Genomic Instability in Cancer II: 4N-Skewed (90°) Reductive Division via Fragile Sites to Fitness Increase for Solid and Hematological Cancer Beginnings
The
objective herein was to connect the ontogeny process of diplochromosomal,
amitotic, 4n-skewed division-system, to cytogenetic deficiency lesions in
satellite, repetitive DNAs, especially in the chromosomal fragile sites, some
100 distributed over the genome. These latter studies had shown that chemical
induced replication-stress led to un-replicated lesions in these fragile sites,
which from inaccurate repair processes caused genomic instability. In the chain
of events of the ontogeny process to the special tetraploidy, it was proposed
that primary damaged human cells could undergo replication stress from
repair-process present during cell replication, a suggestion verified by X-ray
damaged cells producing the unstable fragile sites (see text). The cancer-importance
for therapy is recognition of cell cycle change for the 4n derivative
fitness-gained, diploid progeny cells. An open question is whether RB
controlling G1 to S-period is mutated at this suggested tumorigenesis initiating
phase, and if so, with what consequences for therapy. The fragile site studies
further showed that repair of repetitive DNAs could produce two types of
genomic changes: single gene mutations and CNVs, which were here shown to be chromosomally
located on “borders” to repairing satellite lesions. This genomic placement was
found to correspond to mutations identified in tumor sequencing (p53, Rb, MYC),
favoring a bad luck location for their cancer “mutational nature”. The CNVs in
cancers, are here seen as molecular
expressions of long-known cytogenetic HSRs and DMs also with demonstrated
origin from amplifications of single genes. Over-expression of oncogenes
was hinted of being from duplications, but Drosophila genetics demonstrated the opposite,gene inactivation. The reduced eye-size from dominant,
BAR-Ultra-Bar-eye phenotypes, was caused by duplications, inactivating the
genetic system for eye-size. The finding of CNVs showing “evasion” of the
immune systemsuggests, inactivation of immune-determining genetics.
Since mutated genes on borders to satellite DNAs are a fact in hematological cancers,
the 4n-skewed division-system is suggested to replace
Walen, K. (2018) Genomic Instability in Cancer I: DNA-Repair Triggering Primitive Hereditary 4n-Skewed, Amitotic Division-System, the Culprit in EMT/MET/Metaplasia Cancer Concepts. Journal of Cancer Therapy, 9, 974-997.
https://doi.org/10.4236/jct.2018.912081
Weaver, B.A.A. and Cleveland, D.W. (2009) The Role of Aneuploidy in Promoting and Suppressing Tumors. The Journal of Cell Biology, 185, 935-937.
https://doi.org/10.1083/jcb.200905098
Walen, K.H. (2006) Human Diploid Fibroblast Cells in Senescence: Cycling from Polyploidy to Mitotic Cells. In Vitro Cellular & Developmental Biology—Animal, 42, 216-224. https://doi.org/10.1290/0603019.1
Davoli, T., Denchi, E.L. and de Lange, T. (2010) Persistent Telomere Damage Induces Bypass of Mitosis and Tetraploidy. Cell, 141, 81-93.
https://doi.org/10.1016/j.cell.2010.01.031
Walen, K.H. (2007) Bipolar Genome Reductional Division of Human Near-Senescent, Polyploid Fibroblast Cells. Cancer Genetics and Cytogenetics, 173, 43-50. https://doi.org/10.1016/j.cancergencyto.2006.09.013
Hurst, L.D. and Nurse, P. (1991) A Note on the Evolution of Meiosis. Journal of Theoretical Biology, 150, 561-563. https://doi.org/10.1016/S0022-5193(05)80447-3
Raikov, I.B. (1994) The Diversity of Forms of Mitosis in Protozoa. European Journal of Protistology, 30, 253-269. https://doi.org/10.1016/S0932-4739(11)80072-6
Grell, K.G. and Ruthmann, A. (1964) Uber die Karyologie des Radiolars Aulachanta scolymantha und Feinstruktur seiner Chromosomen. Chromosoma, 15, 18.
