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Successful cancer evolution (CE) relies on the sequential molecular and functional events including 1) telomere; 2) sub-telomere; 3) epigenetic; 4-6) hit-episodes; 7) an innovative cell cycle machinery, as the multi-phase, and 8) chromosomal abnormalities. In this regard, eight available, fundamental/evolutionary and strategic key information (Evolutionary- ID) presented.
Telomere length (TL), has the fundamental role in cancer development, with serious challenges in the clinical managements. Breast cancer and brain tumor are an unresolved problem in Science and Medicine. Besides, an early and translatable diagnostic- prognostic-predictive platform, by considering the targets-ID, is required. Diverse TL in two cases affected with astrocytoma with grade IV, revealed to be 12500 and 15000 bp in tumor, and 10000 and 9000 bp at genomic level. Interestingly, TL is declined in the lymph node, i.e., occurrence of evolution.
Sub-telomeres (STs) through the cellular journey, are the neighboring destination at genomic and somatic level. The evolutionary pattern of STs has not been, routinely, decoded to the personalized clinical managements. The ST-sequences, are diversely predisposed to variety of environmental factors and play influential role in healthy individuals and the patients. An early detection is available by analysis of the ST- hybridized signals in the biopsy of auxiliary lymph nodes (ALN), and/or by circulating tumor cells (CTCs) into the blood stream. Diverse pattern of signal frequency and intensity in individual chromosomes at both somatic (ALN) and genomic (lymphocytes) levels were remarkable. The most common involved targets included chromosomes 5 and 9, 16 and 19; with diverse intensity at p and q chromosomal arms respectively. These findings have the predisposing, and an initial influence through the patients’ course of disease.
ST- signals, by providing the STs-ID, offer periodical and predictive, indices in cancer screening and therapy.
Furthermore, the complementary, cell cycle protein expression (PE) including Ki67, cyclin D1, and cyclin E, accelerates an early clinical management through the period of disease based on the CTCs.
Epigenetics is the next molecular destination by focusing on the genomic/somatic index, as an evolutionary Epigenetics-ID with its impact on the cancer management. The target panel is Ataxia Telangiectasia mutated gene (ATM) as the molecular marker and an initiator of different cancers.
ATM has remarkable roles, including: 1) in DNA double strand break (DSB), 2) to initiate different types of neoplastic disorders, including cancer, and 3), polymorphism, D1853N as a peridisposing marker by initiating the hit process. The influential characteristics include: family history of neoplastic disorders through the pedigree, the key role of ATM promoter methylation, cooperation of ATM/Rb protein expression, D1853N- marker, telomere length (TL) and the clinico-pathological characteristics in different types of brain tumors, and the environmental factors. Interestingly, TL has an independent influence on the progressive cancer evolution. An early detection by CTCs based on the D1853N/Sub-TL/Cell cycle checkpoints based on the PE assay and molecular test facilitate an early detection and therapy, based on the personalized approach.
By highlighting the preventive insight in Medicine, a brief record on the “Methylation in Chorionic villus samples (CVS)” with aim of an early detective strategy is provided. All nine CVS samples were methylated for the MCPH1 gene. An early detection is possible either through CV sampling or by the circulating CV cells in the maternal blood.
Evolutionary Hit includes: presence of D1853N polymorphism of ATM, as the hit-initiator through an evolutionary and progressive molecular based sequential alterations led to discovery of three-hit hypothesis in a patient affected with astrocytoma. More hits include five, and eight- hit hypotheses in primary breast cancer patients. Such platforms are considered as the individualized model in cancer. The pedigrees and details at the molecular follow-up studies and functional alteration at protein level are available in the provided sections.
Novel strategy of Cell cycle phases in breast cancer is the major intersection for cancer therapy.
The novel cell cycle hypothesis (CCH) highlights the mosaic based of dual and/or multi-phases, as minor clones at single cell level in the breast cancer (BC) -patients, escorted by the normal cell population. Such mosaicism provided an archetypal, unique diagnostic and therapeutic model, by applying different mosaic patterns (MPs) as well as “G1/S, S/G2 and G1/S/G2, and accompanied by normal phases, as a sole including G1, S, and G2 at the single cells level.
Diagnosis is based on the mode of signal copy numbers (SCN) and the related PE. Interestingly MPs were also unmasked in patients with chronic myelogeneous leukemia and other solid tumors.
Finally, the predisposing/predictive/prognostic/preventive square provides an innovate CDKs inhibitor-based therapy in BC and other cancers.
