Advances in Molecular OncologyAdvances in Molecular OncologyУспехи молекулярной онкологии2313-805X2413-3787Publishing House ABV Press9210.17650/2313-805X-2017-4-2-26-35REVIEW ARTICLESОБЗОРНЫЕ СТАТЬИCancer as a result of genetic mosaicismРак как следствие генетического мозаицизмаLikhtensteynA. V.ЛихтенштейнА. В.
Russian Federation

24 Kashirskoe Shosse, Moscow 115478

115478 Москва, Каширское шоссе, 24

alicht@mail.ruResearch Institute of Carcinogenesis, N.N. Blokhin Russian Cancer Research Center, Ministry of Health of RussiaНИИ канцерогенеза ФГБУ «Российский онкологический научный центр им. Н.Н. Блохина» Минздрава России1505201742263530062017Copyright ©; 2017, Likhtensteyn A.V.Copyright ©; 2017, Лихтенштейн А.В.2017Likhtensteyn A.V.Лихтенштейн А.В.https://creativecommons.org/licenses/by/4.0https://umo.abvpress.ru/jour/article/view/92

Contrary to the generally accepted opinion about stable DNA as the carrier of hereditary information, in a normal (not just cancer) cell, this molecule is subject to the continuous changes as a result of copying errors (in the course of replication), defects of chromosome segregation (in mitosis) and direct chemical attacks (by reactive oxygen species). Genetic diversification of cells starts during embryonic development and lasts during whole life, generating a phenomenon of the somatic mosaicism. New data on genetic variety of somatic cells lead to a different, than earlier, perception of cancer etiology, pathogenesis and prevention.

Вопреки устоявшемуся мнению о стабильной ДНК как носителе наследственной информации, в нормальной (а не только раковой) клетке геном подвержен непрерывным изменениям в результате различных воздействий: ошибок копирования (в процессе репликации), дефектов сегрегации хромосом (в митозе) и прямых химических атак (активными формами кислорода). Процесс генетической диверсификации клеток стартует в эмбриональном развитии и длится всю жизнь, порождая феномен соматического мозаицизма. Новые представления о генетическом разнообразии клеток организма заставляют в ином, чем ранее, ракурсе рассматривать проблемы этиологии, патогенеза и профилактики злокачественных новообразований.

somatic mosaicismcancermutagenesiscarcinogenesiscancer preventiongenome sequencingсоматический мозаицизмракмутагенезканцерогенезпрофилактика ракасеквенирование генома1. Fernandez L.C., Torres M., Real F.X. Somatic mosaicism: on the road to cancer. Nat Rev Cancer 2016;16(1):43–55.Fernandez L.C., Torres M., Real F.X. Somatic mosaicism: on the road to cancer. Nat Rev Cancer 2016;16(1):43–55.2. Forsberg L.A., Gisselsson D., Dumanski J.P. Mosaicism in health and disease – clones picking up speed. Nat Rev Genet 2017;18(2):128–42.Forsberg L.A., Gisselsson D., Dumanski J.P. Mosaicism in health and disease – clones picking up speed. Nat Rev Genet 2017;18(2):128–42.3. Collins R.L., Brand H., Redin C.E. et al. Defining the diverse spectrum of inversions, complex structural variation, and chromothripsis in the morbid human genome. Genome Biol 2017;18(1):1–21.Collins R.L., Brand H., Redin C.E. et al. Defining the diverse spectrum of inversions, complex structural variation, and chromothripsis in the morbid human genome. Genome Biol 2017;18(1):1–21.4. McCulloch S. D., Kunkel T.A. The fidelity of DNA synthesis by eukaryotic replicative and translesion synthesis polymerases. Cell Res 2008;18(1):148–61.McCulloch S. D., Kunkel T.A. The fidelity of DNA synthesis by eukaryotic replicative and translesion synthesis polymerases. Cell Res 2008;18(1):148–61.5. Lynch M. Rate, molecular spectrum, and consequences of human mutation. Proc Natl Acad Sci U S A 2010;107(3):961–8.Lynch M. Rate, molecular spectrum, and consequences of human mutation. Proc Natl Acad Sci U S A 2010;107(3):961–8.6. Lynch M. Evolution of the mutation rate. Trends Genet 2010;26(8):345–52.Lynch M. Evolution of the mutation rate. Trends Genet 2010;26(8):345–52.7. Ju Y.S., Martincorena I., Gerstung M. et al. Somatic mutations reveal asymmetric cellular dynamics in the early human embryo. Nature 2017;543(7647):714–8.Ju Y.S., Martincorena I., Gerstung M. et al. Somatic mutations reveal asymmetric cellular dynamics in the early human embryo. Nature 2017;543(7647):714–8.8. Sender R., Fuchs S., Milo R. Revised estimates for the number of human and