asymptomatic colorectal cancer. Gut 2014; 63: 317-325.

34. Hoque MO, Feng Q, Toure P, Dem A, Critchlow CW, Hawes SE, et al. Detection of aberrant methylation of four genes in plasma DNA for the detection of breast cancer. J Clin Oncol 2006; 24: 4262-4269.

35. Skvortsova TE, Rykova EY, Tamkovich SN, Bryzgunova OE, Starikov AV, Kuznetsova NP, et al. Cell-free and cell-bound circulating DNA in breast tumours: DNA quantification and analysis of tumour-related gene methylation. Br J Cancer 2006; 94: 1492-1495.

36. Ibanez de Caceres I, Battagli C, Esteller M, Herman JG, Dulaimi E, Edelson MI, et al. Tumor cell-specific BRCA1 and RASSF1A hypermethylation in serum, plasma, and peritoneal fluid from ovarian cancer patients. Cancer Res 2004; 64: 6476-6481.

37. Heitzer E, Ulz P, Geigl JB. Circulating tumor DNA as a liquid biopsy for cancer. Clin Chem 2015; 61: 112-123.

38. 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: 985-990.

39. Spindler KL, Pallisgaard N, Vogelius I, Jakobsen A. Quantitative cell-free DNA, KRAS, and BRAF mutations in plasma from patients with metastatic colorectal cancer during treatment with cetuximab and irinotecan. Clin Cancer Res 2012; 18: 1177-1185.

40. 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: 1199-1209.

41. Tanaka H, Tsuda H, Nishimura S, Nomura H, Kataoka F, Chiyoda T, et al. Role of circulating free alu DNA in endometrial cancer. Int J Gynecol Cancer 2012; 22: 82- 86.

42. Catarino R, Ferreira MM, Rodrigues H, Coelho A, Nogal A, Sousa A, et al. Quantification of free circulating tumor DNA as a diagnostic marker for breast cancer. DNA Cell Biol 2008; 27: 415-421.

43. Hashad D, Sorour A, Ghazal A, Talaat I. Free circulating tumor DNA as a diagnostic marker for breast cancer. J Clin Lab Anal 2012; 26: 467-472.

44. Zanetti-Dallenbach RA, Schmid S, Wight E, Holzgreve W, Ladewing A, Hahn S, et al. Levels of circulating cell-free serum DNA in benign and malignant breast lesions. Int J Biol Markers 2007; 22: 95-99.

45. Zanetti-Dallenbach R, Wight E, Fan AX, Lapaire O, Hahn S, Holzgreve W, et al. Positive correlation of cellfree DNA in plasma/serum in patients with malignant and benign breast disease. Anticancer Res 2008; 28: 921-925.

46. 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: 190-196.

47. Schmidt K, Diehl F. A blood-based DNA test for colorectal cancer screening. Discov Med 2007; 7: 7-12.

48. Taback B, Saha S, Hoon DS. Comparative analysis of mesenteric and peripheral blood circulating tumor DNA in colorectal cancer patients. Ann N Y Acad Sci 2006; 1075: 197-203.

49. Flamini E, Mercatali L, Nanni O, Calistri D, Nunziatini R, Zoli W, et al. Free DNA and carcinoembryonic antigen serum levels: an important combination for diagnosis of colorectal cancer. Clin Cancer Res 2006; 12: 6985-6988.

50. Kin C, Kidess E, Poultsides GA, Visser BC, Jeffrey SS. Colorectal cancer diagnostics: biomarkers, cell-free DNA, circulating tumor cells and defining heterogeneous populations by single-cell analysis. Expert Rev Mol Diagn 2013; 13: 581-599.

51. da Silva Filho BF, Gurgel AP, Neto MA, de Azevedo DA, de Freitas AC, Silva Neto Jda C, et al. Circulating cellfree DNA in serum as a biomarker of colorectal cancer. J Clin Pathol 2013; 66: 775-778.

