Aneuploidy Theory of Cancer


By David Rasnick

David Rasnick (Ph.d) is a visiting scientist at the University of California, Berkeley


April 1, 2002 - Peter Duesberg and I are increasingly asked what will it take to convince others of the truth of the aneuploidy theory of cancer. That shows we are making some progress, at least. Our work on aneuploidy and cancer was discussed in the Scientific American last year [1], but here is a brief overview of the subject for those who are still in the dark.

Normal human cells have 23 different chromosomes that come in pairs. They yield a total of 46 chromosomes. Such cells are said to be "diploid." Cells found in solid tumors, on the other hand, typically have between 60 to 90 chromosomes [2]. Their ploidy is "not good," in other words, and the Greek version of that is "aneuploid." It is a word that you will have a hard time finding in the cancer textbooks.

Recall that the genes (of which there may be 40,000 or so in humans) are strung along the chromosomes, so that each chromosome contains thousands of genes. Any cell with a chromosome number different from 46, or with an abnormal complement of chromosomes that add up to 46, is an aneuploid cell. Thus, aneuploid cells contain an imbalance in the complement of genes and chromosomes compared to the normal or "diploid" cell. This imbalance in the chromosomes leads to a wide variety of problems, one of which is cancer.

Another problem is Down’s Syndrome. This results when a baby is born with three copies of chromosome 21 instead of the normal two. Just one extra copy of the smallest chromosome, with its thousand or so normal genes, is sufficient to cause the syndrome [3]. Most Down’s fetuses are spontaneously aborted.

Nonetheless, the imbalance is small enough (47 chromosomes) to permit occasional live births. The level of aneuploidy is therefore far below the threshold of 60-90 chromosomes found in invasive cancer, but it gives these patients a head start toward developing the same cancers that normal people get. Down’s Syndrome patients have up to a 30-fold increased risk of leukemia, for example, compared to the general population [4,5].

There is one important difference between the small aneuploidy found in Down’s Syndrome, and the more pronounced aneuploidy of cancer cells. With Down’s, the defect occurs in the germ line and so the chromosomal error is present in every cell in the body. But the defect that gives rise to the unbalanced complement of chromosomes in cancer cells is "somatic". That is, it occurs in a particular cell after the body is formed.

In the course of life, cells constantly divide by a process called mitosis. When errors in mitosis occur, as they often do, the possibility exists that a daughter cell will be aneuploid.

Aneuploidy destabilizes a cell in much the same way that a dent disrupts the symmetry of a wheel. It leads to ever-greater distortions with each revolution. As aneuploid cells divide, their genomes become increasingly disorganized to the point where most of these cells stop dividing and die. But rarely, and disastrously, an aneuploid cell with the right number and combination of extra chromosomes wins the genetic lottery and keeps right on going. Then it has become a cancer cell.

Cells with a normal number of chromosomes are intrinsically stable and not prone to transformation into cancer. What, therefore, causes normal cells to become aneuploid? That is a hotly contested question. It is known, however, that if radioactive particles strike the nucleus of a cell, chromosomes can be shattered. When that damaged cell then divides by mitosis, an error may arise. Chromosomal imbalance may then result.

Radiation can cause aneuploidy, in short. And certain chemicals, such as tars, also give rise to aneuploid cells. Tars and radiation sources are known carcinogens. In fact, all carcinogens that have been so far examined do cause aneuploidy.

That is a very convincing argument for the aneuploidy theory of cancer, but in order to understand the controversy one must understand the alternative theory. Everyone has heard of it, because it is in the newspapers all the time. It is the gene-mutation theory of cancer. According to this theory, certain genes, when they are mutated, turn a normal cell into a cancer cell.

This theory has endured since the 1970s, and more than one Nobel Prize has been awarded to researchers who have made claims about it. One prize-winner was the former director of the National Institutes of Health, Harold Varmus. According to some researchers, the mutation of just three, or perhaps several genes, may be sufficient to transform a normal cell into a cancer cell.