bacteria cells in the body. PLoS Biology 2016;14(8):e1002533.Sender R., Fuchs S., Milo R. Revised estimates for the number of human and bacteria cells in the body. PLoS Biology 2016;14(8):e1002533.9. Bianconi E., Piovesan A., Facchin F. et al. An estimation of the number of cells in the human body. Ann Hum Biol 2013;40(6):463–71.Bianconi E., Piovesan A., Facchin F. et al. An estimation of the number of cells in the human body. Ann Hum Biol 2013;40(6):463–71.10. Frank S.A., Nowak M.A. Cell biology: developmental predisposition to cancer. Nature 2003;422(6931):494.Frank S.A., Nowak M.A. Cell biology: developmental predisposition to cancer. Nature 2003;422(6931):494.11. Tomasetti C., Vogelstein B. Cancer etiology. Variation in cancer risk among tissues can be explained by the number of stem cell divisions. Science 2015;347(6217):78–81.Tomasetti C., Vogelstein B. Cancer etiology. Variation in cancer risk among tissues can be explained by the number of stem cell divisions. Science 2015;347(6217):78–81.12. Kurnosov A.A., Ustyugova S.V., Nazarov V.I. et al. The evidence for increased L1 activity in the site of human adult brain neurogenesis. PLoS One 2015;10(2):e0117854.Kurnosov A.A., Ustyugova S.V., Nazarov V.I. et al. The evidence for increased L1 activity in the site of human adult brain neurogenesis. PLoS One 2015;10(2):e0117854.13. Coufal N.G., Garcia-Perez J.L., Peng G.E. et al. L1 retrotransposition in human neural progenitor cells. Nature 2009;460(7259):1127–31.Coufal N.G., Garcia-Perez J.L., Peng G.E. et al. L1 retrotransposition in human neural progenitor cells. Nature 2009;460(7259):1127–31.14. Gonitel R., Moffitt H., Sathasivam K. et al. DNA instability in postmitotic neurons. Proc Natl Acad Sci USA 2008;105(9):3467–72.Gonitel R., Moffitt H., Sathasivam K. et al. DNA instability in postmitotic neurons. Proc Natl Acad Sci USA 2008;105(9):3467–72.15. Lieber M.R., Gu J., Lu H. et al. Nonhomologous DNA end joining (NHEJ) and chromosomal translocations in humans. Subcell Biochem 2010;50:279–96.Lieber M.R., Gu J., Lu H. et al. Nonhomologous DNA end joining (NHEJ) and chromosomal translocations in humans. Subcell Biochem 2010;50:279–96.16. Hastings P.J., Lupski J.R., Rosenberg S.M., Ira G. Mechanisms of change in gene copy number. Nat Rev Genet 2009;10(8):551–64.Hastings P.J., Lupski J.R., Rosenberg S.M., Ira G. Mechanisms of change in gene copy number. Nat Rev Genet 2009;10(8):551–64.17. Leslie R., O’Donnell C.J., Johnson A.D. GRASP: analysis of genotype-phenotype results from 1390 genome-wide association studies and corresponding open access database. Bioinformatics 2014;30(12):185–94.Leslie R., O’Donnell C.J., Johnson A.D. GRASP: analysis of genotype-phenotype results from 1390 genome-wide association studies and corresponding open access database. Bioinformatics 2014;30(12):185–94.18. Nowak M.A. Five rules for the evolution of cooperation. Science 2006;314(5805):1560–3.Nowak M.A. Five rules for the evolution of cooperation. Science 2006;314(5805):1560–3.19. Bissell M.J., Hines W.C. Why don’t we get more cancer? A proposed role of the microenvironment in restraining cancer progression. Nat Med 2011;17(3):320–9.Bissell M.J., Hines W.C. Why don’t we get more cancer? A proposed role of the microenvironment in restraining cancer progression. Nat Med 2011;17(3):320–9.20. Greaves M. Does everyone develop covert cancer? Nat Rev Cancer 2014;14(4): 209–10.Greaves M. Does everyone develop covert cancer? Nat Rev Cancer 2014;14(4): 209–10.21. Folkman J., Kalluri R. Cancer without disease. Nature 2004;427(6977):787.Folkman J., Kalluri R. Cancer without disease. Nature 2004;427(6977):787.22. Paget S. The distribution of secondary growths in cancer of the breast. Lancet 1889;133:571–3.Paget S. The distribution of secondary growths in cancer of the breast. Lancet 1889;133:571–3.23. Gupta G.P., Massague J. Cancer metastasis: building a framework. Cell 2006;127(4):679–95.Gupta G.P., Massague J. Cancer metastasis: building a framework. Cell 2006;127(4):679–95.24. Armitage P., Doll R. The age distribution of cancer and a multi-stage theory of carcinogenesis. Br J Cancer 1954;8:1–12.Armitage P., Doll R. The age distribution of cancer and a multi-stage theory of carcinogenesis. Br J Cancer 1954;8:1–12.25. Nowell P.C. The clonal evolution of