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

53. Xie GS, Hou AR, Li LY, Gao YN, Cheng SJ. Quantification of plasma DNA as a screening tool for lung cancer. Chin Med J (Engl) 2004; 117: 1485-1488.

54. Xue X, Zhu YM, Woll PJ. Circulating DNA and lung cancer. Ann N Y Acad Sci 2006; 1075: 154-164.

55. Yoon KA, Park S, Lee SH, Kim JH, Lee JS. Comparison of circulating plasma DNA levels between lung cancer patients and healthy controls. J Mol Diagn 2009; 11: 182-185.

56. van der Drift MA, Hol BE, Klaassen CH, Prinsen CF, van Aarssen YA, Donders R, et al. Circulating DNA is a noninvasive prognostic factor for survival in non-small cell lung cancer. Lung Cancer 2010; 68: 283-287.

57. Lee SM, Park JY, Kim DS. Methylation of TMEFF2 gene in tissue and serum DNA from patients with non-small cell lung cancer. Mol Cells 2012; 34: 171-176.

58. Board RE, Williams VS, Knight L, Shaw J, Greystoke A, Ranson M, et al. Isolation and extraction of circulating tumor DNA from patients with small cell lung cancer. Ann N Y Acad Sci 2008; 1137: 98-107.

59. Tamkovich SN, Litviakov NV, Bryzgunova OE, Dobrodeev AY, Rykova EY, Tuzikov SA, et al. Cell-surfacebound circulating DNA as a prognostic factor in lung cancer. Ann N Y Acad Sci 2008; 1137: 214-217.

60. Goessl C, Muller M, Straub B, Miller K. DNA altera tions in body fluids as molecular tumor markers for urological malignancies. Eur Urol 2002; 41: 668-676.

61. 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: 983-986.

62. 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: 1032- 1038.

63. Sunami E, Shinozaki M, Higano CS, Wollman R, Dorff TB, Tucker SJ, et al. Multimarker circulating DNA assay for assessing blood of prostate cancer patients. Clin Chem 2009; 55: 559-567.

64. Bryzgunova OE, Morozkin ES, Yarmoschuk SV, Vlassov VV, Laktionov PP. 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 2008; 1137: 222-225.

65. Ellinger J, Albers P, Perabo FG, Muller SC, von Ruecker A, Bastian PJ. CpG island hypermethylation of cell-free circulating serum DNA in patients with testicular cancer. J Urol 2009; 182: 324-329.

66. Chun FK, Muller I, Lange I, Friedrich MG, Erbersdobler A, Karakiewicz PI, et al. Circulating tumour-associated plasma DNA represents an independent and informative predictor of prostate cancer. BJU Int 2006; 98: 544- 548.

67. Guan T, Guo XY, Ye CL, Jiang YH. [Analysis of circulating DNA level in the plasma of cervical cancer patients]. Nan Fang Yi Ke Da Xue Xue Bao 2008; 28: 1663-1664, 1667.

68. Widschwendter A, Ivarsson L, Blassnig A, Muller HM, Fiegl H, Wiedemair A, et al. CDH1 and CDH13 methylation in serum is an independent prognostic marker in cervical cancer patients. Int J Cancer 2004; 109: 163-166.

69. Widschwendter A, Muller HM, Fiegl H, Ivarsson L, Wiedemair A, Muller-Holzner E, et al. DNA methylation in serum and tumors of cervical cancer patients. Clin Cancer Res 2004; 10: 565-571.

70. Zachariah RR, Schmid S, Buerki N, Radpour R, Holzgreve W, Zhong X. Levels of circulating cell-free nuclear and mitochondrial DNA in benign and malignant ovarian tumors. Obstet Gynecol 2008; 112: 843-850.

71. Tomita H, Ichikawa D, Sai S, Morimura R, Murayama Y, Komatsu S, et al. [Quantification of circulating plasma DNA fragments as tumor markers in patients with esophageal and gastric cancer]. Gan To Kagaku Ryoho 2007; 34: 1908-1910.

