Advances in Molecular OncologyAdvances in Molecular OncologyУспехи молекулярной онкологии2313-805X2413-3787Publishing House ABV Press13310.17650/2313-805X-2018-5-1-26-34REVIEW ARTICLESОБЗОРНЫЕ СТАТЬИAsynchronous replication in oncological patientsАсинхронная репликация у онкологических больныхMikhailovaG. F.МихайловаГ. Ф.
Russian Federation

4 Korolyova St., Obninsk 249036

249036 Обнинск, ул. Королева, 4

tais1260@mail.ruTsepenkoV. V.ЦепенкоВ. В.
Russian Federation

4 Korolyova St., Obninsk 249036

249036 Обнинск, ул. Королева, 4

ShkavrovaT. G.ШкавроваТ. Г.
Russian Federation

4 Korolyova St., Obninsk 249036

249036 Обнинск, ул. Королева, 4

GoloubE. V.ГолубЕ. В.
Russian Federation

4 Korolyova St., Obninsk 249036

249036 Обнинск, ул. Королева, 4

A.F. Tsyb Medical Radiological Research Center – branch of the National Medical Research Center of Radiology, Ministry of Health of RussiaМедицинский радиологический научный центр им А.Ф. Цыба – филиал ФГБУ «Национальный медицинский исследовательский центр радиологии» Минздрава России150120185126341405201814052018Copyright ©; 2018, Mikhailova G.F., Tsepenko V.V., Shkavrova T.G., Goloub E.V.Copyright ©; 2018, Михайлова Г.Ф., Цепенко В.В., Шкаврова Т.Г., Голуб Е.В.2018Mikhailova G.F., Tsepenko V.V., Shkavrova T.G., Goloub E.V.Михайлова Г.Ф., Цепенко В.В., Шкаврова Т.Г., Голуб Е.В.https://creativecommons.org/licenses/by/4.0https://umo.abvpress.ru/jour/article/view/133

Epigenetics is a science studying mechanisms of heritable changes in gene function that occur without a change in the DNA sequence. One of the most important marks of epigenetic misbalance of cell genome is an replication asynchrony of genes with biallelic expression. Interphase fluorescence in situ hybridization (I-FISH) in phytohaemagglutinin-stimulated lymphocytes of peripheral blood is a proper method of estimation of aberrant DNA replication time e. g. DNA replication asynchrony. In this review we analyzed reports referring to asynchronous DNA replication of biallelically expressed genes in lymphocytes of peripheral blood of cancer patients. Analysis shows the DNA replication asynchrony is a nonspecific tumor marker observing both in tumor cells and lymphocytes of peripheral blood in oncohematological patients and patients with solid tumors. It’s stated the frequency of lymphocytes with asynchronous DNA replication of studied genes in cancer patients is increased significantly compares with healthy donors and is enhanced during malignance process. It gives the opportunity of potential using asynchronous replication as molecular genetic marker for cancer patients early revealing.

asynchronous replicationfluorescence in situ hybridizationperipheral blood lymphocytecancer biomarkerасинхронная репликацияфлуоресцентная in situ гибридизациялимфоциты периферической кровионкологический биомаркер1. Cancer Biomarkers. Minimal and noninvasive early diagnosis and prognosis. Eds. D. Barh, A. Carpi, M. Verma, M.L. Gunduz. N.-Y.: CRC Press, 2014. P. 929. DOI: 10.1201/b16389.Cancer Biomarkers. Minimal and noninvasive early diagnosis and prognosis. Eds. D. Barh, A. Carpi, M. Verma, M.L. Gunduz. N.-Y.: CRC Press, 2014. P. 929. DOI: 10.1201/b16389.2. Holdenrieder S., Pagliaro L., Morgenstern D., Dayyani F. Clinically meaningful use of blood tumor markers in oncology. Biomed Res Int 2016;2016: 9795269. DOI: 10.1155/2016/9795269. PMID: 28042579.Holdenrieder S., Pagliaro L., Morgenstern D., Dayyani F. Clinically meaningful use of blood tumor markers in oncology. Biomed Res Int 2016;2016: 9795269. DOI: 10.1155/2016/9795269. PMID: 28042579.3. Duffy M.J., O’Donovan N., McDermott E., Crown J. Validated biomarkers: the key to precision treatment in patients with breast cancer. Breast 2016;29:192–201. DOI: 10.1016/j.breast.2016.07.009. PMID: 27521224.Duffy M.J., O’Donovan N., McDermott E., Crown J. Validated biomarkers: the key to precision treatment in patients with breast cancer. Breast 2016;29:192–201. DOI: 10.1016/j.breast.2016.07.009. PMID: 27521224.4. Залетаев Д.