tumor cell populations. Science 1976; 194(4260):23–8.Nowell P.C. The clonal evolution of tumor cell populations. Science 1976; 194(4260):23–8.26. Hanahan D., Coussens L.M. Accessories to the crime: functions of cells recruited to the tumor microenvironment. Cancer Cell 2012;21(3):309–22.Hanahan D., Coussens L.M. Accessories to the crime: functions of cells recruited to the tumor microenvironment. Cancer Cell 2012;21(3):309–22.27. DeClerck Y. A., Pienta K.J., Woodhouse E.C. et al. The tumor microenvironment at a turning point knowledge gained over the last decade, and challenges and opportunities ahead: a white paper from the NCI TME Network. Cancer Res 2017;77(5):1051–9.DeClerck Y. A., Pienta K.J., Woodhouse E.C. et al. The tumor microenvironment at a turning point knowledge gained over the last decade, and challenges and opportunities ahead: a white paper from the NCI TME Network. Cancer Res 2017;77(5):1051–9.28. Sonnenschein C., Soto A.M., Rangarajan A. et al. Competing views on cancer. J Biosci 2014;39(2):281–302.Sonnenschein C., Soto A.M., Rangarajan A. et al. Competing views on cancer. J Biosci 2014;39(2):281–302.29. Sonnenschein C., Soto A.M. The aging of the 2000 and 2011 Hallmarks of Cancer reviews: a critique. J Biosci 2013;38(3):651–63.Sonnenschein C., Soto A.M. The aging of the 2000 and 2011 Hallmarks of Cancer reviews: a critique. J Biosci 2013;38(3):651–63.30. Mintz B., Illmensee K. Normal genetically mosaic mice produced from malignant teratocarcinoma cells. Proc Natl Acad Sci USA 1975;72(9):3585–9.Mintz B., Illmensee K. Normal genetically mosaic mice produced from malignant teratocarcinoma cells. Proc Natl Acad Sci USA 1975;72(9):3585–9.31. Shachaf C.M., Kopelman A.M., Arvanitis C. et al. MYC inactivation uncovers pluripotent differentiation and tumour dormancy in hepatocellular cancer. Nature 2004;431(7012):1112–7.Shachaf C.M., Kopelman A.M., Arvanitis C. et al. MYC inactivation uncovers pluripotent differentiation and tumour dormancy in hepatocellular cancer. Nature 2004;431(7012):1112–7.32. Hendrix M.J., Seftor E.A., Seftor R.E. et al. Reprogramming metastatic tumour cells with embryonic microenvironments. Nat Rev Cancer 2007;7(4):246–55.Hendrix M.J., Seftor E.A., Seftor R.E. et al. Reprogramming metastatic tumour cells with embryonic microenvironments. Nat Rev Cancer 2007;7(4):246–55.33. Telerman A., Amson R. The molecular programme of tumour reversion: the steps beyond malignant transformation. Nat Rev Cancer 2009;9(3):206–16.Telerman A., Amson R. The molecular programme of tumour reversion: the steps beyond malignant transformation. Nat Rev Cancer 2009;9(3):206–16.34. Maffini M.V., Soto A.M., Calabro J.M. et al. The stroma as a crucial target in rat mammary gland carcinogenesis. J Cell Sci 2004;117(Pt 8):1495–502.Maffini M.V., Soto A.M., Calabro J.M. et al. The stroma as a crucial target in rat mammary gland carcinogenesis. J Cell Sci 2004;117(Pt 8):1495–502.35. Albini A., Sporn M.B. The tumour microenvironment as a target for chemoprevention. Nat Rev Cancer 2007;7(2):139–47.Albini A., Sporn M.B. The tumour microenvironment as a target for chemoprevention. Nat Rev Cancer 2007;7(2):139–47.36. Bhowmick N.A., Chytil A., Plieth D. et al. TGF-β signaling in fibroblasts modulates the oncogenic potential of adjacent epithelia. Science 2004;303(5659):848–51.Bhowmick N.A., Chytil A., Plieth D. et al. TGF-β signaling in fibroblasts modulates the oncogenic potential of adjacent epithelia. Science 2004;303(5659):848–51.37. Olumi A.F., Grossfeld G.D., Hayward S.W. et al. Carcinoma-associated fibroblasts direct tumor progression of initiated human prostatic epithelium. Cancer Res 1999;59(19):5002–11.Olumi A.F., Grossfeld G.D., Hayward S.W. et al. Carcinoma-associated fibroblasts direct tumor progression of initiated human prostatic epithelium. Cancer Res 1999;59(19):5002–11.38. Hayward S.W., Wang Y., Cao M. et al. Malignant transformation in a nontumorigenic human prostatic epithelial cell line. Cancer Res 2001;61(22):8135–42.Hayward S.W., Wang Y., Cao M. et al. Malignant transformation in a nontumorigenic human prostatic epithelial cell line. Cancer Res 2001;61(22):8135–42.39. Witz I.P. Yin-yang activities and vicious cycles in the tumor microenvironment. Cancer Research 2008;68(1):9–13.Witz I.P. Yin-yang