72. Hoffmann AC, Vallbohmer D, Prenzel K, Metzger R, Heitmann M, Neiss S, et al. Methylated DAPK and APC promoter DNA detection in peripheral blood is significantly associated with apparent residual tumor and outcome. J Cancer Res Clin Oncol 2009; 135: 1231- 1237.

73. Ellinger J, Albers P, Muller SC, von Ruecker A, Bastian PJ. Circulating mitochondrial DNA in the serum of patients with testicular germ cell cancer as a novel noninvasive diagnostic biomarker. BJU Int 2009; 104: 48-52.

74. Ren N, Ye QH, Qin LX, Zhang BH, Liu YK, Tang ZY. Circulating DNA level is negatively associated with the longterm survival of hepatocellular carcinoma patients. World J Gastroenterol 2006; 12: 3911-3914.

75. Iizuka N, Sakaida I, Moribe T, Fujita N, Miura T, Stark M, et al. Elevated levels of circulating cell-free DNA in the blood of patients with hepatitis C virus-associated hepatocellular carcinoma. Anticancer Res 2006; 26: 4713-4719.

76. Tangkijvanich P, Hourpai N, Rattanatanyong P, Wisedopas N, Mahachai V, Mutirangura A. Serum LINE-1 hypomethylation as a potential prognostic marker for hepatocellular carcinoma. Clin Chim Acta 2007; 379: 127-133.

77. Chan KC, Leung SF, Yeung SW, Chan AT, Lo YM. Persistent aberrations in circulating DNA integrity after radiotherapy are associated with poor prognosis in nasopharyngeal carcinoma patients. Clin Cancer Res 2008; 14: 4141-4145.

78. Jiang WW, Zahurak M, Goldenberg D, Milman Y, Park HL, Westra WH, et al. Increased plasma DNA integrity index in head and neck cancer patients. Int J Cancer 2006; 119: 2673-2676.

79. Jiang Y, Pan SY, Xia WY, Chen D, Wang H, Zhang LX, et al. [Dynamic monitoring of plasma circulating DNA in patients with acute myeloid leukemia and its clinical significance]. Zhongguo Shi Yan Xue Ye Xue Za Zhi 2012; 20: 53-56.

80. Hohaus S, Giachelia M, Massini G, Mansueto G, Vannata B, Bozzoli V, et al. Cell-free circulating DNA in Hodgkin’s and non-Hodgkin’s lymphomas. Ann Oncol 2009; 20: 1408-1413.

81. Hosny G, Farahat N, Hainaut P. TP53 mutations in circulating free DNA from Egyptian patients with non- Hodgkin’s lymphoma. Cancer Lett 2009; 275: 234-239.

82. Mussolin L, Burnelli R, Pillon M, Carraro E, Farruggia P, Todesco A, et al. Plasma cell-free DNA in paediatric lymphomas. J Cancer 2013; 4: 323-329.

83. Daniotti M, Vallacchi V, Rivoltini L, Patuzzo R, Santinami M, Arienti F, et al. Detection of mutated BRAFV600E variant in circulating DNA of stage III-IV melanoma patients. Int J Cancer 2007; 120: 2439-2444.

84. Nakamoto D, Yamamoto N, Takagi R, Katakura A, Mizoe JE, Shibahara T. Detection of microsatellite alterations in plasma DNA of malignant mucosal melanoma using whole genome amplification. Bull Tokyo Dent Coll 2008; 49: 77-87.

85. Calistri D, Casadio V, Bravaccini S, Zoli W, Amadori D. Urinary biomarkers of non-muscle-invasive bladder cancer: current status and future potential. Expert Rev Anticancer Ther 2012; 12: 743-752.

86. Su YH, Wang M, Aiamkitsumrit B, Brenner DE, Block TM. Detection of a K-ras mutation in urine of patients with colorectal cancer. Cancer Biomark 2005; 1: 177- 182.

87. Szarvas T, Kovalszky I, Bedi K, Szendroi A, Majoros A, Riesz P, et al. Deletion analysis of tumor and urinary DNA to detect bladder cancer: urine supernatant versus urine sediment. Oncol Rep 2007; 18: 405-409.