In contrast, chromosomal imbalance disrupts the normal balance and interactions of many thousands of genes, because just one chromosome may contain several thousand genes. And a cancer cell may have several copies of a given chromosome. For this reason alone, aneuploidy is likely to be far more devastating to the life of a cell than a small handful of gene mutations.

The fundamental difference between the aneuploidy theory and the reigning gene-mutation theory may be put this way. If the whole genome is a biological dictionary, divided into volumes called chromosomes, then the life of a cell is a Shakespearean drama. If one were to misspell a word here and there, in Hamlet for example, such "mutations" would be irrelevant to the vast majority of readers, or theater-goers. A multicellular organism is at least as resistant to "gene mutations" as a Shakespeare play.

On the other hand, without "mutating" a single word, one could transform the script of Hamlet into a legal document, a love letter, a declaration of independence, or more likely gibberish, by simply shifting and shuffling, copying and deleting numerous individual words, sentences and whole paragraphs.

That is the literary equivalent of what aneuploidy does. The most efficient means of rewriting a cell’s script is the wholesale shifting and shuffling of the genes, which aneuploidy or chromosomal imbalance accomplishes admirably.

Aneuploidy is known to be an efficient mechanism for altering the properties of cells, and it is also conceded that aneuploid cells are found in virtually all solid tumors. Bert Vogelstein of Johns Hopkins University has said that "at least 90 percent of human cancers are aneuploid." The true figure may be 100 percent. For references supporting the claim that cancers are invariably aneuploid see Li et al. 2000 [14].

Nonetheless, the presence of mutations in a handful of genes continues to be viewed as a significant, even a causal factor in carcinogenesis, even though any given mutated gene is found in only a minority of cancers. Cells with mutated genes can indeed be found in cancerous as well as normal cells, but the most likely reason is that they are innocuous.

Hence they are readily accommodated during the expansion of barely viable aneuploid cells as they compete for survival with their more viable chromosomally balanced counterparts. The current emphasis in cancer research on the search for mutant genes in a perpetual background of aneuploidy is a classic example of not seeing the forest for the trees.

Thomas Kuhn remarked that the great theoretical advances of Copernicus, Newton, Lavoisier, and Einstein had less to do with definitive experiments than with looking at old data from a new perspective. Sufficient (indeed overwhelming) evidence is already in hand to convict aneuploidy of the crime of cancer and release gene mutations from custody [6-17].

Nevertheless, the gene-mutation theorists, when faced with the undeniable evidence that aneuploidy is necessary for cancer, have adopted a fall-back position. They argue that gene mutations must initiate the aneuploidy [18], or as the Scientific American reported, referring to a researcher in Vogelstein’s lab, "[Christoph] Lengauer insists aneuploidy must be a consequence of gene mutations" [1].

There would be no need for him to "insist" if there were proof that gene mutations really do cause cancer. What would gravely weaken the aneuploidy theory would be confirmed cases of diploid cancer (in which the tumor cells have balanced chromosomes), and with the culprit genes found lurking in every cell.

That would go a long way toward proving the gene mutation theory. But where has that been demonstrated? It would be a front-page story. The truth is that researchers have not yet produced any convincing examples of diploid cancer.

In fact, the evidence is going the other way. There is a growing list of carcinogens that do not mutate genes at all. In addition, there are no cancer-specific gene mutations. Even tumors of a single organ rarely have uniform genetic alterations. And, in a rebuttal that should be decisive, no genes have yet been isolated from cancers that can transform normal human or animal cells into cancer cells.

Furthermore, the latent periods between the application of a carcinogen and the appearance of cancer are exceedingly long, ranging from many months to decades. In contrast, the effects of mutation are instantaneous.

If the medical profession and biotechnology industries were to embrace the aneuploidy theory of cancer, cancer research and the flood of new technologies would at last become biologically and clinically relevant. There are, however, two formidable barriers to the ascendance of the aneuploidy theory of cancer: the first is conceptual; the second is political and sociological.

WITH THANKS — to Tom Bethell and Anthony Liversidge for advice and criticism and especially for making the article more accessible and understandable to non-scientists

Overcoming the Conceptual Barriers

David Rasnick, PhD


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