В., Стрельников В.В., Немцова М.В. и др. Структурно-функциональный анализ опухолевых геномов и разработка тест-систем для ран- ней диагностики, прогноза течения и оптимизации терапии злокачественных новообразований. Вестник РАМН 2013;9:7–14. [Zaletaev D.V., Strelnikov V.V., Nemtsov M.V. et al. Structural and functional analysis of tumor genomes and the development of test systems for early diagnosis, prognosis and cancer therapy optimization. Vestnik RAMN = Annals of the Russian Academy of Medical Sciences 2013;9:7–14. (In Russ.)].Залетаев Д.В., Стрельников В.В., Немцова М.В. и др. Структурно-функциональный анализ опухолевых геномов и разработка тест-систем для ран- ней диагностики, прогноза течения и оптимизации терапии злокачественных новообразований. Вестник РАМН 2013;9:7–14. [Zaletaev D.V., Strelnikov V.V., Nemtsov M.V. et al. Structural and functional analysis of tumor genomes and the development of test systems for early diagnosis, prognosis and cancer therapy optimization. Vestnik RAMN = Annals of the Russian Academy of Medical Sciences 2013;9:7–14. (In Russ.)].5. Kamel H.F.M., Al-Amodi H.S.A.B. Exploitation of gene expression and cancer biomarkers in paving the path to era of personalized medicine. Genomics Proteomics Bioinformatics 2017;15(4):220–35. DOI: 10.1016/j.gpb.2016.11.005. PMID: 28813639.Kamel H.F.M., Al-Amodi H.S.A.B. Exploitation of gene expression and cancer biomarkers in paving the path to era of personalized medicine. Genomics Proteomics Bioinformatics 2017;15(4):220–35. DOI: 10.1016/j.gpb.2016.11.005. PMID: 28813639.6. Cree I.A., Charlton P. Molecular chess? Hallmarks of anti-cancer drug resistance. BMC Cancer 2017;17(1):10. DOI: 10.1186/s12885-016-2999-1. PMID: 28056859.Cree I.A., Charlton P. Molecular chess? Hallmarks of anti-cancer drug resistance. BMC Cancer 2017;17(1):10. DOI: 10.1186/s12885-016-2999-1. PMID: 28056859.7. Эпигенетика. Под ред. С.Д. Эллиса, Т. Дженювейна, Д. Рейнберга, М.Л. Капаррос. М.: Техносфера, 2010. С. 495. [Epigenetics. Eds. C.D. Allis, T. Jenuwein, D. Reinberg, M.L. Caparros. Moscow: Tekhnosphera, 2010. P. 495. (In Russ.)].Эпигенетика. Под ред. С.Д. Эллиса, Т. Дженювейна, Д. Рейнберга, М.Л. Капаррос. М.: Техносфера, 2010. С. 495. [Epigenetics. Eds. C.D. Allis, T. Jenuwein, D. Reinberg, M.L. Caparros. Moscow: Tekhnosphera, 2010. P. 495. (In Russ.)].8. Колесникова Т.Д. Механизмы про- странственно-временной регуляции репликации. Молекулярная биология 2013;47(1):12–37. [Kolesnikova T.D. Regulation of DNA replication timing. Molekulyarnaya biologiya = Molecular Biology 2013;47(1):12–37. (In Russ.)]. DOI: 10.7868/S0026898412060110.Колесникова Т.Д. Механизмы про- странственно-временной регуляции репликации. Молекулярная биология 2013;47(1):12–37. [Kolesnikova T.D. Regulation of DNA replication timing. Molekulyarnaya biologiya = Molecular Biology 2013;47(1):12–37. (In Russ.)]