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

89. Zancan M, Galdi F, Di Tonno F, Mazzariol C, Orlando C, Malentacchi F, et al. Evaluation of cell-free DNA in urine as a marker for bladder cancer diagnosis. Int J Biol Markers 2009; 24: 147-155.

90. Casadio V, Calistri D, Salvi S, Gunelli R, Carretta E, Amadori D, et al. Urine cell-free DNA integrity as a marker for early prostate cancer diagnosis: a pilot study. Biomed Res Int 2013; 2013: 270457.

91. Casadio V, Calistri D, Tebaldi M, Bravaccini S, Gunelli R, Martorana G, et al. Urine cell-free DNA integrity as a marker for early bladder cancer diagnosis: preliminary data. Urol Oncol 2013; 31: 1744-1750.

92. Salvi S, Gurioli G, Martignano F, Foca F, Gunelli R, Cicchetti G, et al. Urine Cell-Free DNA Integrity Analysis for Early Detection of Prostate Cancer Patients. Dis Markers 2015; 2015: 574120.

93. Song BP, Jain S, Lin SY, Chen Q, Block TM, Song W, et al. Detection of hypermethylated vimentin in urine of patients with colorectal cancer. J Mol Diagn 2012; 14: 112-119.

94. Su YH, Wang M, Brenner DE, Norton PA, Block TM. Detection of mutated K-ras DNA in urine, plasma, and serum of patients with colorectal carcinoma or adenomatous polyps. Ann N Y Acad Sci 2008; 1137: 197-206.

95. Lo YM, Tein MS, Lau TK, Haines CJ, Leung TN, Poon PM, et al. Quantitative analysis of fetal DNA in maternal plasma and serum: implications for noninvasive prenatal diagnosis. Am J Hum Genet 1998; 62: 768- 775.

96. 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: 88-92.

97. 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: 218-224.

98. Lo YM, Patel P, Wainscoat JS, Sampietro M, Gillmer MD, Fleming KA. Prenatal sex determination by DNA amplification from maternal peripheral blood. Lancet 1989; 2: 1363-1365.

99. Lun FM, Chiu RW, Chan KC, Leung TY, Lau TK, Lo YM. Microfluidics digital PCR reveals a higher than expected fraction of fetal DNA in maternal plasma. Clin Chem 2008; 54: 1664-1672.

100. Lo YM, Lau TK, Zhang J, Leung TN, Chang AM, Hjelm NM, et al. Increased fetal DNA concentrations in the plasma of pregnant women carrying fetuses with trisomy 21. Clin Chem 1999; 45: 1747-1751.

101. Chiu RW, Akolekar R, Zheng YW, Leung TY, Sun H, Chan KC, et al. Non-invasive prenatal assessment of trisomy 21 by multiplexed maternal plasma DNA sequencing: large scale validity study. BMJ 2011; 342: c7401.

102. Allyse M, Minear MA, Berson E, Sridhar S, Rote M, Hung A, et al. Non-invasive prenatal testing: a review of international implementation and challenges. Int J Womens Health 2015; 7: 113-126.

103. Gil MM, Quezada MS, Revello R, Akolekar R, Nicolaides KH. Analysis of cell-free DNA in maternal blood in screening for fetal aneuploidies: updated meta-analysis. Ultrasound Obstet Gynecol 2015; 45: 249-266.

104. Bianchi DW, Parker RL, Wentworth J, Madankumar R, Saffer C, Das AF, et al. DNA sequencing versus standard prenatal aneuploidy screening. N Engl J Med 2014; 370: 799-808.

105. Norton ME, Wapner RJ. Cell-free DNA Analysis for Noninvasive Examination of Trisomy. N Engl J Med 2015; 373: 2582.

106. Benn P, Borrell A, Chiu RW, Cuckle H, Dugoff L, Faas B, et al. Position statement from the Chromosome Abnormality Screening Committee on behalf of the Board of the International Society for Prenatal Diagnosis. Prenat Diagn 2015; 35: 725-734.