https://doi.org/10.1007/BF00285729
Walen, K.H. (2011) Normal Human Cell Conversion to 3-D Cancer-Like Growth: Genome Damage, Endopolyploidy, Senescence Escape, and Cell Polarity Change/Loss. Journal of Cancer Therapy, 2, 181-189.
https://doi.org/10.4236/jct.2011.22023
Tanaka, K., Goto, H., Nishimura, Y., Kasahara, K., et al. (2018) Tetraploidy in Cancer and Its Possible Link to Aging. Cancer Science, 109, 2632-2640.
https://doi.org/10.1111/cas.13717
Zasadil, L.M., Britigan, E.M.C. and Weaver, B.A. (2013) 2n or Not 2n: Aneuploidy, Polyploidy and Chromosomal Instability in Primary and Tumor Cells. Seminars in Cell and Developmental Biology, 24, 370-379.
https://doi.org/10.1016/j.semcdb.2013.02.001
Brito, D. and Rieder, C.L. (2006) Mitotic Slippage in Humans Occurs via Cyclin B Destruction in the Presence of an Active Checkpoint. Current Biology, 16, 194-200.
https://doi.org/10.1016/j.cub.2006.04.043
Sheltzer, J.M. and Amon, A. (2011) The Aneuploidy Paradox: Costs and Benefits of an Incorrect Karyotype. Trends in Genetics, 27, 446-455.
https://doi.org/10.1016/j.tig.2011.07.003
Gascoigne, K. and Taylor, S.S. (2008) Cancer Cells Display Profound Intra- and Interline Variation Following Prolonged Exposure to Antimitotic Drugs. Cancer Cell, 14, 111-122. https://doi.org/10.1016/j.ccr.2008.07.002
Dikovskaya, D., Schiffmann, D., Newton, I.P., Oakley, A., Kroboth, K., Sansom, O., et al. (2007) Loss of APC Induces Polyploidy as a Result of a Combination of Defects in Mitosis and Apoptosis. The Journal of Cell Biology, 176, 183-193.
https://doi.org/10.1083/jcb.200610099
Walen, K.H. (2013) Normal Human Cells Acquiring Proliferative Advantage to Hyperplasia-Like Growth-Morphology: Aberrant Progeny Cells Associated with Endopolyploid and Haploid Divisions. Cancer and Clinical Oncology, 2, 1-15.
https://doi.org/10.5539/cco.v2n2p19
Walen, K.H. (2014) Haploidization of Human Diploid Metaphase Cells: Is This Genome Reductive Mechanism Operational in Near-Haploid Leukemia? Journal of Cancer Therapy, 5, 101-114. https://doi.org/10.4236/jct.2014.51013
Walen, K.H. (2014) Neoplastic-Like Cell Changes of Normal Fibroblast Cells Associated with Evolutionary Conserved Maternal and Paternal Genomic Autonomous Behavior (Gonomery). Journal of Cancer Therapy, 5, 860-877.
https://doi.org/10.4236/jct.2014.59094
Castagnetti, S., Oliferenko, S. and Nurse, P. (2010) Fission Yeast Cells Undergo Nuclear Division in the Absence of Spindle Microtubules. PLOS Biology, 8, e1000515. https://doi.org/10.1371/journal.pbio.1000512
Walen, K.H. (2011) Normal Human Cell Conversion to 3-D Cancer-Like Growth: Genome Damage, Endopolyploidy, Senescence Escape, and Cell Polarity Change/Loss. Journal of Cancer Therapy, 2, 181-189.
https://doi.org/10.4236/jct.2011.22023
Bignold, L.P., Coghlan, B.L.D., Jersmann, H.P.A. and von Hansemann, D. (2007) Contributions to Oncology, Context, Comments, and Translations. Birkhauser Verlag, Basel.