. DOI: 10.7868/S0026898412060110.9. Dimitrova D.S., Gilbert D.M. The spatial position and replication timing of chromosomal domains are both established in early G1 phase. Mol Cell 1999;4(6):983–93. DOI: 10.1016/S1097-2765(00)80227-0. PMID: 10635323.Dimitrova D.S., Gilbert D.M. The spatial position and replication timing of chromosomal domains are both established in early G1 phase. Mol Cell 1999;4(6):983–93. DOI: 10.1016/S1097-2765(00)80227-0. PMID: 10635323.10. Sadoni N., Cardoso M.C., Stelzer E.H. et al. Stable chromosomal units determine the spatial and temporal organization of DNA replication. J Cell Sci 2004;117 (Pt 22):5353–65. DOI: 10.1242/jcs.01412. PMID: 15466893.Sadoni N., Cardoso M.C., Stelzer E.H. et al. Stable chromosomal units determine the spatial and temporal organization of DNA replication. J Cell Sci 2004;117 (Pt 22):5353–65. DOI: 10.1242/jcs.01412. PMID: 15466893.11. Hiratani I., Gilbert D.M. Replication timing as an epigenetic mark. Epigenetics 2009;4(2):93–7. DOI: 10.4161/ epi.4.2.7772. PMID: 19242104.Hiratani I., Gilbert D.M. Replication timing as an epigenetic mark. Epigenetics 2009;4(2):93–7. DOI: 10.4161/ epi.4.2.7772. PMID: 19242104.12. Pope B.D., Gilbert D.M. The replication domain model: regulating replicon firing in the context of large-scale chromosome architecture. J Mol Biol 2013;425(23): 4690–5. DOI: 10.1016/j.jmb.2013.04.014. PMID: 23603017.Pope B.D., Gilbert D.M. The replication domain model: regulating replicon firing in the context of large-scale chromosome architecture. J Mol Biol 2013;425(23): 4690–5. DOI: 10.1016/j.jmb.2013.04.014. PMID: 23603017.13. Gilbert D.M. Cell fate transitions and the replication timing decision point. J Cell Biol 2010;191(5):899–903. DOI: 10.1083/jcb.201007125. PMID: 21115801.Gilbert D.M. Cell fate transitions and the replication timing decision point. J Cell Biol 2010;191(5):899–903. DOI: 10.1083/jcb.201007125. PMID: 21115801.14. Reddy K.L., Feinberg A.P. Higher order chromatin organization in cancer. Semin Cancer Biol 2013;23(2):109–15. DOI: 10.1016/j.semcancer.2012.12.001. PMID: 23266653.Reddy K.L., Feinberg A.P. Higher order chromatin organization in cancer. Semin Cancer Biol 2013;23(2):109–15. DOI: 10.1016/j.semcancer.2012.12.001. PMID: 23266653.15. Loupart M., Krause S., Heck M.S. Aberrant replication timing induces defective chromosome condensation in Drosophila ORC2 mutants. Curr Biol 2000;10(24):1547–56. DOI: 10.1016/S0960-9822(00)00844-7. PMID: 11137005.Loupart M., Krause S., Heck M.S. Aberrant replication timing induces defective chromosome condensation in Drosophila ORC2 mutants. Curr Biol 2000;10(24):1547–56. DOI: 10.1016/S0960-9822(00)00844-7. PMID: 11137005.16. Pflumm M.F., Botchan M.R. Orc mutants arrest in metaphase with abnormally condensed chromosomes. Development 2001;128(9):1697–707. PMID: 11290306.Pflumm M.F., Botchan M.R. Orc mutants arrest in metaphase with abnormally condensed chromosomes. Development 2001;128(9):1697–707. PMID: 11290306.17. Breger K.S., Smith L., Thayer M.J. Engineering translocations with delayed replication: evidence for cis control of chromosome replication timing. Hum Mol Genet 2005;14(19):2813–27. DOI: 10.1093/hmg/ddi314. PMID: 16115817.Breger K.S., Smith L., Thayer M.J. Engineering translocations with delayed replication: evidence for cis control of chromosome replication timing. Hum Mol Genet 2005;14(19):2813–27. DOI: 10.1093/hmg/ddi314. PMID: 16115817.18. Chang B.H., Smith L., Huang J., Thayer M.J. Chromosomes with delayed replication timing lead to checkpoint activation, delayed recruitment of Aurora B and chromosome instability. Oncogene 2007;26(13):1852–61. DOI: 10.1038/sj.onc.1209995. PMID: 17001311.Chang B.H., Smith L., Huang J., Thayer M.J. Chromosomes with delayed replication timing lead to checkpoint activation, delayed recruitment of Aurora B and chromosome instability. Oncogene 2007;26(13):1852–61. DOI: 10.1038/sj.onc.1209995. PMID: 17001311.19. Lang G.I., Murray