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“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.

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Presentation on theme: "“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."— Presentation transcript:

1 “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)

2 High Magnification Explanation of Cancer

3 Normal cells 46 chromosomes Subtlety is not a Hallmark of cancer Cancer cells chromosomes

4 Poorly Differentiated Cancer of Cervix 78 Chromosomes, DNA index =1.7

5 Virchows Archiv für pathologische Anatomie und Physiologie und für klinische Medicine 123: , 1891 Hansemann’s Low Magnification Explanation David Hansemann

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 is Carcinogenesis

9 How Cancer Starts and Progresses copies Normal cell (DNA index 1.0) (DNA index = 1.0) Chromosome Number 2 4 8

10 How Cancer Starts and Progresses copies Initiation & Pre-cancer (0.5  DNA index  1.2) Low level aneuploidy caused by radiation, carcinogen, bad cell division Chromosome Number

11 How Cancer Starts and Progresses copies Early cancer Tetraploidization (DNA index 1.9) (DNA index ≈ 1.9) Chromosome Number

12 How Cancer Starts and Progresses copies Mature Cancer (DNA index 1.7) (DNA index ≈ 1.7) Chromosome Number

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

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

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

16 Properties of Aneuploid Cells Massive change in gene dose produces highly non- linear (i.e. qualitative) changes in the physiology and metabolism of cells and tissues.  (aneuploid fraction)  (fold change) F d (diploid) F d (diploid) F a (aneuploid) F a (aneuploid) Live tetraploid births Live triploid births cancer

17 but there are optimal values of  and  At equilibrium,  =0.7 & DNA index =1.7 for mature solid cancer There is an infinite number of combinations of  and 

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

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 AND Suggests the fraction of aneuploid cells is diagnostic of stage 0 NCIN1CICANCERCIN2CIN3

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

22 Predicted Curve of Stability Index S F Most unstable DNA index is halfway between diploid and tetraploid S 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:

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

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. Rasnick, D (2000) Biochem J 348: lung men lung women breast cervical prostatecolon men

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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