Cell Free DNA and Genometastasis

Yıl 2019, Cilt: 9 Sayı: 2, 69 - 74, 01.08.2019

Cemal Çağıl Koçana Selin Toprak , Büşra Yaşa , Hilal Hekimoğlu Selçuk Sözer Tokdemir

Öz

DOI: 10.26650/experimed.2019.19015

Cell free DNAs (cfDNA) are short DNA
fragments which are present in all biological fluids and cell culture medium.
They were first detected in blood plasma by Mandel and Metais in 1948. cfDNAs
are mostly endogenous-derived fragments that are determined in lipid/protein
rich complexes or particles with membranes. In healthy individuals, there are
small amounts of mono-nucleosome forms of cfDNA in the peripheral circulation.
cfDNA can bind to proteins and phospholipids on cell surfaces. This mechanism
may related to absorbance and release of cfDNA. Different enzymes such as
deoxyribonuclease (DNase) may facilitate the unbounding and recirculation of
membrane bound cfDNAs.

The investigation of cfDNA that circulates
freely in the blood initiated its application in clinical research including
diagnosis. Especially, cfDNA in mother’s blood, which originated in fetus, has
been in widely used in prenatal diagnosis already. Moreover, cfDNA has been
applied in much clinical research, including cancer, organ transplantation,
auto-immune diseases, trauma, myocardial infarcts, and sepsis. Although it is
extremely useful to analyze cfDNA for certain pathologies and physiological
conditions, there is no definite information about their fragment dimensions,
origins nor their character.

In this review, the possible origins of
cfDNA are explored with an overview of the literature regarding cfDNA and also,
its role in genometastasis has been investigated.

In addition, the rapidly increasing
diagnostic use in recent years, especially its advantages in prenatal diagnosis
are discussed.

Cite this article as: Koçana CÇ, Toprak SF,
Yaşa B, Hekimoğlu H, Tokdemir SS. Cell Free DNA and Genometastasis. Experimed
2019; 9(2): 69-74.

Anahtar Kelimeler

Cell free DNA, genometastasis, Cell free fetal DNA

Hücre Dışı DNA ve Genometastaz

Öz

DOI: 10.26650/experimed.2019.19015

1948 yılında, kan plazmasında Mandel ve
Metais tarafından keşfedilen hücre dışı DNA’lar (hdDNA), tüm biyolojik sıvılar
ve hücre kültür medyasında var olduğu bilinen kısa DNA parçalarıdır. Bu
hdDNA’lar ağırlıklı olarak endojen kökenli olup lipid ve protein içeren
komplekslerde veya membranlı partiküllerin içinde bulunabilirler. Sağlıklı
bireylerde periferik dolaşımda, mono-nükleozomlar şeklinde az miktarda hdDNA
bulunur. hdDNA, hücre yüzeylerindeki bağlayıcı proteinlere veya fosfolipitlere
tutunabilir. Bu mekanizma hdDNA emilimi veya salınımıyla ilişkilendirilebilir.
Deoksiribonükleaz (DNaz) gibi enzimler aracılığıyla hücreye tutunmuş olan
hdDNA’ların yüzeyden ayırıp sirkülasyona geri salınımı sağlanabilir.

Kanda serbest halde dolaşan hdDNA‘nın
keşfedilmesi ile farklı klinik alanlarda tanı amaçlı kullanımlarına ilişkin
çalışmalar da başlamıştır. Özellikle prenatal tanıda, anne dolaşımında bulunan
fetüse ait hdDNA analizleri halihazırda uygulanmaktadır. Bunun yanında, kanser,
organ nakli, otoimmün hastalıklar, travma, miyokardial infarktüs ve sepsis gibi
diğer klinik alanlar için de kullanılabildiği bilinmektedir. hdDNA analizi,
çeşitli patolojiler ve spesifik fizyolojik durumların araştırılması ve
tanısında yararlı görülse de, fragman boyutları dahil olmak üzere, kökenleri ve
doğası hakkında kesin bir bilgi yoktur.

Bu derlemede, muhtemel hdDNA orjini
hakkında literatür bilgileri bir araya getirilerek bir sentez oluşturulmaya
çalışılmış bunun yanında genometestazdaki rolü de irdelenmiştir. Son yıllarda
hızla artan tanı amaçlı kullanımına özellikle de prenatal tanıdaki avantajları
ele alınmıştır.

Cite this article as: Koçana CÇ, Toprak SF,
Yaşa B, Hekimoğlu H, Tokdemir SS. Cell Free DNA and Genometastasis. Experimed
2019; 9(2): 69-74.