A.W. Mutation rates across budding yeast chromosome VI are correlated with replication timing. Genome Biol Evol 2011;3:799–811. DOI: 10.1093/gbe/evr054. PMID: 21666225.Lang G.I., Murray A.W. Mutation rates across budding yeast chromosome VI are correlated with replication timing. Genome Biol Evol 2011;3:799–811. DOI: 10.1093/gbe/evr054. PMID: 21666225.20. Donley N., Stoffregen E.P., Smith L. et al. Asynchronous replication, mono-allelic expression, and long range Cis-effects of ASAR6. PLoS Genet 2013;9(4):e1003423. DOI: 10.1371/ journal.pgen.1003423. PMID: 23593023.Donley N., Stoffregen E.P., Smith L. et al. Asynchronous replication, mono-allelic expression, and long range Cis-effects of ASAR6. PLoS Genet 2013;9(4):e1003423. DOI: 10.1371/ journal.pgen.1003423. PMID: 23593023.21. De S., Michor F. DNA replication timing and long-range DNA interactions predict mutational landscapes of cancer genomes. Nat Biotechnol 2011;29(11):1103–8. DOI: 10.1038/nbt.2030. PMID: 22101487.De S., Michor F. DNA replication timing and long-range DNA interactions predict mutational landscapes of cancer genomes. Nat Biotechnol 2011;29(11):1103–8. DOI: 10.1038/nbt.2030. PMID: 22101487.22. Woo Y.H., Li W.H. DNA replication timing and selection shape the landscape of nucleotide variation in cancer genomes. Nat Commun 2012;3:1004. DOI: 10.1038/ ncomms1982. PMID: 22893128.Woo Y.H., Li W.H. DNA replication timing and selection shape the landscape of nucleotide variation in cancer genomes. Nat Commun 2012;3:1004. DOI: 10.1038/ ncomms1982. PMID: 22893128.23. Soutoglou E., Misteli T. On the contribution of spatial genome organization to cancerous chromosome translocations. J Natl Cancer Inst Monogr 2008;(39):16–9. DOI: 10.1093/jncimonographs/lgn017. PMID: 18647996.Soutoglou E., Misteli T. On the contribution of spatial genome organization to cancerous chromosome translocations. J Natl Cancer Inst Monogr 2008;(39):16–9. DOI: 10.1093/jncimonographs/lgn017. PMID: 18647996.24. Engreitz J.M., Agarwala V., Mirny L.A. Three-dimensional genome architecture influences partner selection for chromosomal translocations in human disease. PLoS One 2012;7(9):e44196. DOI: 10.1371/journal.pone.0044196. PMID: 23028501.Engreitz J.M., Agarwala V., Mirny L.A. Three-dimensional genome architecture influences partner selection for chromosomal translocations in human disease. PLoS One 2012;7(9):e44196. DOI: 10.1371/journal.pone.0044196. PMID: 23028501.25. Meaburn K.J., Misteli T., Soutoglou E. Spatial genome organization in the formation of chromosomal translocations. Semin Cancer Biol 2007;17(1):80–90. DOI: 10.1016/j.semcancer.2006.10.008. PMID: 17137790.Meaburn K.J., Misteli T., Soutoglou E. Spatial genome organization in the formation of chromosomal translocations. Semin Cancer Biol 2007;17(1):80–90. DOI: 10.1016/j.semcancer.2006.10.008. PMID: 17137790.26. Ozeri-Galai E., Bester A.C., Kerem B. The complex basis underlying common fragile site instability in cancer. Trends Genet 2012;28(6):295–302. DOI: 10.1016/j.tig.2012.02.006. PMID: 22465609.Ozeri-Galai E., Bester A.C., Kerem B. The complex basis underlying common fragile site instability in cancer. Trends Genet 2012;28(6):295–302. DOI: 10.1016/j.tig.2012.02.006. PMID: 22465609.27. Simon I., Tenzen T., Reubinoff B.E. et al. Asynchronous replication of imprinted genes is established in the gametes and maintained during development. Nature 1999;401(6756):929–32. DOI: 10.1038/44866. PMID: 10553911.Simon I., Tenzen T., Reubinoff B.E. et al. Asynchronous replication of imprinted genes is established in the gametes and maintained during development. Nature 