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Aneuploidy in Cancer.

For over 30 years, researchers have sought mutated regulatory genes (oncogenes), believed to cause cancer. The failure to find any oncogene whose presence on its own initiates cancer has pushed some researchers to reconsider a 100-year-old theory, first proposed by German scientist Theodor Boveri: the aneuploid cancer theory. The aneuploid theory focuses on chromosomes instead of genes. Normal human cells have pairs of 23 standard chromosomes (a diploid karyotype). All cancer cells, however, have highly irregular chromosome patterns (aneuploid karyotypes): "entire chromosomes, which carry thousands of genes, are ... severely scrambled--duplicated, broken, structurally rearranged or missing entirely," says molecular biologist Peter Duesberg in a 2007 article for Scientific American.

A missing chromosome means that the genes it holds are also gone--genes that regulate the expression of important proteins. Conversely, extra copies of a chromosome means more copies of the genes and more of the corresponding polypeptides. "Such gross imbalances would inevitably disrupt the work of critical teams of enzymes, including those involved in repair or disposal of damaged DNA, and would destabilize cellular structures and regulatory circuits," Duesberg explains. Usually, cells that become aneuploid during mitosis do not survive. Those that do will propagate increasingly irregular cells, eventually forming a tumor. "Once cancer progression is underway, random chromosome reshuffling can rapidly generate gratuitous traits that include lethal properties such as drug resistance and metastasis," says Duesberg.

The aneuploid theory was tossed aside about 50 years ago because researchers were unable to detect any chromosomal patterns with available technology. New technology, however, lets researchers track chromosomal changes using colored DNA-specific probes. Research teams are finding chromosomal patterns in the same cancer types found in different people. Duesberg says that these patterns may reflect essential chromosome changes needed to create a viable aneuploid cell from the original normal tissue. Researchers are also finding chromosomal patterns associated with cancer stage, metastatic potential, and drug resistance.

All carcinogens cause aneuploidy, even though they may not cause genes to mutate. Asbestos, aromatic hydrocarbons, nickel, arsenic, lead, plastic and metallic prosthetic implants, and dioxin are among the carcinogens that disrupt chromosomes but do not cause gene mutation. Duesberg says, "The dose of carcinogen needed to initiate the process that forms malignant tumors years later was found to be less than one-thousandth the dose required to mutate any specific gene."

If the aneuploid theory proves correct, diagnosticians will be able to distinguish early cancers from benign tumors by looking for aneuploidy. They will also be able to use chromosomal patterns to determine cancer cells' metastatic potential and drug resistance. Moreover, regulators and manufacturers will be able to identify aneuploid-inducing substances before adding them to foods, drugs, and other consumer products.

Perhaps, cancer prevention can go even one step further and identify factors that decrease aneuploidy and encourage cells to remain diploid.

Duesberg P. Chromosomal chaos and cancer. Sci Am. May 2007;53-59. Available at www. Accessed June 29, 2015.

briefed by Jule Klotter
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Title Annotation:Shorts
Author:Klotter, Jule
Publication:Townsend Letter
Date:Aug 1, 2015
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