Aneuploidy and Cancer: From Correlation to Causation

Abstract

Conventional genetic theories have failed to explain why cancer (1) is not found in newborns and thus not heritable; (2) develops only years to decades after 'initiation' by carcinogens; (3) is caused by non-mutagenic carcinogens; (4) is chromosomally and phenotypically 'unstable'; (5) carries cancer-specific aneuploidies; (6) evolves polygenic phenotypes; (7) nonselective phenotypes such as multidrug resistance, metastasis or affinity for non-native sites and 'immortality' that is not necessary for tumorigenesis; (8) contains no carcinogenic mutations. We propose instead that cancer is a chromosomal disease: Accordingly, carcinogens initiate chromosomal evolutions via unspecific aneuploidies. By unbalancing thousands of genes aneuploidy corrupts teams of proteins that segregate, synthesize and repair chromosomes. Aneuploidy is thus a steady source of karyotypic-phenotypic variations from which, in classical Darwinian terms, selection of cancer-specific aneuploidies encourages the evolution and subsequent malignant 'progressions' of cancer cells. The rates of these variations are proportional to the degrees of aneuploidy, and can exceed conventional mutation by 4-7 orders of magnitude. This makes cancer cells new cell 'species' with distinct, but unstable karyotypes, rather than mutant cells. The cancer-specific aneuploidies generate complex, malignant phenotypes, through the abnormal dosages of the thousands of genes, just as trisomy 21 generates Down syndrome. Thus cancer is a chromosomal rather than a genetic disease. The chromosomal theory explains (1) nonheritability of cancer, because aneuploidy is not heritable; (2) long 'neoplastic latencies' by the low probability of evolving competitive new species; (3) nonselective phenotypes via genes hitchhiking on selective chromosomes, and (4) 'immortality', because chromosomal variations neutralize negative mutations and adapt to inhibitory conditions much faster than conventional mutation. Based on this article a similar one, entitled 'The chromosomal basis of cancer', has since been published by us in Cellular Oncology 2005;27:293-318. Copyright © 2006 S. Karger AG, Basel Despite over 100 years of cancer research, the cause of cancer is still a matter of debate . We propose here that the problem of cancer is still

Modelling Malignant Progression with a Finite State Machine Supports a Two Checkpoint Theory of Cancer

“…The alternative theory of malignant progression, the Duesberg hypothesis [4], can be modelled by assuming that the obligatory first step is formation of an aneuploid cell ( Figure 2). This has two important consequences for the daughter cells.…”

“…This undoubtedly occurs, but the dynamics of malignant progression suggests that it may not be the whole story. A number of authors have recently postulated that the essential event in malignant transformation is loss of function of the mitotic spindle assembly checkpoint [3][4][5][6].…”

“…Loss of control of these checkpoints has been described in cancer by many authors [3][4][5][6][7][8], and these events have been considered to be part of the multi-stage process often described as malignant progression.…”

MOS, aneuploidy and the ploidy cycle of cancer cells

“…It is clear that, although genetic change and tumor progression require CIN (which results in miss-segregation of chromosomes and aneuploidy), limitless accumulation of CIN ultimately interferes with a cells capacity to divide (Cahill et al, 1999;Duesberg et al, 2006;Weaver and Cleveland, 2007;Chandhok and Pellman, 2009). In a recent paper (Vitale et al, 2010), a decrease in aneuploidy through unstable transient tetraploidy to para-diploidy was reported for the first time.…”

Detección de aneuploidías del cromosoma 17 y deleción del gen TP53 en una amplia variedad de tumores sólidos mediante hibridación in situ fluorescente bicolor

“…Numerosos estudios informan la presencia de aneuploidías en casi todos los tumores sólidos humanos que se han analizado (2,4). Los recientes trabajos realizados por Duesberg et al (5) están dirigidos a corroborar la anterior teoría y en ellos se establece que la inestabilidad cromosómica de las células tumorales es proporcional al grado de la aneuploidía o del desequilibrio cromosómico (6). Por esta vía, las alteraciones cromosómicas afectan la expresión de genes clave, como son los del control del ciclo celular, de la estabilidad genómica, de la angiogénesis, de la apoptosis y de la reparación, entre muchos otros (4).…”