Royer, C. and Lu, X. (2011) Epithelial Cell Polarity: A Major Gatekeeper against Cancer? Cell Death and Differentiation, 18, 1470-1477.
https://doi.org/10.1038/cdd.2011.60
Cortes, F., Mateos, S., Pastor, N. and Dominguez, I. (2004) Toward a Comprehensive Model for Induced Endoreduplication. Life Sciences, 76, 121-135.
https://doi.org/10.1016/j.lfs.2004.08.006
Wood, L.D., Parsons, D.W., Jones, S., Lin, J., Sjoblom, T., Leary, R.J., et al. (2007) The Genomic Landscapes of Human Breast and Colorectal Cancer. Science, 318, 1108-1113. https://doi.org/10.1126/science.1145720
Bozic, I., Antal, T., Ohtsuki, H., Carter, H., Kim, D., Chen, S., Karchin, R., et al. (2010) Accumulation of Driver and Passenger Mutations during Tumor Progression. Proceedings of the National Academy of Sciences, 107, 18545-18550.
https://doi.org/10.1073/pnas.1010978107
Tomasetti, C., Vogelstein, B. and Parmigiani, G. (2013) Half or More of the Somatic Mutations in Cancers of Self-Renewing Tissues Originate Prior to Tumor Initiation. Proceedings of the National Academy of Sciences of the United States of America, 110, 1999-2004. https://doi.org/10.1073/pnas.1221068110
Collins, F.S. and Varmus, H. (2015) A New Initiative on Precision Medicine. The New England Journal of Medicine, 372, 793-798.
https://doi.org/10.1056/NEJMp1500523
Lawrence, M.S., Stojano, P., Polak, P., Kryukov, G.V., Cibulskis, K., et al. (2013) Mutational Heterogeneity in Cancer and the Search for New Cancer-Associated Genes. Nature, 499, 214-218.
Bloomfield, M. and Duesberg, P. (2015) Karyotype Alteration Generates the Neoplastic Phenotypes of SV40-Infected Human and Rodent Cells. Molecular Cytogenetics, 8, 79-109. https://doi.org/10.1186/s13039-015-0183-y
Heim, S. and Mitelman, F. (1995) Cancer Cytogenetics: Chromosomal and Molecular Genetic Aberrations of Tumor Cells. 2nd Edition, Wiley-Liss Inc., New York.
Duesberg, P., Madrioli, D., MCCormack, A. and Nicholson, J.M. (2011) Is Carcinogenesis a Form of Speciation? Cell Cycle, 10, 2100-2114.
https://doi.org/10.4161/cc.10.13.16352
Stepanenko, A.A. and Kavasan, V.M. (2012) Evolutionary Karyotypic Theory of Cancer versus Conventional Cancer Gene Mutation Theory. Biopolymers and Cell, 28, 267-280. https://doi.org/10.7124/bc.000059
Weinberg, R.A. (2014) Coming Full Circle—From Endless Complexity to Simplicity and Back Again. Cell, 157, 267-271. https://doi.org/10.1016/j.cell.2014.03.004
Todaro, G.J. and Green, H. (1963) Quantitive Studies of Growth of Mouse Embryo Cells in Culture and Their Development to Established Lines. The Journal of Cell Biology, 17, 299-313. https://doi.org/10.1083/jcb.17.2.299
Brenner, S., Branch, A., Meredith, S. and Berns, M.W. (1977) The Absence of Centrioles from Spindle Poles of Rat Kangaroo PtK1 Cells Undergoing Meiotic-Like Reduction Division in Vitro. The Journal of Cell Biology, 72, 368-379.
