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Large-scale genetic changes drive breast cancer

A commonly accepted view of cancer is that tumors occur when cells accumulate a series of mutations in key genes. In a new study, researchers extend this notion from individual genes to regions of the genome. They report that DNA duplications or losses in human cells alter the activity of hundreds of genes, and these changes may spur the transformation of healthy cells into tumors.

The widespread loss or gain of DNA has "a large, pervasive and direct effect" on the behavior of genes in breast cancer tumors, the researchers found. Patrick O. Brown, a Howard Hughes Medical Institute investigator at Stanford University School of Medicine in California, led the study.

Diagram comparing DNA copy number and gene expression. View full

"For years, people have thought of cancer in terms of the effects of gaining or losing an individual gene," says Jonathan R. Pollack, a Stanford researcher on the team. The loss or gain of DNA can be localized to a single gene or group of genes; or it can occur on a larger scale, involving part or all of a chromosome.

"This study shows that when you gain or lose chromosomes, you are altering the normal expression levels of hundreds or thousands of genes across the genome," says Pollack. Normal cells have two copies of most genes—unless DNA is copied or deleted, as often happens in cancer.

Using gene chips representing more than 6,000 genes, the researchers tracked changes in DNA relative to changes in gene activity in the cell. At least 60 percent of the highly duplicated genes in breast cancer cells were significantly more active than normal, according to their report in Proceedings of the National Academy of Sciences.

The increased expression of these genes, the researchers say, may disrupt the life cycle of the cell and contribute to the development or progression of tumors. Cells apparently do not have a mechanism to compensate for the altered number of genes and produce the correct number of gene products.

Even in diseases involving the gain or loss of an entire chromosome, most studies have focused on how that change affects a single gene on that chromosome.

Pollack's team analyzed tumor cells that were missing, for example, a region of chromosome 17 that contains an anti-cancer gene. They found that the deletion had effects on gene expression far beyond the loss of one gene.

"Our data suggest that you're not only losing the expression of a tumor-suppressor gene, but also as many as several hundred nearby genes," says Pollack. "This may have consequences that contribute to the development or progression of a tumor."

Another study, published earlier this year in Cancer Research, found very different results in colon cancer cells. Only four percent of the highly duplicated genes were significantly more active than normal. Sanford Markowitz, of Case Western Reserve University School of Medicine in Cleveland, Ohio, led the study.

The differences between the two studies may be related to the types of cancer or how the studies were conducted. The Stanford group is currently repeating the breast cancer study with other cancers and getting similar results, according to Pollack. The data indicate that changes in the numbers of genes are driving significant changes in the expression of those genes.

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Pollack, J.R. et al. Microarray analysis reveals a major direct role of DNA copy number alteration in the transcriptional program of human breast tumors. Proc Natl Acad Sci USA. Published online September 24, 2002.
Platzer, P. et al. Silence of chromosomal amplifications in colon cancer. Cancer Res 62, 1134-1138 (February 15, 2002).

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