activities and vicious cycles in the tumor microenvironment. Cancer Research 2008;68(1):9–13.40. Rak J. Extracellular vesicles – biomarkers and effectors of the cellular interactome in cancer. Front Pharmacol 2013;4:21.Rak J. Extracellular vesicles – biomarkers and effectors of the cellular interactome in cancer. Front Pharmacol 2013;4:21.41. Zhang L., Zhang S., Yao J. et al. Microenvironment-induced PTEN loss by exosomalZhang L., Zhang S., Yao J. et al. Microenvironment-induced PTEN loss by exosomalmicroRNA primes brain metastasis outgrowth. Nature 2015;527(7576): 100–4.42. Bindra R.S., Glazer P.M. Genetic instability and the tumor microenvironment: towards the concept of microenvironmentinduced mutagenesis. Mutat Res 2005;569(1–2):75–85.Bindra R.S., Glazer P.M. Genetic instability and the tumor microenvironment: towards the concept of microenvironmentinduced mutagenesis. Mutat Res 2005;569(1–2):75–85.43. Ishiguro K., Yoshida T., Yagishita H. et al. Epithelial and stromal genetic instability contributes to genesis of colorectal adenomas. Gut 2006;55(5):695–702.Ishiguro K., Yoshida T., Yagishita H. et al. Epithelial and stromal genetic instability contributes to genesis of colorectal adenomas. Gut 2006;55(5):695–702.44. Kim B.G., Li C., Qiao W. et al. Smad4 signalling in T cells is required for suppression of gastrointestinal cancer. Nature 2006;441(7096):1015–9.Kim B.G., Li C., Qiao W. et al. Smad4 signalling in T cells is required for suppression of gastrointestinal cancer. Nature 2006;441(7096):1015–9.45. Weber F., Shen L., Fukino K. et al. Totalgenome analysis of BRCA1/2-related invasive carcinomas of the breast identifies tumor stroma as potential landscaper for neoplastic initiation. Am J Hum Genet 2006;78(6):961–72.Weber F., Shen L., Fukino K. et al. Totalgenome analysis of BRCA1/2-related invasive carcinomas of the breast identifies tumor stroma as potential landscaper for neoplastic initiation. Am J Hum Genet 2006;78(6):961–72.46. Parrinello S., Coppe J.P., Krtolica A., Campisi J. Stromal-epithelial interactions in aging and cancer: senescent fibroblasts alter epithelial cell differentiation. J Cell Sci 2005;118(Pt 3):485–96.Parrinello S., Coppe J.P., Krtolica A., Campisi J. Stromal-epithelial interactions in aging and cancer: senescent fibroblasts alter epithelial cell differentiation. J Cell Sci 2005;118(Pt 3):485–96.47. Coppe J.P., Patil C.K., Rodier F. et al. Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS Biol 2008;6(12):2853–68.Coppe J.P., Patil C.K., Rodier F. et al. Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS Biol 2008;6(12):2853–68.48. Abyzov A., Mariani J., Palejev D. et al. Somatic copy number mosaicism in human skin revealed by induced pluripotent stem cells. Nature 2012;492(7429):438–42.Abyzov A., Mariani J., Palejev D. et al. Somatic copy number mosaicism in human skin revealed by induced pluripotent stem cells. Nature 2012;492(7429):438–42.49. Cai X., Evrony G.D., Lehmann H.S. et al. Single-cell, genome-wide sequencing identifies clonal somatic copy-number variation in the human brain. Cell Rep 2014;8(5):1280–9.Cai X., Evrony G.D., Lehmann H.S. et al. Single-cell, genome-wide sequencing identifies clonal somatic copy-number variation in the human brain. Cell Rep 2014;8(5):1280–9.50. Lodato M.A., Woodworth M.B., Lee S. et al. Somatic mutation in single human neurons tracks developmental and transcriptional history. Science 2015;350(6256):94–8.Lodato M.A., Woodworth M.B., Lee S. et al. Somatic mutation in single human neurons tracks developmental and transcriptional history. Science 2015;350(6256):94–8.51. Taylor T.H., Gitlin S.A., Patrick J.L. et al. The origin, mechanisms, incidence and clinical consequences of chromosomal mosaicism in humans. Hum Reprod Update 2014;20(4):571–81.Taylor T.H., Gitlin S.A., Patrick J.L. et al. The origin, mechanisms, incidence and clinical consequences of chromosomal mosaicism in humans. Hum Reprod Update 2014;20(4):571–81.52. Sims D., Sudbery I., Ilott N.E. et al. Sequencing depth and coverage: key considerations in genomic analyses. Nat Rev Genet 2014;15(2):121–32.Sims D., Sudbery I., Ilott N.E. et al. Sequencing depth and coverage: key considerations in genomic analyses. Nat Rev Genet 2014;15(2):121–32.53. Moreno E., Rhiner C. Darwin’s multicellularity: from neurotrophic theories and cell competition to fitness fingerprints. Curr Opin Cell Biol 2014;31:16–22.Moreno E., Rhiner C. Darwin’s multicellularity: from neurotrophic theories and cell competition to fitness fingerprints. Curr Opin Cell Biol 2014;31:16–22.54. Burrell R.A., McGranahan N., Bartek J. et al. The causes and consequences of genetic heterogeneity in cancer evolution. Nature 2013;501(7467):338–45.Burrell R.A., McGranahan N., Bartek J. et al. The causes and consequences of genetic heterogeneity in cancer evolution. Nature 2013;501(7467):338–45.55. Ghajar C.M., Peinado H., Mori H. et al. The perivascular niche regulates breast tumour dormancy. Nat Cell Biol 2013;15(7):807–17.Ghajar C.M., Peinado H., Mori H. et al. The perivascular niche regulates breast tumour dormancy. Nat Cell Biol 2013;15(7):807–17.56. Martincorena I., Roshan A., Gerstung M. et al. Tumor evolution. High burden and pervasive positive selection of somatic mutations in normal human skin. Science 2015;348(6237):880–6.Martincorena I., Roshan A., Gerstung M. et al. Tumor evolution. High burden and pervasive positive selection of somatic mutations in normal human skin. Science 2015;348(6237):880–6.57. Goriely A., Hansen R.M., Taylor I.B. et al. Activating mutations in FGFR3 and HRAS reveal a shared genetic origin for congenital disorders and testicular tumors. Nat Genet 2009;41(11):1247–52.Goriely A., Hansen R.M., Taylor I.B. et al. Activating mutations in FGFR3 and HRAS reveal a shared genetic origin for congenital disorders and testicular tumors. Nat Genet 2009;41(11):1247–52.58. Hao D., Wang L., Di L.J. Distinct mutation accumulation rates among tissues determine the variation in cancer risk. Sci Rep 2016;6:19458.Hao D., Wang L., Di L.J. Distinct mutation accumulation rates among tissues determine the variation in cancer risk. Sci Rep 2016;6:19458.59. Шабад Л.М. Некоторые общие сопоставления и закономерности развития предраковых изменений. В кн.: Предрак в экспериментально-морфологическом аспекте. М.: Медицина, 1967. C. 352–373. [Shabad L.M. Some common comparisons and patterns of development of precancerous changes. In book: Predak in the experimental-morphological aspect. Moscow: Meditsina, 1967. Pp. 352–373. (In Russ.)].Шабад Л.М. Некоторые общие сопоставления и закономерности развития предраковых изменений. В кн.: Предрак в экспериментально-морфологическом аспекте. М.: Медицина, 1967. C. 352–373. [Shabad L.M. Some common comparisons and patterns of development of precancerous changes. In book: Predak in the experimental-morphological aspect. Moscow: Meditsina, 1967. Pp. 352–373. (In Russ.)].60. Fisher R., Pusztai L., Swanton C. Cancer heterogeneity: implications for targeted therapeutics. Br J Cancer 2013;108(3):479–85.Fisher R., Pusztai L., Swanton C. Cancer heterogeneity: implications for targeted therapeutics. Br J Cancer 2013;108(3):479–85.61. Swanton C. Intratumor heterogeneity: evolution through space and time. Cancer Research 2012;72(19):4875–82.Swanton C. Intratumor heterogeneity: evolution through space and time. Cancer Research 2012;72(19):4875–82.62. Gerlinger M., Rowan A.J., Horswell S. et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med 2012;366(10):883–92.Gerlinger M., Rowan A.J., Horswell S. et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med 2012;366(10):883–92.63. Gould S.J., Eldredge N. Punctuated equilibrium comes of age. Nature 1993;366(6452):223–7.Gould S.J., Eldredge N. Punctuated equilibrium comes of age. Nature 1993;366(6452):223–7.64. Eldredge N., Gould S.J. On punctuated equilibria. Science 1997;276(5311):338–41.Eldredge N., Gould S.J. On punctuated equilibria. Science 1997;276(5311):338–41.65. Stepanenko A.A., Kavsan V.M. Evolutionary karyotypic theory of cancer versus conventional cancer gene mutation theory. Biopolymer Cell 2012;28:267–80.Stepanenko A.A., Kavsan V.M. Evolutionary karyotypic theory of cancer versus conventional cancer gene mutation theory. Biopolymer Cell 2012;28:267–80.66. Sato F., Saji S., Toi M. Genomic tumor evolution of breast cancer. Breast Cancer 2016;23(1):4–11.Sato F., Saji S., Toi M. Genomic tumor evolution of breast cancer. Breast Cancer 2016;23(1):4–11.67. Baca S.C., Prandi D., Lawrence M.S. et al. Punctuated evolution of prostate cancer genomes. Cell 