https://doi.org/10.1083/jcb.72.2.368
Nik-Zanail, S., Davies, H., Staff, J., Ramakrishna, M., Glodzik, D., Xou, X., Martincorena, I., et al. (2016) Landscape of Somatic Mutations in 560 Breast Cancer Whole Genome Sequences. Nature, 534, 47-54. https://doi.org/10.1038/nature17676
Rajaraman, R., Guernsey, D.L., Rajaraman, M.M. and Rajaraman, S.R. (2006) Stem Cells, Senescence, Neosis, and Self-Renewal in Cancer. Cancer Cell International, 29, 6-25. https://doi.org/10.1186/1475-2867-6-25
Richardson, C. and Jasin, M. (2000) Frequent Chromosomal Translocations Induced by DNA Double-Strand Breaks. Nature, 405, 697-700.
https://doi.org/10.1038/35015097
Denals, C.M., Gilbert, R.M., Isermann, P., McGregor, A.L., te Lindert, M., Weigelin, B., et al. (2017) Nuclear Envelope Rupture and Repair during Cancer Cell Migration. Science, 352, 353-358. https://doi.org/10.1126/science.aad7297
Raab, M., Gentili, M., de Belly, H., Thiam, H.R., Vargas, P., Jimenez, A.J., et al. (2017) ESCRT III Repairs Nuclear Envelope Ruptures during Cell Migration to Limit DNA Damage and Cell Death. Science, 352, 359-362.
https://doi.org/10.1126/science.aad7611
Dexter, T.M. and Spooncer, E. (1987) Growth and Differentiation in the Hemopoietic System. Annual Review of Cell Biology, 3, 423-441.
https://doi.org/10.1146/annurev.cb.03.110187.002231
Nagele, R.G., Freeman, T., McMorrow, L. and Lee, H.Y. (1995) Precise Spatial Positioning of Chromo-Somes during Prometaphase: Evidence for Chromosomal Order. Science, 270, 1831-1835. https://doi.org/10.1126/science.270.5243.1831
Bolzer, A., Kreth, G., Solovei, I., Koehler, D., Saracoglu, K., Fauth, C., et al. (2005) Three-Dimensional Maps of All Chromosomes in Human Male Fibroblast Nuclei and Prometaphase Rosettes. PLOS Biology, 3, 0826-0842.
https://doi.org/10.1371/journal.pbio.0030157
Fabarius, A., Kalmanti, L., Dietz, C.T., Lauseker, M., Rinaldetti, S., Haferlach, C., et al. (2015) Impact of Unbalanced Minor Route versus Major Route Karyotypes at Diagnosis on Prognosis of CML. Annals of Hematology, 94, 2015-2024.
https://doi.org/10.1007/s00277-015-2494-9
Wang, W., et al. (2016) Risk Stratification of Chromosomal Abnormalities in Chronic Myelogenous Leukemia in the Area of Tyrosine Kinase Inhibitor Therapy. Blood, 127, 2742-2750. https://doi.org/10.1182/blood-2016-01-690230
Werner, M., Kaloutsi, V., Buhr, T., Delventhal, S., Vykoupi, K.F. and Georgii, A. (1991) Cytogenetics of Chronic Myelogenous Leukemia (CML) Correlated to the Histopathology of Bone Marrow Biopsies. Annals of Hematology, 63, 201-205.
https://doi.org/10.1007/BF01703443
Ley, T.J., Mardis, E.R., Ding, L., Fulton, B., McLellan, M.D., Chen, K., Dooling, D., Dunford-Shore, B.H., McGrath, S., et al. (2008) DNA Sequencing of a Cytogenetically Normal Acute Myeloid Leukemia Genome. Nature, 456, 66-72.
https://doi.org/10.1038/nature07485
Houston, E.M., Levin, W.C. and Ritaman, S.E. (1964) Endoreduplication in Untreated Early Leukemia. The Lancet, 2, 496-497.
https://doi.org/10.1016/S0140-6736(64)90451-9
Therman, E. and Susman, M. (1993) Human Chromosomes—Structure, Behavior, and Effects. Third Edition, Springer Verlag, Berlin.