1999;401(6756):929–32. DOI: 10.1038/44866. PMID: 10553911.28. Gunaratne P.H., Nakao M., Ledbetter D.H. et al. Tissue-specific and allele-specific replication timing control in the imprinted human Prader-Willi syndrome region. Genes Dev 1995;9(7):808–20. DOI: 10.1101/ gad.9.7.808. PMID: 7705658.Gunaratne P.H., Nakao M., Ledbetter D.H. et al. Tissue-specific and allele-specific replication timing control in the imprinted human Prader-Willi syndrome region. Genes Dev 1995;9(7):808–20. DOI: 10.1101/ gad.9.7.808. PMID: 7705658.29. LaSalle J.M., Lalande M. Domain organization of allele-specific replication within the GABRB3 gene cluster requires a biparental 15q11–13 contribution. Nat Genet 1995;9(4):386–94. DOI: 10.1038/ng0495-386. PMID: 7795644.LaSalle J.M., Lalande M. Domain organization of allele-specific replication within the GABRB3 gene cluster requires a biparental 15q11–13 contribution. Nat Genet 1995;9(4):386–94. DOI: 10.1038/ng0495-386. PMID: 7795644.30. Torchia B.S., Call L.M., Migeon B.R. DNA replication analysis of FMR1, XIST, and factor 8C loci by FISH shows nontranscribed X-linked genes replicate late. Am J Hum Genet 1994;55(1):96–104. PMID: 8023856.Torchia B.S., Call L.M., Migeon B.R. DNA replication analysis of FMR1, XIST, and factor 8C loci by FISH shows nontranscribed X-linked genes replicate late. Am J Hum Genet 1994;55(1):96–104. PMID: 8023856.31. Yeshaya J., Shalgi R., Shohat M., Avivi L. FISH-detected delay in replication timing of mutated FMR1 alleles on both active and inactive X-chromosomes. Hum Genet 1999;105(1–2):86–97. DOI: 10.1007/s004399900081. PMID: 10480360.Yeshaya J., Shalgi R., Shohat M., Avivi L. FISH-detected delay in replication timing of mutated FMR1 alleles on both active and inactive X-chromosomes. Hum Genet 1999;105(1–2):86–97. DOI: 10.1007/s004399900081. PMID: 10480360.32. Koren A., McCarroll S.A. Random replication of the inactive X chromosome. Genome Res 2014;24(1):64–9. DOI: 10.1101/gr.161828.113. PMID: 24065775.Koren A., McCarroll S.A. Random replication of the inactive X chromosome. Genome Res 2014;24(1):64–9. DOI: 10.1101/gr.161828.113. PMID: 24065775.33. Goldmit M., Bergman Y. Monoallelic gene expression: a repertoire of recurrent themes. Immun Rev 2004;200(1):197–214. DOI: 10.1111/j.0105-2896.2004.00158.x. PMID: 15242406.Goldmit M., Bergman Y. Monoallelic gene expression: a repertoire of recurrent themes. Immun Rev 2004;200(1):197–214. DOI: 10.1111/j.0105-2896.2004.00158.x. PMID: 15242406.34. Chess A., Simon I., Cedar H., Axel R. Allelic inactivation regulates olfactory receptor gene expression. Cell 1994;78(5):823–34. DOI: 10.1016/S0092-8674(94)90562-2. PMID: 8087849.Chess A., Simon I., Cedar H., Axel R. Allelic inactivation regulates olfactory receptor gene expression. Cell 1994;78(5):823–34. DOI: 10.1016/S0092-8674(94)90562-2. PMID: 8087849.35. Mostoslavsky R., Singh N., Tenzen T. et al. Asynchronous replication and allelic exclusion in the immune system. Nature 2001;414(6860):221–5. DOI: 10.1038/35102606. PMID: 11700561.Mostoslavsky R., Singh N., Tenzen T. et al. Asynchronous replication and allelic exclusion in the immune system. Nature 2001;414(6860):221–5. DOI: 10.1038/35102606. PMID: 11700561.36. Ensminger A.W., Chess A. Coordinated replication timing of monoallelically expressed genes along human autosomes. Hum Mol Genet 2004;13(6):651–8. DOI: 10.1093/hmg/ddh062. PMID: 14734625.Ensminger A.W., Chess A. Coordinated replication timing of monoallelically expressed genes along human autosomes. Hum Mol Genet 2004;13(6):651–8. DOI: 10.1093/hmg/ddh062. PMID: 14734625.37. Gribnau J., Hochedlinger K., Hata