Personalized base cancer therapy is the confusing procedure and requires the pedigree-based data, personalized, evolutionary based information including molecular and functional at both genomic and somatic, at single cell level. The target territories comprise cell cycle phases, proteins, Telomere length, telomerase, sub-telomere, and Epigenetics. The aim is directing the cell cycle fundamental forces back to normal, by performing:
1) Applying personalized, single cell-based approach, at molecular, functional level, pedigree analysis, and balancing the micro-/macro-environmental factors, including nutrition.
2) Satisfactory high single cell enumeration based on the FISH and protein expression assays;
3) Decoding the required dosage and combined therapeutic regimens accordingly,
4) Unmasking the cell cycle combined (mosaic) phases including different Cyclins; and
5) Bilateral cooperation between Pharmacology, Medicine, and Cancer Genetics/cell biology.
Let’s combine the evolutionary based strategy by translating the personalized data at molecular/ Functional/ Informative, and pedigree-based level to the personalized therapy.
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 Counter CM, Avilion AA, LeFeuvre CE. Telomerase shortening associated with chromosome instability is arrested in immortal cells which express telomerase activity. EMBO J 1992;11:1921-9.
 Sandell LL, Zakian VA. Lost of a yeast telomere: Arrest, recovery and chromosome loss. Cell. 1993;75:729-39.
 Moyzis RK, Buckingham JM, Carm LS, Dani M, Deaven LL, Jones MD. A highly repetitive sequence (TTAGGG)n, present at the telomeres of human chromosomes. Proc Natl Acad Sci USA. 1988;85:6622-6.
 Harley CB, Futcher AB, Greider CW. Telomeres shorten during ageing of human fibroblasts. Nature (Lond). 1990;345:458-60.
 Levy MZ, Allsopp RC, Futcher AB, Greider CW, Harley CB. Telomere end-duplication problem and cell aging. J Mol Biol. 1992;225:951-60.
 Surralles J, Hande MP, Marcos R, Lansdorp PM. Accelerated telomere shortening in the human inactive X chromosome. Am J Hum Genet 1999;65:1617–22.
 Lansdorp PM, Verwoerd NP, Rijke FMvd, Dragowska V, Little MT, Dirks RW. Heterogeneity in telomere length of human chromosomes. Human Mol Genet 1995;5(5):685-91.
 Greider CW. Telomerase activity, cell proliferation, and cancer. Proc Natl Acad Sci USA. 1998;95:90-2.
 Harrington L, McPhail T, Mar V, Zhou W, Oulton R, Bass MB, et al. A mammalian telomerase-associated protein. Science. 1997;275:973-7.
 Hayflick L, Moorhead PS. The serial cultivation of human diploid cell strains. Exp Cell Res,. 1961;25:585-621.
 Kheirollahi M, Mehr-Azin M , Kamalian N Mehdipour P*. Alterations in Telomere Length in Human Brain Tumors.Med Oncol (2011) 28:864–870. DOI 10.1007/s12032-010-9506-3
 Kleihues P, Burger P, Scheithauer BW. Histological Typing of Tumors of the Central Nervous System (International Histological Classification of Tumors). 2nd. ed. Berlin: Springer-verlag 1993.
 Hiraga S, Ohnishi T, Izumoto S, Miyahara E, Kanemura Y, Matsumura H, et al. Telomerase Activity and Alterations in Telomere Length in Human Brain Tumors. Cancer Res. 1998; 58:2117-25.
 Tatter SB, Wilson CB, Harsh GRIV. Neuroepithelial tumors of the adult brain. Fourth Edition ed. Philadelphia: W.B. Saunders Co 1995.
 Harley CB, Villeponteau B. Telomeres and telomerase in aging and cancer. Curr Opin Genet Dev. 1995;5:249–55.
 Bisoffi M, Heaphy CM, Griffith JK. Telomeres: prognostic markers for solid tumors. Int J Cancer. 2006;119:2255–60.
 Heaphy CM, Baumgartner KB, Bisoffi M, Baumgartner RN, Griffith JK. Telomere DNA content predicts breast cancer-free survival interval Clin Cancer Res. 2007;13:7037–43.
 Mehdipour P*, Kheirollahi M, Mehrazin M, Kamalian N and Atri M. Evolutionary hypothesis of telomere length in primary breast cancer and brain tumor patients: a tracer for genomic–tumor heterogeneity and instability. Cell Biol. Int. (2011) 35, 915–925.
 Muller HY. The re-making of chromosomes. Collecting Net 1938;13:181–95.
 McClintock B. The study of broken ends of chromosomes in Zea mays. Genetics 1941;26:234–82.
 Blackburn EH and Gall JG. A tandemly repeated sequence at the termini of the xtrachromosomal ribosomal RNA genes in Tetrahymena. J Mol Biol 1978;120(1):33–53.