107. Jiang X, Liu C, Yu T, Zhang L, Meng K, Xing Z, et al. Genetic dissection of the Down syndrome critical region. Hum Mol Genet 2015; 24: 6540-6551.

108. Hahn S, Lapaire O, Tercanli S, Kolla V, Hosli I. Determination of fetal chromosome aberrations from fetal DNA in maternal blood: has the challenge finally been met? Expert Rev Mol Med 2011; 13: e16.

109. Chiu EKL, Hui WWI, Chiu RWK. cfDNA screening and diagnosis of monogenic disorders - where are we heading? Prenat Diagn 2018; 38: 52-58.

110. Li Y, Page-Christiaens GC, Gille JJ, Holzgreve W, Hahn S. Non-invasive prenatal detection of achondroplasia in size-fractionated cell-free DNA by MALDI-TOF MS assay. Prenat Diagn 2007; 27: 11-17.

111. Saito H, Sekizawa A, Morimoto T, Suzuki M, Yanaihara T. Prenatal DNA diagnosis of a single-gene disorder from maternal plasma. Lancet 2000; 356: 1170.

112. Amicucci P, Gennarelli M, Novelli G, Dallapiccola B. Prenatal diagnosis of myotonic dystrophy using fetal DNA obtained from maternal plasma. Clin Chem 2000; 46: 301-302.

113. Gonzalez-Gonzalez MC, Trujillo MJ, Rodriguez de Alba M, Garcia-Hoyos M, Lorda-Sanchez I, Diaz-Recasens J, et al. Huntington disease-unaffected fetus diagnosed from maternal plasma using QF-PCR. Prenat Diagn 2003; 23: 232-234.

114. Chiu RW, Lau TK, Leung TN, Chow KC, Chui DH, Lo YM. Prenatal exclusion of beta thalassaemia major by examination of maternal plasma. Lancet 2002; 360: 998- 1000.

115. Li Y, Di Naro E, Vitucci A, Zimmermann B, Holzgreve W, Hahn S. Detection of paternally inherited fetal point mutations for beta-thalassemia using size-fractionated cell-free DNA in maternal plasma. JAMA 2005; 293: 843-849.

116. Bustamante-Aragones A, Gallego-Merlo J, Trujillo- Tiebas MJ, de Alba MR, Gonzalez-Gonzalez C, Glover G, et al. New strategy for the prenatal detection/ exclusion of paternal cystic fibrosis mutations in maternal plasma. J Cyst Fibros 2008; 7: 505-510.

117. Gonzalez-Gonzalez MC, Garcia-Hoyos M, Trujillo MJ, Rodriguez de Alba M, Lorda-Sanchez I, Diaz-Recasens J, et al. Prenatal detection of a cystic fibrosis mutation in fetal DNA from maternal plasma. Prenat Diagn 2002; 22: 946-948.

118. Chiu RW, Lau TK, Cheung PT, Gong ZQ, Leung TN, Lo YM. Noninvasive prenatal exclusion of congenital adrenal hyperplasia by maternal plasma analysis: a feasibility study. Clin Chem 2002; 48: 778-780.

119. Hudecova I, Sahota D, Heung MM, Jin Y, Lee WS, Leung TY, et al. Maternal plasma fetal DNA fractions in pregnancies with low and high risks for fetal chromosomal aneuploidies. PLoS One 2014; 9: e88484.

120. Lun FM, Tsui NB, Chan KC, Leung TY, Lau TK, Charoenkwan P, et al. Noninvasive prenatal diagnosis of monogenic diseases by digital size selection and relative mutation dosage on DNA in maternal plasma. Proc Natl Acad Sci U S A 2008; 105: 19920-19925.

121. Barrett AN, McDonnell TC, Chan KC, Chitty LS. Digital PCR analysis of maternal plasma for noninvasive detection of sickle cell anemia. Clin Chem 2012; 58: 1026-1032.