https://doi.org/10.1007/978-1-4684-0529-3
Gorgoulis, V.G., Vassillou, L.-V.F., Karakaldos, P., Zacharatos, P., Kotsinas, A., Liloglou, T., et al. (2005) Activation of the DNA Damage Checkpoint and Genomic Instability in Human Precancerous Lesions. Nature, 434, 907-912.
https://doi.org/10.1038/nature03485
Chan, K.L., Palmai-Pallag, T., Ying, S. and Hickson, I.D. (2009) Replication Stress Induces Sister-Chromatid Bridging at Fragile Site Loci in Mitosis. Nature Cell Biology, 11, 753-760. https://doi.org/10.1038/ncb1882
Gisselsson, D., Petterson, L., Hoglund, M., Heldenbla, M., Gorunova, L., et al. (2000) Chromosomal Breakage-Fusion-Bridge Events Cause Genetic Intratumor Heterogeneity. Proceedings of the National Academy of Sciences of the United States of America, 97, 5357-5362. https://doi.org/10.1073/pnas.090013497
Helsmoortel, C., Vandeweyer, G. and Kooy, R.F. (2012) On the Spot: Very Local Chromosomal Rearrangements. F1000 Biology Reports, 4, 22.
https://doi.org/10.3410/B4-22
Beroukhlim, R., Mermel, C.H., Porter, D., Wei, G., Raychaudhuri, S., Donovan, J., Barretina, J., Boehm, J.S., Bobson, J., et al. (2010) The Landscape of Somatic Copy Number Alterations across Human Cancers. Nature, 463, 899-905.
https://doi.org/10.1038/nature08822
Arlt, M.F., Wilson, T.E. and Glover, T.W. (2009) Replication Stress and Mechanisms of CNV Formation. Current Opinion in Genetics & Development, 22, 204-210.
https://doi.org/10.1016/j.gde.2012.01.009
Wilson, T., Artl, M.F., Park, S.H., Rajendran, S., Paulsen, M., Ljungman, M. and Glover, T.W. (2015) Large Transcription Units Unify Copy Number Variant and Common Fragile Sites Arising under Replication Stress. Genome Research, 25, 189-200. https://doi.org/10.1101/gr.177121.114
Argueso, J.L., Westmoreland, J., Mieczkowski, P.A., Gawel, M., Petes, T.D. and Resnick, M.A. (2008) Double-Strand Breaks Associated with Repetitive DNA Can Reshape the Genome. Proceedings of the National Academy of Sciences of the United States of America, 105, 11845-118450.
https://doi.org/10.1073/pnas.0804529105
Davoli, T., Uno, H., Wooten, E.C. and Elledge, S.J. (2017) Tumor Aneuploidy Correlates with Markers of Immune Evasion and with Reduced Response to Immunotherapy. Science, 355, 261. https://doi.org/10.1126/science.aaf8399
Shimizu, N. (2009) Extrachromosomal Double Minutes and Chromosomal Homogeneously Staining Regions as Probes for Chromosome Research. Cytogenet Genome Research, 124, 312-326. https://doi.org/10.1159/000218135
Storlazzi, C.T., Lonoce, A., Guastadisegni, M.C., Trombetta, D., et al. (2010) Gene Amplification as Double Minutes or Homogeneously Staining Regions in Solid Tumors: Origin and Structure. Genome Research, 20, 1198-1206.
https://doi.org/10.1101/gr.106252.110
Alitalo, K., Schwab, M., Lin, C.C., Varmus, H.E. and Bishop, J.M. (1983) Homogeneously Staining Choromosomal Regions Contain Amplified Copies of an Abundantly Expressed Cellular Oncogene (c-myc) in Malignant Neuroendocrine Cells from a Human Colon Carcinoma. Proceedings of the National Academy of Sciences of the United States of America, 80, 1707-1711.