K. et al. Asynchronous replication timing of imprinted loci is independent of DNA methylation, but consistent with differential subnuclear localization. Genes Dev 2003;17(6):759–3. DOI: 10.1101/gad.1059603. PMID: 12651894.Gribnau J., Hochedlinger K., Hata K. et al. Asynchronous replication timing of imprinted loci is independent of DNA methylation, but consistent with differential subnuclear localization. Genes Dev 2003;17(6):759–3. DOI: 10.1101/gad.1059603. PMID: 12651894.38. Bergman Y., Cedar H. A stepwise epigenetic process controls immunoglobulin allelic exclusion. Nat Rev Immun 2004;4(10):754–61. DOI: 10.1038/nri1458. PMID: 15459667.Bergman Y., Cedar H. A stepwise epigenetic process controls immunoglobulin allelic exclusion. Nat Rev Immun 2004;4(10):754–61. DOI: 10.1038/nri1458. PMID: 15459667.39. Donley N., Thayer M.J. DNA replication timing, genome stability and cancer: late and/or delayed DNA replication timing is associated with increased genomic instability. Semin Cancer Biol 2013;23(2):80–9. DOI: 10.1016/ j.semcancer.2013.01.001. PMID: 23327985.Donley N., Thayer M.J. DNA replication timing, genome stability and cancer: late and/or delayed DNA replication timing is associated with increased genomic instability. Semin Cancer Biol 2013;23(2):80–9. DOI: 10.1016/ j.semcancer.2013.01.001. PMID: 23327985.40. Liu L., De S., Michor F. DNA replication timing and higher-order nuclear organization determine single-nucleotide substitution patterns in cancer genomes. Nat Commun 2013;4:1502. DOI: 10.1038/ncomms2502. PMID: 23422670.Liu L., De S., Michor F. DNA replication timing and higher-order nuclear organization determine single-nucleotide substitution patterns in cancer genomes. Nat Commun 2013;4:1502. DOI: 10.1038/ncomms2502. PMID: 23422670.41. Tomasetti C., Li L., Vogelstein B. Stem cell divisions, somatic mutations, cancer etiology, and cancer prevention. Science 2017;355(6331):1330–4. DOI: 10.1126/science.aaf9011. PMID: 28336671.Tomasetti C., Li L., Vogelstein B. Stem cell divisions, somatic mutations, cancer etiology, and cancer prevention. Science 2017;355(6331):1330–4. DOI: 10.1126/science.aaf9011. PMID: 28336671.42. Ryba T., Battaglia D., Chang B.H. et al. Abnormal developmental control of replication-timing domains in pediatric acute lymphoblastic leukemia. Genome Res 2012;22(10):1833–44. DOI: 10.1101/gr.138511.112. PMID: 22628462.Ryba T., Battaglia D., Chang B.H. et al. Abnormal developmental control of replication-timing domains in pediatric acute lymphoblastic leukemia. Genome Res 2012;22(10):1833–44. DOI: 10.1101/gr.138511.112. PMID: 22628462.43. Selig S., Okumura K., Ward D.C., Cedar H. Delineation of DNA replication time zones by fluorescence in situ hybridization. EMBO J 1992;11(3):1217–25. DOI: 10.1016/0962-8924(92)90032-I. PMID: 1547781.Selig S., Okumura K., Ward D.C., Cedar H. Delineation of DNA replication time zones by fluorescence in situ hybridization. EMBO J 1992;11(3):1217–25. DOI: 10.1016/0962-8924(92)90032-I. PMID: 1547781.44. Amiel A., Litmanovich T., Gaber E. et al. Asynchronous replication of p53 and 21q22 loci in chronic lymphocytic leukemia. Hum Genet 1997;101(2):219–22. DOI: 10.1007/s004390050619. PMID: 9402974.Amiel A., Litmanovich T., Gaber E. et al. Asynchronous replication of p53 and 21q22 loci in chronic lymphocytic leukemia. Hum Genet 1997;101(2):219–22. DOI: 10.1007/s004390050619. PMID: 9402974.45. Amiel A., Litmanovitch T., Lishner M. et al. Temporal differences in replication timing of homologous loci in malignant cells derived from CML and lymphoma patients. Genes Chromosomes Cancer 1998;22(3):225–31. DOI: 10.1002/ (SICI)1098-2264(199807)22:33.0.CO;2-Y. PMID: 9624534.Amiel A., Litmanovitch T., Lishner M. et al. Temporal differences in replication timing of homologous loci in malignant cells derived from CML and lymphoma patients. Genes Chromosomes Cancer 1998;22(3):225–31. DOI: 10.1002/ (SICI)1098-2264(199807)22:33.0.CO;2-Y. PMID: 9624534.46. Dotan Z.A., Dotan A., Litmanovitch T. et al. Modification in the inherent mode of allelic replication in lymphocytes of patients suffering from renal cell carcinoma: a novel genetic alteration associated with malignancy. Genes Chromosomes Cancer 2000;27(3):270–7. DOI: 10.1002/(SICI)1098-2264(200003) 27:33.0.CO;2-7. PMID: 10679916.Dotan Z.A., Dotan A., Litmanovitch T. et al. Modification in the inherent mode of allelic replication in lymphocytes of patients suffering from renal cell carcinoma: a novel genetic alteration associated with malignancy. Genes Chromosomes Cancer 2000;27(3):270–7. DOI: 10.1002/(SICI)1098-2264(200003) 27:33.0.CO;2-7. PMID: 10679916.47. Reish O., Orlovski A., Mashevich M. et al. Modified allelic replication in lymphocytes of patients with neurofibromatosis type 1. Cancer Genet Cytogenet 2003;143(2):133–9. DOI: 10.1016/S0165-4608(02)00858-0. PMID: 12781447.Reish O., Orlovski A., Mashevich M. et al. Modified allelic replication in lymphocytes of patients with neurofibromatosis type 1. Cancer Genet Cytogenet 2003;143(2):133–9. DOI: 10.1016/S0165-4608(02)00858-0. PMID: 12781447.48. Nagler A., Cytron S., Mashevich M. et al. The aberrant asynchronous replication – characterizing lymphocytes of cancer patients – is erased following stem cell transplantation. BMC Cancer 2010;10(1):230. DOI: 10.1186/ 1471-2407-10-230. PMID: 20497575.Nagler A., Cytron S., Mashevich M. et al. The aberrant asynchronous replication – characterizing lymphocytes of cancer patients – is erased following stem cell transplantation. BMC Cancer 2010;10(1):230. DOI: 10.1186/ 1471-2407-10-230. PMID: 20497575.49. Dotan Z.A., Dotan A., Ramon J., Avivi L. Altered mode of allelic replication accompanied by aneuploidy in peripheral blood lymphocytes of prostate cancer patients. Int J Cancer 2004;111(1):60–6. DOI: 10.1002/ijc.20237. PMID: 15185343.Dotan Z.A., Dotan A., Ramon J., Avivi L. Altered mode of allelic replication accompanied by aneuploidy in peripheral blood lymphocytes of prostate cancer patients. Int J Cancer 2004;111(1):60–6. DOI: 10.1002/ijc.20237. PMID: 15185343.50. Grinberg-Rashi H., Cytron S., GelmanKohan Z. et al. Replication timing aberrations and aneuploidy in peripheral blood lymphocytes of breast cancer patients. Neoplasia 2010;12(8):668–74. DOI: 10.1593/neo.10568. PMID: 20689761.Grinberg-Rashi H., Cytron S., GelmanKohan Z. et al. Replication timing aberrations and aneuploidy in peripheral blood lymphocytes of breast cancer patients. Neoplasia 2010;12(8):668–74. DOI: 10.1593/neo.10568. PMID: 20689761.51. Litmanovitch T., Altaras M.M., Dotan A., Avivi L. Asynchronous replication of homologous alpha-satellite DNA loci in man is associated with nondisjunction. Cytogenet Cell Genet 1998;81(1):26–35. DOI: 10.1159/000015003. PMID: 9691171.Litmanovitch T., Altaras M.M., Dotan A., Avivi L. Asynchronous replication of homologous alpha-satellite DNA loci in man is associated with nondisjunction. Cytogenet Cell Genet 1998;81(1):26–35. DOI: 10.1159/000015003. PMID: 9691171.52. Korenstein-Ilan A., Amiel A., Lalezari S. et al. Allele-specific replication associated with aneuploidy in blood cells of patients with hematologic malignancies. Cancer Genet Cytogenet 2002;139(2):97–103. DOI: 10.1016/S0165-4608(02)00610-6. PMID: 12550768.Korenstein-Ilan