 Starling JA, Maule J, Hastie ND and Allshire RC. Extensive telomere repeat arrays in mouse are hypervariable. Nucleic Acids Res 1990;18(23):6881–8.
 De-Lange T, Shiue L, Myers RM, Cox DR, Naylor SL, Killery AM and Varmus HE. Structure and variability of human chromosome ends. Mol Cell Biol 1990;10(2):518–27.
 Hastie ND, Dempster M, Dunlop MG, Thompson AM, Green DK and Allshire RC. Telomere reduction in human colorectal carcinoma and with ageing. Nature 1990;345(6287):866–8.
 Bechter OE, Eisterer W, Pall G, Hilbe W, Ku¨ hr T and Thaler J. Telomere length and telomerase activity predict survival in patients with B cell chronic lymphocytic leukemia. 1998; Cancer Research 58(21):4918-22.
 Terasaki Y, Okumura H, Ohtake S and Nakao S. Accelerated telomere length shortening in granulocytes: a diagnostic marker for myeloproliferative diseases. Exp Hematol 2002;30(12):1399–404.
 Kirkpatrick KL, Clark G, Ghilchick M, Newbold RF and Mokbel K. hTERT mRNA expression correlates with telomerase activity in human breast cancer. Eur J Surg Oncol 2003;29(4):321–6.
 Bendnareck AK, Sahin A Brenner AJ, Johnston DA, Aldaz CM. Analysis of telomerase activity levels in breast cancer: positive detection at the in situ breast carcinoma stage.1997. Clin Cancer Res 3:11-16
 Hosseini-Asl, S.Telomerase: Basic and clinical approaches. In: Telomere territory and cancer. Ed. P.Mehdipour. Springer, 2013. 29-39. Dordrecht
 Bechter OE, Eisterer W, Pall G, Hilbe W, Ku¨ hr T and Thaler J. Telomere length and telomerase activity predict survival in patients with B cell chronic lymphocytic leukemia. Cancer Res 58:4918-4922. https://www.researchgate.net/publication/13476561
 Harley CB, Futcher AB, Greider CW. Telomeres shorten during aging of human fibroblasts. Nature 345, 458-460.
 Nawas S, Hasizumi TL, Markham NE, Shroyer AL, Shroyer KR. Telomerase expression in human breast with and without node metastasis. Ann J Clin Pathol 107:542-547.
 Mehdipour P, Pirouzpanah S, Sarafnejad A, Atri M, Shahrestani ST and Haidari M. Prognostic implication of CDC25A and cyclin E expression on primary breast cancer patients. Cell Biology International 2009;33:1050–6.
 Olovnikov, A. M. Principle of marginotomy in template synthesis of polynucleotides. Dokl Akad Nauk SSSR.1971.201:1496-1499
 Olovnikov, A. M. A theory of marginotomy. The incomplete copying of template margin in enzymic synthesis of polynucleotides and biological significance of the phenomenon. J Theor Biol.1973.41:181-190
 Churikov D., P. C. Telomeric and subtelomeric repeat sequences. 2008.
 Denayrolles, M., de Villechenon, E. P., Lonvaud-Funel,A. and Aigle, M. Incidence of SUC-RTM telomeric repeated genes in brewing and wild wine strains of Saccharomyces. Curr Genet.1997.31:457-461
 Linardopoulou, E., Mefford, H. C., Nguyen, O., Friedman, C., van den Engh, G., Farwell, D. G., et a.l Transcriptional activity of multiple copies of a subtelomerically located olfactory receptor gene that is polymorphic in number and location. Hum Mol Genet.2001.10:2373-2383
 Fregnani, J. H. T. G. and Macea, J. R. Lymphatic drainage of the breast: from theory to surgical practice. International Journal of Morphology.2009.27:873-878
 Zheng WJ, Li Su L.Evaluation of housekeeping genes as references for quantitative real time RT-PCR analysis of gene expression in Japanese flounder (Paralichthys olivaceus). Fish & Shellfish Immunology, 30(12), 2011: 638-645
 Maiti S, Huls H Harjeet, Singh H, Dawson M,Matthew Figliola,M, et al. Sleeping Beauty system to redirect T-cell specificity for human applications. J Immunother. 2013; 36(2): 112–123. PMCID: PMC3568214. doi: 10.1097/CJI.0b013e3182811ce9
 Mehdipour, P. Telomere territory and cancer. 2013 Netherland. Springer
 Mehdipour, P., Kheirollahi, M., Mehrazin, M., Kamalian, N. and Atri, M. Evolutionary hypothesis of telomere length in primary breast cancer and brain tumour patients: a tracer for genomic-tumour heterogeneity and instability. Cell Biol Int.2011.35:915-925
 Mehdipour,P., Javan, F., and Atri M. Novel evolutionary models and periodic charts in p- and q-individual chromosomes of auxiliary lymph node and buccal cells. Disease Markers, vol. 35, 2013, Issue 6, Pages 833–845
 Moyzis, R. K., Buckingham, J. M., Cram, L. S., Dani, M., Deaven, L. L., Jones, M. D., et al A highly conserved repetitive DNA sequence, (TTAGGG)n, present at the telomeres of human chromosomes. Proc Natl Acad Sci U S A.1988.85:6622-6626
 Brown, W. R., MacKinnon, P. J., Villasante, A., Spurr, N., Buckle, V. J. and Dobson, M. J. Structure and polymorphism of human telomere-associated DNA. Cell.1990.63:119-132
. Saccone, S., De Sario, A., Della Valle, G. and Bernardi, G. The highest gene concentrations in the human genome are in telomeric bands of metaphase chromosomes. Proc Natl Acad Sci U S A.1992.89:4913-4917.