https://doi.org/10.1073/pnas.80.6.1707
Holden, J.J.A., Hough, M., Reimer, D.L., et al. (1987) Evidence for Unequal Crossing over as the Mechanism for Amplification of Some Homogeneously Staining Regions. Cancer Genetics and Cytogenetics, 29, 139-149.
https://doi.org/10.1016/0165-4608(87)90041-0
Yunis, J.J. and Yasmineh, W.G. (1971) Heterochromatin, Satellite DNA, and Cell Function. Structural DNA of Eucaryotes May Support and Protect Genes and Aid in Speciation. Science, 174, 1200-1209. https://doi.org/10.1126/science.174.4015.1200
Arlt, M.F., Rajendran, S., Birkeland, S.R., Wilson, T.E. and Glover, T.W. (2014) Copy Number Variants Are Produced in Response to Low-Dose, Ionizing Radiation in Cultured Cells. Environmental and Molecular Mutagenesis, 55, 103-113.
https://doi.org/10.1002/em.21840
Walen, K.H. (1987) Chromosome Instability in Cell Lineages of Amniocyte Clones Morphologically Transformed by Simian Virus 40. Cancer Genetics and Cytogenetics, 25, 149-159. https://doi.org/10.1016/0165-4608(87)90170-1
Saldivar, J.C., Miuma, S., Bene, J., Hosseini, S.A., Shibata, H., et al. (2012) Initiation of Genome Instability and Preneoplastic Processes through Loss of Fhit Expression. PLOS Genetics, 8, e1003077. https://doi.org/10.1371/journal.pgen.1003077
Bene, J. (2012) The Role of the Common Fragile Site Gene Product, Fhit, in Protection from DNA Damage. The Ohio State, Honors Distinction, Kay Huebner, Dep. of Med Genet.
O’Keefe, C.L., Mc Dervitt, M.A. and Maciejewski, J.P. (2010) Copy Neutral Loss of Heterozygosity: A Novel Chromosomal Lesion in Myeloid Malignancies. Blood, 115, 2731-2739. https://doi.org/10.1182/blood-2009-10-201848
Gondek, L.P., Tiu, R., O’Keefe, C.L., Sekeres, M.A., Theil, K.S. and Maciejewski, P. (2013) Chromosomal Lesions and Uniparental Disomy Detected by SNP Arrays in MDS, MDS/MPD and MDS-Derived AML. Blood, 111, 1534-1542.
https://doi.org/10.1182/blood-2007-05-092304
Mullighan, C.G., Goorha, S., Radtke, I., Miller, C.B., Coustan-Smith, E., Dalton, J.D., Girtman, K., et al. (2007) Genome-Wide Analysis of Genetic Alterations in Acute Lymphoblastic Leukemia. Nature, 446, 758-764.
https://doi.org/10.1038/nature05690
Solary, E., Bernard, O.A., Tefferi, A., Fuks, F. and Vainchenker, W. (2014) The Ten-Eleven Trans-Location-2 (TET2) Gene in Hematopoiesis and Hematopoietic Diseases. Leukemia, 28, 485-496. https://doi.org/10.1038/leu.2013.337
Rach, E.M. and Wyngaard, G.A. (2008) Gonomery and Chromatin Diminution in Mesocyclops longisetus (Copepoda). Journal of Crustacean Biology, 28, 180-184.
https://doi.org/10.1651/07-2847R.1
Stern, C. (1958) The Nucleus and Somatic Cell Variation. Journal of Cellular and Comparative Physiology, 52, 1-34. https://doi.org/10.1002/jcp.1030520404
Alabrudzinska, M., Skoneczny, M. and Skoneczna, A. (1978) Diploid-Specific Genome Stability Genes of S. cerevisiae: Genomic Screen Reveals Haploidization as an Escape from Persisting DNA Rearrangement Stress. PLoS ONE, 6, 15-24.
https://doi.org/10.1371/annotation/77daccf9-9976-4d0e-b666-35a900cb2d17