2013;153(3):666–77.Baca S.C., Prandi D., Lawrence M.S. et al. Punctuated evolution of prostate cancer genomes. Cell 2013;153(3):666–77.68. Kim T.M., Xi R., Luquette L.J. et al. Functional genomic analysis of chromosomal aberrations in a compendium of 8000 cancer genomes. Genome Res 2013;23(2):217–27.Kim T.M., Xi R., Luquette L.J. et al. Functional genomic analysis of chromosomal aberrations in a compendium of 8000 cancer genomes. Genome Res 2013;23(2):217–27.69. Kloosterman W.P., Koster J., Molenaar J.J. Prevalence and clinical implications of chromothripsis in cancer genomes. Curr Opin Oncol 2014;26(1):64–72.Kloosterman W.P., Koster J., Molenaar J.J. Prevalence and clinical implications of chromothripsis in cancer genomes. Curr Opin Oncol 2014;26(1):64–72.70. Cross W.C., Graham T.A., Wright N.A. New paradigms in clonal evolution: punctuated equilibrium in cancer. J Pathol 2016;240(2):126–36.Cross W.C., Graham T.A., Wright N.A. New paradigms in clonal evolution: punctuated equilibrium in cancer. J Pathol 2016;240(2):126–36.71. Graham T.A., Sottoriva A. Measuring cancer evolution from the genome. J Pathol 2017;241(2):183–91.Graham T.A., Sottoriva A. Measuring cancer evolution from the genome. J Pathol 2017;241(2):183–91.72. Martincorena I., Campbell P.J. Somatic mutation in cancer and normal cells. Science 2015;349(6255):1483–9.Martincorena I., Campbell P.J. Somatic mutation in cancer and normal cells. Science 2015;349(6255):1483–9.73. Bunting S.F., Nussenzweig A. End-joining, translocations and cancer. Nat Rev Cancer 2013;13(7):443–54.Bunting S.F., Nussenzweig A. End-joining, translocations and cancer. Nat Rev Cancer 2013;13(7):443–54.74. Forment J.V., Kaidi A., Jackson S.P. Chromothripsis and cancer: causes and consequences of chromosome shattering. Nat Rev Cancer 2012;12(10):663–70.Forment J.V., Kaidi A., Jackson S.P. Chromothripsis and cancer: causes and consequences of chromosome shattering. Nat Rev Cancer 2012;12(10):663–70.75. Stephens P.J., Greenman C.D., Fu B. et al. Massive genomic rearrangement acquired in a single catastrophic event during cancer development. Cell 2011;144(1):27–40.Stephens P.J., Greenman C.D., Fu B. et al. Massive genomic rearrangement acquired in a single catastrophic event during cancer development. Cell 2011;144(1):27–40.76. Shen M.M. Chromoplexy: a new category of complex rearrangements in the cancer genome. Cancer Cell 2013;23(5):567–9.Shen M.M. Chromoplexy: a new category of complex rearrangements in the cancer genome. Cancer Cell 2013;23(5):567–9.77. Swanton C., McGranahan N., Starrett G.J. et al. APOBEC enzymes: mutagenic fuel for cancer evolution and heterogeneity. Cancer Discov 2015;5(7):704–12.Swanton C., McGranahan N., Starrett G.J. et al. APOBEC enzymes: mutagenic fuel for cancer evolution and heterogeneity. Cancer Discov 2015;5(7):704–12.78. Sottoriva A., Kang H., Ma Z. et al. A Big Bang model of human colorectal tumor growth. Nat Genet 2015;47(3):209–16.Sottoriva A., Kang H., Ma Z. et al. A Big Bang model of human colorectal tumor growth. Nat Genet 2015;47(3):209–16.79. Robertson-Tessi M., Anderson A.R. Big Bang and context-driven collapse. Nat Genet 2015;47(3):196–7.Robertson-Tessi M., Anderson A.R. Big Bang and context-driven collapse. Nat Genet 2015;47(3):196–7.80. Zilber L.A. On the interaction between tumor viruses and cells: a virogenetic concept of tumorigenesis. J Natl Cancer Inst 1961;26:1311–9.Zilber L.A. On the interaction between tumor viruses and cells: a virogenetic concept of tumorigenesis. J Natl Cancer Inst 1961;26:1311–9.81. Shabad L.M. Studies in the USSR on the distribution, circulation, and fate of carcinogenic hydrocarbons in the human environment and the role of their deposition in tissues in carcinogenesis: a review. Cancer Res 1967;27(6):1132–7.Shabad L.M. Studies in the USSR on the distribution, circulation, and fate of carcinogenic hydrocarbons in the human environment and the role of their deposition in tissues in carcinogenesis: a review. Cancer Res 1967;27(6):1132–7.82. Thilly W.G. Have environmental mutagens caused oncomutations in people? Nat Genet 2003;34(3):255–9.Thilly W.G. Have environmental mutagens caused oncomutations in people? Nat Genet 2003;34(3):255–9.83. Lichtenstein A.V. Cancer: bad luck or punishment? Biochemistry(Moscow) 2017;82(1):75–80.Lichtenstein