Anahtar Kelimeler

Hücre dışı DNA, Genometastaz, Hücre dışı fetal DNA

Kaynakça

• 1. Volik S, Alcaide M, Morin RD, Collins C. Cell-free DNA (cfDNA): Clinical Significance and Utility in Cancer Shaped By Emerging Technologies. Mol Cancer Res 2016; 14: 898-908. [CrossRef] 2. Rykova EY, Morozkin ES, Ponomaryova AA, Loseva EM, Zaporozhchenko IA, Cherdyntseva NV, et al. Cell-free and cell-bound circulating nucleic acid complexes: mechanisms of generation, concentration and content. Expert Opin Biol Ther 2012; 12 Suppl 1: 141-53. [CrossRef] 3. Harraway J. Non-invasive prenatal testing. Aust Fam Physician 2017; 46: 735-9. 4. Duvvuri B, Lood C. Cell-Free DNA as a Biomarker in Autoimmune Rheumatic Diseases. Front Immunol 2019;10: 502. [CrossRef] 5. Sanchez C, Snyder MW, Tanos R, Shendure J, Thierry AR. New insights into structural features and optimal detection of circulating tumor DNA determined by single-strand DNA analysis. NPJ Genom Med 2018; 3: 31. [CrossRef] 6. Grunt M, Hillebrand T, Schwarzenbach H. Clinical relevance of size selection of circulating DNA. Transl Cancer Res 2018; 7(Suppl 2): 171-84. [CrossRef] 7. Heitzer E, Auer M, Hoffmann EM, Pichler M, Gasch C, Ulz P, et al. Establishment of tumor-specific copy number alterations from plasma DNA of patients with cancer. Int J Cancer 2013; 133: 346-56. [CrossRef] 8. Zhivotosky B, Orrenius S. Assessment of apoptosis and necrosis by DNA fragmentation and morphological criteria. Curr Protoc Cell Biol 2001; Chapter 18: Unit 18.3. [CrossRef] 9. Jahr S, Hentze H, Englisch S, Hardt D, Fackelmayer FO, Hesch RD, et al. DNA fragments in the blood plasma of cancer patients: Quantitations and evidence for their origin from apoptotic and necrotic cells. Cancer Res 2001; 61: 1659-65. 10. 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: 157-65. [CrossRef] 11. Aucamp J, Bronkhorst AJ, Badenhorst CPS, Pretorius PJ. The diverse origins of circulating cell-free DNA in the human body: a critical re-evaluation of the literature. Biol Rev Camb Philos Soc 2018; 93: 1649-83. [CrossRef] 12. Stroun M, Lyautey J, Lederrey C, Olson-Sand A, Anker P. About the possible origin and mechanism of circulating DNA: Apoptosis and active DNA release. Clin Chim Acta 2001; 313: 139-42. [CrossRef] 13. Nagata S. DNA degradation in development and programmed cell death. Annu Rev Immunol 2005; 23: 853-75. [CrossRef] 14. Nagata S, Nagase H, Kawane K, Mukae N, Fukuyama H. Degradation of chromosomal DNA during apoptosis. Cell Death Differ 2003; 10: 108-16. [CrossRef] 15. Mouliere F, Robert B, Arnau Peyrotte E, Del Rio M, Ychou M, Molina F, et al. High fragmentation characterizes tumour-derived circulating DNA. PLoS One 2011; 6: doi: 10.1371/journal.pone.0023418. [CrossRef] 16. Schwarzenbach H, Hoon DS, Pantel K. Cell-free nucleic acids as biomarkers in cancer patients. Nat Rev Cancer 2011; 11: 426-37. [CrossRef] 17. Thakur BK, Zhang H, Becker A, Matei I, Huang Y, Costa-Silva B, et al. Double-stranded DNA in exosomes: a novel biomarker in cancer detection. Cell Res 2014; 24: 766-9. [CrossRef] 18. Bergsmedh A, Szeles A, Henriksson M, Bratt A, Folkman MJ, Spetz AL, et al. Horizontal transfer of oncogenes by uptake of apoptotic bodies. Proc Natl Acad Sci 2001; 98: 6407-11. [CrossRef] 19. Holland AJ, Cleveland DW. Chromoanagenesis and cancer: Mechanisms and consequences of localized, complex chromosomal rearrangements. Nat Med 2012; 18: 1630-8. [CrossRef] 20. Gu W, Zhang F, Lupski JR. Mechanisms for human genomic rearrangements. Pathogenetics 2008; 1: 4. [CrossRef] 21. Zhang F, Khajavi M, Connolly AM, Towne CF, Batish SD, Lupski JR. The DNA replication FoSTeS/MMBIR mechanism can generate genomic, genic and exonic complex rearrangements in humans. Nat Genet 2009; 41: 849-53. [CrossRef] 22. Baca SC, Prandi D, Lawrence MS, Mosquera JM, Romanel