122. Tsui NB, Kadir RA, Chan KC, Chi C, Mellars G, Tuddenham EG, et al. Noninvasive prenatal diagnosis of hemophilia by microfluidics digital PCR analysis of maternal plasma DNA. Blood 2011; 117: 3684-3691.

123. Gu W, Koh W, Blumenfeld YJ, El-Sayed YY, Hudgins L, Hintz SR, et al. Noninvasive prenatal diagnosis in a fetus at risk for methylmalonic acidemia. Genet Med 2014; 16: 564-567.

124. Ashoor G, Syngelaki A, Poon LC, Rezende JC, Nicolaides KH. Fetal fraction in maternal plasma cell-free DNA at 11-13 weeks’ gestation: relation to maternal and fetal characteristics. Ultrasound Obstet Gynecol 2013; 41: 26-32.

125. Kinnings SL, Geis JA, Almasri E, Wang H, Guan X, Mc- Cullough RM, et al. Factors affecting levels of circulating cell-free fetal DNA in maternal plasma and their implications for noninvasive prenatal testing. Prenat Diagn 2015; 35: 816-822.

126. Rava RP, Srinivasan A, Sehnert AJ, Bianchi DW. Circulating fetal cell-free DNA fractions differ in autosomal aneuploidies and monosomy X. Clin Chem 2014; 60: 243-250.

127. Nicolaides KH, Syngelaki A, del Mar Gil M, Quezada MS, Zinevich Y. Prenatal detection of fetal triploidy from cell-free DNA testing in maternal blood. Fetal Diagn Ther 2014; 35: 212-217.

128. Poon LC, Musci T, Song K, Syngelaki A, Nicolaides KH. Maternal plasma cell-free fetal and maternal DNA at 11-13 weeks’ gestation: relation to fetal and maternal characteristics and pregnancy outcomes. Fetal Diagn Ther 2013; 33: 215-223.

129. Wang E, Batey A, Struble C, Musci T, Song K, Oliphant A. Gestational age and maternal weight effects on fetal cell-free DNA in maternal plasma. Prenat Diagn 2013; 33: 662-666.

130. Canick JA, Palomaki GE, Kloza EM, Lambert-Messerlian GM, Haddow JE. The impact of maternal plasma DNA fetal fraction on next generation sequencing tests for common fetal aneuploidies. Prenat Diagn 2013; 33: 667-674.

131. Choi H, Lau TK, Jiang FM, Chan MK, Zhang HY, Lo PS, et al. Fetal aneuploidy screening by maternal plasma DNA sequencing: ‘false positive’ due to confined placental mosaicism. Prenat Diagn 2013; 33: 198-200.

132. Grati FR, Malvestiti F, Ferreira JC, Bajaj K, Gaetani E, Agrati C, et al. Fetoplacental mosaicism: potential implications for false-positive and false-negative noninvasive prenatal screening results. Genet Med 2014; 16: 620-624.

133. Futch T, Spinosa J, Bhatt S, de Feo E, Rava RP, Sehnert AJ. Initial clinical laboratory experience in noninvasive prenatal testing for fetal aneuploidy from maternal plasma DNA samples. Prenat Diagn 2013; 33: 569-574.

134. Snyder MW, Gammill HS, Shendure J. Copy-Number Variation and False Positive Results of Prenatal Screening. N Engl J Med 2015; 373: 2585.

135. Wang Y, Chen Y, Tian F, Zhang J, Song Z, Wu Y, et al. Maternal mosaicism is a significant contributor to discordant sex chromosomal aneuploidies associated with noninvasive prenatal testing. Clin Chem 2014; 60: 251-259.

136. Osborne CM, Hardisty E, Devers P, Kaiser-Rogers K, Hayden MA, Goodnight W, et al. Discordant noninvasive prenatal testing results in a patient subsequently diagnosed with metastatic disease. Prenat Diagn 2013; 33: 609-611.

137. Bianchi DW, Chudova D, Sehnert AJ, Bhatt S, Murray K, Prosen TL, et al. Noninvasive Prenatal Testing and Incidental Detection of Occult Maternal Malignancies. JAMA 2015; 314: 162-169.