A.V. Cancer: bad luck or punishment? Biochemistry(Moscow) 2017;82(1):75–80.84. Tomasetti C., Vogelstein B. Musings on the theory that variation in cancer risk among tissues can be explained by the number of divisions of normal stem cells. arXiv:1501.05035 2015.Tomasetti C., Vogelstein B. Musings on the theory that variation in cancer risk among tissues can be explained by the number of divisions of normal stem cells. arXiv:1501.05035 2015.85. Tomasetti C., Li L., Vogelstein B. Stem cell divisions, somatic mutations, cancer etiology, and cancer prevention. Science 2017;355(6331):1330–4.Tomasetti C., Li L., Vogelstein B. Stem cell divisions, somatic mutations, cancer etiology, and cancer prevention. Science 2017;355(6331):1330–4.86. Tomasetti C., Vogelstein B. Cancer risk: role of environment-response. Science 2015;347(6223):729–31.Tomasetti C., Vogelstein B. Cancer risk: role of environment-response. Science 2015;347(6223):729–31.87. Ashford N.A., Bauman P., Brown H.S. et al. Cancer risk: role of environment. Science 2015;347(6223):727.Ashford N.A., Bauman P., Brown H.S. et al. Cancer risk: role of environment. Science 2015;347(6223):727.88. Albini A., Cavuto S., Apolone G., Noonan D.M. Strategies to prevent “bad luck” in cancer. J Natl Cancer Inst 2015;107(10):1–7.Albini A., Cavuto S., Apolone G., Noonan D.M. Strategies to prevent “bad luck” in cancer. J Natl Cancer Inst 2015;107(10):1–7.89. Song M., Giovannucci E.L. Cancer risk: many factors contribute. Science 2015;347(6223):728–9.Song M., Giovannucci E.L. Cancer risk: many factors contribute. Science 2015;347(6223):728–9.90. Tarabichi M., Detours V. Comment on “Variation in cancer risk among tissues can be explained by the number of stem cell divisions”. bioRxiv 2015. DOI: http://dx.doi.org/10.1101/024497.Tarabichi M., Detours V. Comment on “Variation in cancer risk among tissues can be explained by the number of stem cell divisions”. bioRxiv 2015. DOI: http://dx.doi.org/10.1101/024497.91. Potter J.D., Prentice R.L. Cancer risk: tumors excluded. Science 2015;347(6223):727.Potter J.D., Prentice R.L. Cancer risk: tumors excluded. Science 2015;347(6223):727.92. Gotay C., Dummer T., Spinelli J. Cancer risk: prevention is crucial. Science 2015;347(6223):728.Gotay C., Dummer T., Spinelli J. Cancer risk: prevention is crucial. Science 2015;347(6223):728.93. Couzin-Frankel J. Biomedicine. The bad luck of cancer. Science 2015;347(6217):12.Couzin-Frankel J. Biomedicine. The bad luck of cancer. Science 2015;347(6217):12.94. Rozhok A.I., Wahl G.M., DeGregori J. A critical examination of the “bad luck” explanation of cancer risk. Cancer Prev Res(Phila) 2015;8:762–4.Rozhok A.I., Wahl G.M., DeGregori J. A critical examination of the “bad luck” explanation of cancer risk. Cancer Prev Res(Phila) 2015;8:762–4.95. Ledford H. Cancer studies clash over mechanisms of malignancy. Nature 2015;528(7582):317.Ledford H. Cancer studies clash over mechanisms of malignancy. Nature 2015;528(7582):317.96. Couzin-Frankel J. Science communication. Backlash greets “bad luck” cancer study and coverage. Science 2015;347(6219):224.Couzin-Frankel J. Science communication. Backlash greets “bad luck” cancer study and coverage. Science 2015;347(6219):224.97. O’Callaghan M. Cancer risk: accuracy of literature. Science 2015;347(6223):729.O’Callaghan M. Cancer risk: accuracy of literature. Science 2015;347(6223):729.98. Wu S., Powers S., Zhu W. et al. Substantial contribution of extrinsic risk factors to cancer development. Nature 2016;529(7584):43–7.Wu S., Powers S., Zhu W. et al. Substantial contribution of extrinsic risk factors to cancer development. Nature 2016;529(7584):43–7.99. Alderton G.K. Cancer risk: debating the odds. Nat Rev Cancer 2016;16(2):68.Alderton G.K. Cancer risk: debating the odds. Nat Rev Cancer 2016;16(2):68.100. Blokzijl F., de Ligt J., Jager M. et al. Tissue-specific mutation accumulation in human adult stem cells during life. Nature 2016;538(7624):260–4.Blokzijl F., de Ligt J., Jager M. et al. Tissue-specific mutation accumulation in human adult stem cells during life. Nature 2016;538(7624):260–4.101. Zhu L., Finkelstein D., Gao C. et al. Multi-organ mapping of cancer risk. Cell 2016;166(5):1132–46.Zhu L., Finkelstein D., Gao C. et al. Multi-organ mapping of cancer risk. Cell 