A, Drier Y, et al. Punctuated evolution of prostate cancer genomes. Cell 2013; 153: 666-77. [CrossRef] 23. Stephens PJ, Greenman CD, Fu B, Yang F, Bignell GR, Mudie LJ, et al. Massive genomic rearrangement acquired in a single catastrophic event during cancer development. Cell 2011; 144: 27-40. [CrossRef] 24. Maher CA, Wilson RK. Chromothripsis and human disease: Piecing together the shattering process Cell 2012; 148: 29-32. [CrossRef] 25. Korbel JO, Campbell PJ. Criteria for inference of chromothripsis in cancer genomes. Cell 2013: doi:10.1016/j.cell.2013.02.023 [CrossRef] 26. L’Abbate A, Tolomeo D, Cifola I, Severgnini M, Turchiano A, Augello B, et al. MYC-containing amplicons in acute myeloid leukemia: genomic structures, evolution, and transcriptional consequences. Leukemia 2018; 32: 2152-66. [CrossRef] 27. Duijf PHG, Schultz N, Benezra R. Cancer cells preferentially lose small chromosomes. Int J Cancer 2013; https://doi.org/10.1002/ijc.27924 [CrossRef] 28. Bakhoum SF, Ngo B, Laughney AM, Cavallo JA, Murphy CJ, Ly P, et al. Chromosomal instability drives metastasis through a cytosolic DNA response. Nature 2018; 553: 467-72. [CrossRef] 29. Knudson AG. Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci U. S. A. 1971; 68: 820-3. [CrossRef] 30. Barták BK, Nagy ZB, Spisák S, Tulassay Z, Dank M, Igaz P, et al. In vivo analysis of circulating cell-free DNA release and degradation. Orv Hetil 2018; 159: 223-33. [CrossRef] 31. García-Olmo D, García-Olmo DC, Ontañón J, Martinez E, Vallejo M. Tumor DNA circulating in the plasma might play a role in metastasis. The hypothesis of the genometastasis. Histol Histopathol 1999; 14: 1159-64. 32. Abdouh M, Zhou S, Arena V, Arena M, Lazaris A, Onerheim R, et al. Transfer of malignant trait to immortalized human cells following exposure to human cancer serum. J Exp Clin Cancer Res 2014; 33: 1-12. [CrossRef] 33. Hamam D, Abdouh M, Gao ZH, Arena V, Arena M, Arena GO. Transfer of malignant trait to BRCA1 deficient human fibroblasts following exposure to serum of cancer patients. J Exp Clin Cancer Res 2016; doi:10.1186/s13046-016-0360-9. [CrossRef] 34. Arena GO, Arena V, Arena M, Abdouh M. Transfer of malignant traits as opposed to migration of cells: A novel concept to explain metastatic disease. Med Hypotheses 2017; 100: 82-6. [CrossRef] 35. Abdouh M, Hamam D, Gao ZH, Arena V, Arena M, Arena GO. Exosomes isolated from cancer patients’ sera transfer malignant traits and confer the same phenotype of primary tumors to oncosuppressor-mutated cells. J Exp Clin Cancer Res 2017; 36: doi: 10.1186/s13046-017-0587-0. [CrossRef] 36. Leon SA, Shapiro B, Sklaroff DM, Yaros MJ. Free DNA in the Serum of Cancer Patients and the Effect of Therapy. Cancer Res 1977; 37: 646-50. 37. Sorenson GD, Pribish DM, Valone FH, Memoli VA, Bzik DJ, Yao SL. Soluble Normal and Mutated DNA Sequences from Single-Copy Genes in Human Blood. Cancer Epidemiol Biomarkers Prev 1994; 3: 67-71. 38. Vasioukhin V, Anker P, Maurice P, Lyautey J, Lederrey C, Stroun M. Point mutations of the N-ras gene in the blood plasma DNA of patients with myelodysplastic syndrome or acute myelogenous leukaemia. Br J Haematol 1994; 86: 774-9. [CrossRef] 39. X, Teare MD, Holen I, Zhu YM, Woll PJ. Optimizing the yield and utility of circulating cell-free DNA from plasma and serum. Clin Chim Acta 2009; 404: 100-4. [CrossRef] 40. Diaz LA, Williams RT, Wu J, Kinde I, Hecht JR, Berlin J, et al. The molecular evolution of acquired resistance to targeted EGFR blockade in colorectal cancers. Nature 2012; 486: 537-540. [CrossRef] 41. Russo M, Siravegna G, Blaszkowsky LS, Corti G, Crisafulli G, Ahronian LG, et al. Tumor heterogeneity and Lesion-Specific response to targeted therapy in colorectal cancer. Cancer Discov 2016; doi: 10.1158/2159-8290.CD-15-1283. [CrossRef] 42. Goyal