 Flint, J., Wilkie, A. O., Buckle, V. J., Winter, R. M., Holland, A. J. and McDermid, HE.The detection of subtelomeric chromosomal rearrangements in idiopathic mental retardation. Nat Genet.1995.9:132-140
 Poon L LM, Tse N Leung Tse N, Lau T K , Chow Katherine CK , Lo YM D. Differential DNA Methylation between Fetus and Mother as a Strategy for Dtecting Fetal DNA in Maternal
Plasma. Clinical Chemistry, Volume 48, Issue 1, 1 January 2002,35-4 1 https://doi.org/10.1093/clinchem/48.1.35
 Shivakumar, L., J. Minna, et al. (2002). "The RASSF1A tumor suppressor blocks cell cycle progression and inhibits cyclin D1 accumulation." Mol Cell Biol 22(12): 4309-4318.
 Chiu, R. W., S. S. Chim, et al. (2007). "Hypermethylation of RASSF1A in human and rhesus placentas." Am J Pathol 170(3): 941-950.
 Chim, S. S., Y. K. Tong, et al. (2005). "Detection of the placental epigenetic signature of the maspin gene in maternal plasma." Proc Natl Acad Sci U S A 102(41): 14753-14758.
 Schneider, E., G. Pliushch, et al. (2010). "Spatial, temporal and interindividual epigenetic variation of functionally important DNA methylation patterns." Nucleic Acids Res 38(12): 3880-3890.
 Olivier, M. H., S. P. Caron de Fromentel, C. Hainaut, P. Harris, C. C. (2004). TP53 mutation spectra and load: a tool for generating hypotheses on the etiology of cancer. IARC Sci Publ. , 247-70.
 Hurt, E. M., Thomas, S. B., Peng, B. &Farrar, W. L. (2006). Reversal of p53 epigenetic silencing in multiple myeloma permits apoptosis by a p53 activator. Cancer Biol Ther 5, 1154-60
 Kang, J. H., Kim, S. J., Noh, D. Y., Park, I. A., Choe, K. J., Yoo, O. J., et al. (2001). Methylation in the p53 promoter is a supplementary route to breast carcinogenesis: correlation between CpG methylation in the p53 promoter and the mutation of the p53 gene in the progression from ductal carcinoma in situ to invasive ductal carcinoma. Lab Invest 81, 573-9.
 Gonzalez-Gomez, P. B., M. J. Lomas, J. Arjona, D. Alonso, M. E. Amiñoso, C. Lopez-Marin, I. Anselmo, N.P. Sarasa, J.L. Gutierrez, M. Casartelli, C. Rey, J. A. (2003). Aberrant methylation of multiple genes in neuroblastic tumours; and relationship with MYCN amplification and allelic status at 1p. Eur J Cancer 39, 1478-85.
 Mehdipour P, Karami F, Javan F, Mehrazin M: Linking ATM promoter methylation to cell cycle PE in brain tumor patients: cellular molecular triangle correlation in ATM territory. Molecular neurobiology 2015; 52:293-302.
 Knudson A G.Mutation and cancer: statistical study of retinoblastoma.Proceedings of the National Academy of Sciences 1971;68:820-823 [PMID:5279523]
 Mehdipour P., Habibi L., Mohammadi-Asl J., Kamalian N., Azin M. M. Three-hit hypothesis in astrocytoma: tracing the polymorphism D1853N in ATM gene through a pedigree of the proband affected with primary brain tumor. J Cancer Res Clin Oncol, 134, 1173-1180 (2008). DOI: 10.1007/s00432-008-0404-4.
