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Gene Mutation vs Aneuploidy (competing theories of cancer)

“Wherefore by their fruits ye shall know them.” Jesus, according to Matthew, New Testament , 7:20 (00??) From the Sermon on the Mount. Gene Mutation vs Aneuploidy (competing theories of cancer). High Magnification Explanation of Cancer. Subtlety is not a Hallmark of cancer. Normal cells

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Gene Mutation vs Aneuploidy (competing theories of cancer)

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  1. “Wherefore by their fruits ye shall know them.”Jesus,according toMatthew,New Testament, 7:20 (00??) From the Sermon on the Mount Gene Mutation vs Aneuploidy (competing theories of cancer)

  2. High Magnification Explanation of Cancer

  3. Subtlety is not a Hallmark of cancer Normal cells 46 chromosomes Cancer cells 60-90 chromosomes

  4. Poorly Differentiated Cancer of Cervix 78 Chromosomes, DNAindex=1.7

  5. Hansemann’s Low Magnification Explanation Virchows Archiv für pathologische Anatomie und Physiologie und für klinische Medicine 123:356-370, 1891 David Hansemann 1858-1920

  6. Theodor Boveri …formulated the first aneuploidy theory of cancer in 1914 Aneuploidy is an imbalance in the number or composition of chromosomes, hence an imbalance in thousands of genes

  7. Boveri’s Mutation-Free Mechanism for the Production of Aneuploidy

  8. Autocatalyzed Progression of Aneuploidy isCarcinogenesis

  9. How Cancer Starts and Progresses copies Normal cell (DNAindex= 1.0) 8 4 2 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 Chromosome Number

  10. How Cancer Starts and Progresses copies Initiation & Pre-cancer (0.5  DNAindex1.2) 8 Low level aneuploidy caused by radiation, carcinogen, bad cell division 4 2 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 Chromosome Number

  11. How Cancer Starts and Progresses Early cancer Tetraploidization (DNAindex≈ 1.9) copies 8 4 2 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 Chromosome Number

  12. How Cancer Starts and Progresses copies Mature Cancer (DNAindex≈ 1.7) 8 4 2 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 Chromosome Number

  13. The Molecular Basis of Dominance Kacser H & Burns JA. Genetics 97:639-666, 1981 “dominant-negative” Mutation of one gene is undetectable in multi-gene phenotype

  14. DATE Applied to Cancer DATE analysis is a modification of MCA Rasnick & Duesberg (1999) Biochem J 340:621-630

  15. DATE Analysis Fundamental Equation • Fa, aneuploid   phenotype • , aneuploid • fraction • , ploidy factor Fa represents the phenotype of a cancer cell relative to the normal cell.

  16. Properties of Aneuploid Cells Live tetraploid births Massive change in gene dose produces highly non-linear (i.e. qualitative) changes in the physiology and metabolism of cells and tissues. f (aneuploid fraction) p (fold change) Fd (diploid) Fa (aneuploid) Live triploid births cancer

  17. There is an infinite number of combinations of f and p but there are optimal values of f and p At equilibrium, f=0.7 & DNAindex=1.7 for mature solid cancer

  18. Aneuploidy Diagnostic of All Stages of Cancer Normalized average CI=1.7 Normal cells on same slide

  19. Our Results Confirm Bulten et al. Chromosomes 7 & 17 equally useful for detecting cervical cancer percent of cells aneuploid for Cep-7 percent of cells aneuploid for Cep-17

  20. Hariu & Matsuta Confirm Bulten et al. Chromosomes 1&17 equally useful for cervical cancer AND Suggests the fraction of aneuploid cells is diagnostic of stage 0 N CIN1 CIN2 CIN3 CI CANCER

  21. Hallmark of Cancer, Genetic Instability, is Quantifiable A measure of genetic instability is the imbalance between overall metabolic activity (Fa) and DNA content of aneuploid cells. SF=flux stability index (0SF1) Rasnick & Duesberg (1999) Biochem J 340:621-630

  22. Predicted Curve of Stability Index SF 1.0 Most unstable DNAindex is halfway between diploid and tetraploid S 0.9 0.8 1.0 1.5 2.0 DNA index

  23. Aneuploid Cells in Culture Confirm Genetic Instability Theory Colon cancer cell line data from Lengauer et al. (1997) show that the least stable cells have DNA indices halfway between diploid and tetraploid values. Rasnick & Duesberg (1999) Biochem J 340:621-630 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.5 1.0 1.5 2.0 2.5 3.0

  24. DATE Applied to Colon Cancer Rasnick & Duesberg (1999) Biochem J 340:621-630 …analyzed… colon cancer data from Zhang et al. (1997) Science 276:1268-1272

  25. Autocatalyzed Progression of Aneuploidy Explains the Time Course of Human Cancer Equation (solid line) fitted to data from Armitage & Doll (1954) Br J Cancer 8:1-12. Broken lines are for best-fit 7-gene mutation model. lung men lung women breast prostate colon men cervical Rasnick, D (2000) Biochem J 348:497-506

  26. Closing Comment • The “my-favorite-gene” approach of molecular biology is hopelessly inadequate when trying to understand and explain multi-gene phenotypes. However, dynamical methods, such as MCA and DATE, provide powerful new tools for investigating complex phenotypes that span many orders of magnitude.

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