L, Saha SK, Liu LY, Siravegna G, Leshchiner I, Ahronian LG, et al. Polyclonal secondary FGFR2 mutations drive acquired resistance to FGFR inhibition in patients with FGFR2 fusion-positive cholangiocarcinoma. Cancer Discov 2017; 7: 252-63. [CrossRef] 43. Hazar-Rethinam M, Kleyman M, Han GC, Liu D, Ahronian LG, Shahzade HA. Convergent therapeutic strategies to overcome the heterogeneity of acquired resistance in BRAFv600E colorectal cancer. Cancer Discov 2018; DOI: 10.1158/2159-8290.CD-17-1227. [CrossRef] 44. Bakhoum SF, Cantley LC. The Multifaceted Role of Chromosomal Instability in Cancer and Its Microenvironment. Cell 2018; 174: 1347-60. [CrossRef] 45. Piotrowska, Z, Niederst MJ, Karlovich CA, Wakelee HA, Neal JW, Mino-Kenudson M, et al. Heterogeneity underlies the emergence of EGFRT790 wild-type clones following treatment of T790M-positive cancers with a third-generation EGFR inhibitor. Cancer Discov 2015; doi: 10.1158/2159-8290.CD-15-0399. [CrossRef] 46. Blakely CM, Watkins TBK, Wu W, Gini B, Chabon JJ, McCoach CE, et al. Evolution and clinical impact of co-occurring genetic alterations in advanced-stage EGFR-mutant lung cancers. Nat Genet 2017; 49: 1963-704. [CrossRef] 47. Malapelle U, Sirera R, Jantus-Lewintre E, Reclusa P, Calabuig-Fariñas S, Blasco A, et al. Profile of the Roche cobas® EGFR mutation test v2 for non-small cell lung cancer. Expert Rev Mol Diagn 2017; 17: 209-15. [CrossRef] 48. Phallen J, Sausen M, Adleff V, Leal A, Hruban C, White J, et al. Direct detection of early-stage cancers using circulating tumor DNA. Sci Transl Med 2017; 16: 403. [CrossRef] 49. Ramezanzadeh M, Khosravi S, Salehi R. Cell-free Fetal Nucleic Acid Identifier Markers in Maternal Circulation. Adv Biomed Res 2017; 6: 89. [CrossRef] 50. Yau M, Khattab A, New MI. Prenatal Diagnosis of Congenital Adrenal Hyperplasia. Endocrinol Metab Clin North Am 2016; 45: 267-81. [CrossRef] 51. Daley R, Hill M, Chitty LS. Non-invasive prenatal diagnosis: Progress and potential. Arch Dis Child Fetal Neonatal Ed 2014; 99: 426-30. [CrossRef] 52. Kenkhuis MJA, Bakker M, Bardi F, Fontanella F, Bakker MK, Fleurke-Rozema JH, et al. Effectiveness of 12-13-week scan for early diagnosis of fetal congenital anomalies in the cell-free DNA era. Ultrasound Obstet Gynecol 2018; 51: 463-9. [CrossRef] 53. Yang Q, Du Z, Song Y, Gao S, Yu S, Zhu H, et al. Size-selective separation and overall-Amplification of cell-free fetal DNA fragments using PCR-based enrichment. Sci Rep 2017; doi:10.1038/srep40936. [CrossRef] 54. D’Aversa E, Breveglieri G, Pellegatti P, Guerra G, Gambari R, Borgatti M. Non-invasive fetal sex diagnosis in plasma of early weeks pregnants using droplet digital PCR. Mol Med 2018; doi:10.1186/s10020-018-0016-7 [CrossRef] 55. Contro E, Bernabini D, Farina A. Cell-Free Fetal DNA for the Prediction of Pre-Eclampsia at the First and Second Trimesters: A Systematic Review and Meta-Analysis. Mol Diagn Ther 2017; 21: 125-35. [CrossRef] 56. Sherwood K, Weimer ET. Characteristics, properties, and potential applications of circulating cell-free dna in clinical diagnostics: a focus on transplantation. J Immunol Methods 2018; 463: 27-38. [CrossRef] 57. Fernando MR, Jiang C, Krzyzanowski GD, Ryan WL. New evidence that a large proportion of human blood plasma cell-free DNA is localized in exosomes. PLoS One 2017; doi:10.1371/journal.pone.0183915. [CrossRef] 58. Bronkhorst AJ, Ungerer V, Holdenrieder S The emerging role of cell-free DNA as a molecular marker for cancer management. Biomol Detect Quantif 2019; doi:10.1016/j.bdq.2019.100087. [CrossRef] 59. Kostyuk SV, Ermakov AV, Alekseeva AY, Smirnova TD, Glebova KV, Efremova LV, et al. Role of extracellular DNA oxidative modification in radiation induced bystander effects in human endotheliocytes. Mutat Res 2012; 729: 52-60. [CrossRef]