 Mehdipour P, Mahdavi M, Mohammadi-Asl J.Atri M.Importance of ATM gene as a susceptible trait: predisposition role of D1853N polymorphism in breast cancer.Medical Oncology 2011;28:733-737 [PMID:20396981] DOI:10.1007/s12032-010-9525-0
 Mehdipour P.Azarnezhad A.Five-hit hypothesis in ATM gene: An individualized model in a breast cancer patient.Frontiers in bioscience (Elite edition) 2018;10:375-383. PMID:29293464
 Mehdipour P.*, Azarnezhad A. Eight-Hit Evolutionary Pattern in ATM Gene of a Breast Carcinoma Patient: A Personalized Approach. Journal of Cancer Research Updates, 2021, 10, 23-31.
 Mehdipour P. Evolutionary hypothesis in cell cycle of breast cancer patients:
Mosaic phases in single cancer cells. Journal of Cancer Research Updates, 2022, 11, 43-53.
 Belanger H, Beaulieu P, Moreau C, Labuda D, Hudson TJ, Sinnett D. Functional Promoter SNPs in Cell Cycle Checkpoint Genes. Human Molecular Genetics. 2005; 14: 2641- 8.
 Dickson MA. Molecular pathways: CDK4 inhibitors for cancer therapy. Clinical cancer research. 2014; 20: 3379-3383.
 Dalton S.Linking the cell cycle to cell fate decisions. Trends in cell biology. 2015; 25: 592-600.
 Turnbull C, Ahmed S, Morrison J, Pernet D, Renwick A, Maranian M, Seal S, Ghoussaini M, Hines S, Healey CS, Hughes D. Genome-wide association study identifies five new BC susceptibility loci. Nature genetics. 2010; 42: 504-507.
 Siegel P.M., Hardy W.R., Muller W.J. Mammary gland neoplasia: insights from transgenic mouse models. Bioessays. 2000; 22: 554-563.
 Salmon ES, Sartorelli AC. Cancer Chemotherapy. In: Katzung. BG, editor. Basic & Clinical Phamacology, Appleton & Lange. UK: 1998: 881-915.
 Santamaria D, Barriere, C, Cerqueira, A, et al. Cdk1 is sufficient to drive the mammalian cell cycle. Nature. 2007; 448: 811-815.
 Schwanitz G, Raff R. Application of specific cytologic, cytogenetic and molecular-cytogenetic techniques for the characterization of solid tumors. Annales Academiae Medicae Bialostocensis. 2005; 50: 91-96.
 Therman Eva. Human chromosomes, structure, behavior, effects.2nd ed. Heidelberg: Springer-Verlag,1986: 273-281.
 White MJD. Mitotic cycle. In: Human chromosomes, structure, behavior, effects. 2nd ed. Heidelberg: Springer-Verlag,Therman E, editor, 1986. 28-29.
 Mehdipour P, Pirouzpanaha S, Sarafnejad A, Atri M Shahrestani T, Haidari M. Prognostic implication of CDC25A and cyclin E expression on primary BC patients. Cell Biology International. 2009; 33: 1050-1056.
 Malumbres, M., Barbacid, M. To cycle or not to cycle: a critical decision in cancer. Nat Rev Cancer 1, 222–231 (2001). https://doi.org/10.1038/35106065
. Van den Heuvel S, Harlow Ed. Distinct Roles for Cyclin-Dependent Kinases in Cell Cycle Control. Science 1993; 262, 5142: 2050-2054.DOI: 10.1126/science.8266103
 Jing Liu, Yunhua Peng, Wenyi Wei. Cell cycle on the crossroad of tumorigenesis and cancer therapy. 2022, 32, 1, 30-44, DOI: https://doi.org/10.1016/j.tcb.2021.07.001
. Hahn W.C., Counter C.M., Lundberg A.S., Beijersbergen R.L.Mary W. Brooks & Robert A. Weinberg. Creation of human tumour cells with defined genetic elements.Nature, 1999; 400: 464–468.
. Brooks MW., Weinberg R.A. Creation of human tumour cells with defined genetic elements. Nature volume 400, pages464–468 (1999)
. Pendino F, Flexor M, Delhommeau F, and Ségal-Bendirdjian E. Retinoids down-regulate telomerase and telomere length in a pathway distinct from leukemia cell differentiation. 2001; 98 (12): 6662-6667. https://doi.org/10.1073/pnas.111464998
. Otto T., Sicinski P. Cell cycle proteins as promising targets in cancer therapy. Nature Reviews Cancer , 2017. 17: 93–115.