A., Amiel A., Lalezari S. et al. Allele-specific replication associated with aneuploidy in blood cells of patients with hematologic malignancies. Cancer Genet Cytogenet 2002;139(2):97–103. DOI: 10.1016/S0165-4608(02)00610-6. PMID: 12550768.53. Dotan Z.A., Dotan A., Ramon J., Avivi L. Aberrant allele-specific replication, independent of parental origin, in blood cells of cancer patients. BMC Cancer 2008;8(1):390. DOI: 10.1186/1471-2407-8-390. PMID: 19109880.Dotan Z.A., Dotan A., Ramon J., Avivi L. Aberrant allele-specific replication, independent of parental origin, in blood cells of cancer patients. BMC Cancer 2008;8(1):390. DOI: 10.1186/1471-2407-8-390. PMID: 19109880.54. Hanna M.O., Zayed N.A., Darwish H., Girgis S.I. Asynchronous DNA replication and aneuploidy in lymphocytes of hepatocellular carcinoma patients. Cancer Genet 2012;205(12):636–43. DOI: 10.1016/j.cancergen.2012.10.006. PMID: 23182962.Hanna M.O., Zayed N.A., Darwish H., Girgis S.I. Asynchronous DNA replication and aneuploidy in lymphocytes of hepatocellular carcinoma patients. Cancer Genet 2012;205(12):636–43. DOI: 10.1016/j.cancergen.2012.10.006. PMID: 23182962.55. Amiel A., Kirgner I., Gaber E. et al. Replication pattern in cancer: asynchronous replication in multiple myeloma and in monoclonal gammopathy. Cancer Genet Cytogenet 1999;108(1):32–7. DOI: 10.1016/S0165-4608(98)00107-1. PMID: 9973921.Amiel A., Kirgner I., Gaber E. et al. Replication pattern in cancer: asynchronous replication in multiple myeloma and in monoclonal gammopathy. Cancer Genet Cytogenet 1999;108(1):32–7. DOI: 10.1016/S0165-4608(98)00107-1. PMID: 9973921.56. Amiel A., Kitay-Cohen Y., Fejgin M.D., Lishner M. Replication status as a marker for predisposition for lymphoma in patients with chronic hepatitis C with and without cryoglobulinemia. Exp Hematol 2000;28(2):156–60. DOI: 10.1016/S0301-472X(99)00140-X. PMID: 10706071.Amiel A., Kitay-Cohen Y., Fejgin M.D., Lishner M. Replication status as a marker for predisposition for lymphoma in patients with chronic hepatitis C with and without cryoglobulinemia. Exp Hematol 2000;28(2):156–60. DOI: 10.1016/S0301-472X(99)00140-X. PMID: 10706071.57. Cytron S., Stepnov E., Bounkin I. et al. Epigenetic analyses in blood cells of men suspected of prostate cancer predict the outcome of biopsy better than serum PSA levels. Clin Epigenetics 2011;2(2):383–8. DOI: 10.1007/ s13148-011-0029-3. PMID: 21949550.Cytron S., Stepnov E., Bounkin I. et al. Epigenetic analyses in blood cells of men suspected of prostate cancer predict the outcome of biopsy better than serum PSA levels. Clin Epigenetics 2011;2(2):383–8. DOI: 10.1007/ s13148-011-0029-3. PMID: 21949550.58. Amiel A., Elis A., Maimon O. et al. Replication status in leukocytes of treated and untreated patients with polycythemia vera and essential thrombocytosis. Cancer Genet Cytogenet 2002;133(1):34–8. DOI: 10.1016/S0165-4608(01)00560-X. PMID: 11890987.Amiel A., Elis A., Maimon O. et al. Replication status in leukocytes of treated and untreated patients with polycythemia vera and essential thrombocytosis. Cancer Genet Cytogenet 2002;133(1):34–8. DOI: 10.1016/S0165-4608(01)00560-X. PMID: 11890987.59. Fritz A., Sinha S., Marella N., Berezney R. Alterations in replication timing of cancer-related genes in malignant human breast cancer cells. J Cell Biochem 2013;114(5):1074–83. DOI: 10.1002/jcb.24447. PMID: 23161755.Fritz A., Sinha S., Marella N., Berezney R. Alterations in replication timing of cancer-related genes in malignant human breast cancer cells. J Cell Biochem 2013;114(5):1074–83. DOI: 10.1002/jcb.24447. PMID: 23161755.