2016;166(5):1132–46.102. Alekseenko I.V., Kuzmich A.I., Pleshkan V.V. et al. The cause of cancer mutations: improvable bad life or inevitable stochastic replication errors? Mol Biol (Mosk) 2016;50(6):906–21.Alekseenko I.V., Kuzmich A.I., Pleshkan V.V. et al. The cause of cancer mutations: improvable bad life or inevitable stochastic replication errors? Mol Biol (Mosk) 2016;50(6):906–21.103. Nowak M.A., Waclaw B. Genes, environment, and “bad luck”. Science 2017;355(6331):1266–7.Nowak M.A., Waclaw B. Genes, environment, and “bad luck”. Science 2017;355(6331):1266–7.104. Manskikh V.N. Do external or internal factors lead to tumor development? It is still unknown. Biochemistry (Mosc) 2017;82(1):81–5.Manskikh V.N. Do external or internal factors lead to tumor development? It is still unknown. Biochemistry (Mosc) 2017;82(1):81–5.105. Lichtenstein A.V. Response to comments by V.N. Manskikh: “Do external or internal factors lead to tumor development? It is still unknown”. Biochemistry (Mosc) 2017;82(1):86–7.Lichtenstein A.V. Response to comments by V.N. Manskikh: “Do external or internal factors lead to tumor development? It is still unknown”. Biochemistry (Mosc) 2017;82(1):86–7.106. Manskikh V.N. Remark to response of A.V. Lichtenstein. Biochemistry (Mosc) 2017;82(1):88–9.Manskikh V.N. Remark to response of A.V. Lichtenstein. Biochemistry (Mosc) 2017;82(1):88–9.107. Zhao A.H. Stem cells, environment, and cancer risk. Stem Cell Investig 2015;2:24.Zhao A.H. Stem cells, environment, and cancer risk. Stem Cell Investig 2015;2:24.108. Campisi J. Aging and cancer: the doubleedged sword of replicative senescence. J Am Geriatr Soc 1997;45(4):482–8.Campisi J. Aging and cancer: the doubleedged sword of replicative senescence. J Am Geriatr Soc 1997;45(4):482–8.109. Campisi J. Cancer and ageing: rival demons? Nat Rev Cancer 2003;3(5): 339–49.Campisi J. Cancer and ageing: rival demons? Nat Rev Cancer 2003;3(5): 339–49.110. Campisi J. Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors. Cell 2005;120(4):513–22.Campisi J. Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors. Cell 2005;120(4):513–22.111. Siegel R., Ma J., Zou Z., Jemal A. Cancer statistics, 2014. CA Cancer J Clin 2014;64(1):9–29.Siegel R., Ma J., Zou Z., Jemal A. Cancer statistics, 2014. CA Cancer J Clin 2014;64(1):9–29.112. Siegel R.L., Miller K.D., Jemal A. Cancer statistics, 2017. CA Cancer J Clin 2017;67(1):7–30.Siegel R.L., Miller K.D., Jemal A. Cancer statistics, 2017. CA Cancer J Clin 2017;67(1):7–30.113. Bray F., Jemal A., Grey N. et al. Global cancer transitions according to the Human Development Index(2008–2030): a population-based study. Lancet Oncol 2012;13(8):790–801.Bray F., Jemal A., Grey N. et al. Global cancer transitions according to the Human Development Index(2008–2030): a population-based study. Lancet Oncol 2012;13(8):790–801.114. Nones K., Waddell N., Wayte N. et al. Genomic catastrophes frequently arise in esophageal adenocarcinoma and drive tumorigenesis. Nat Commun 2014;5:5224.Nones K., Waddell N., Wayte N. et al. Genomic catastrophes frequently arise in esophageal adenocarcinoma and drive tumorigenesis. Nat Commun 2014;5:5224.115. Notta F., Chan-Seng-Yue M., Lemire M. et al. A renewed model of pancreatic cancer evolution based on genomic rearrangement patterns. Nature 2016;538(7625):378–82.Notta F., Chan-Seng-Yue M., Lemire M. et al. A renewed model of pancreatic cancer evolution based on genomic rearrangement patterns. Nature 2016;538(7625):378–82.116. Davoli T., Uno H., Wooten E.C., Elledge S.J. Tumor aneuploidy correlates with markers of immune evasion and with reduced response to immunotherapy. Science 2017;355(6322):1–16.Davoli T., Uno H., Wooten E.C., Elledge S.J. Tumor aneuploidy correlates with markers of immune evasion and with reduced response to immunotherapy. Science 2017;355(6322):1–16.117. Zanetti M. Chromosomal chaos silences immune surveillance. Science 2017;355(6322):249–50.Zanetti M. Chromosomal chaos silences immune surveillance. Science 2017;355(6322):249–50.118. Zhao X., Subramanian S. Intrinsic resistance of solid tumors to immune checkpoint blockade therapy. Cancer Res 2017;77(4):817–22.Zhao X., Subramanian S. Intrinsic resistance of solid tumors to immune checkpoint blockade therapy. Cancer Res 2017;77(4):817–22.