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Unchecked DNA replication drives earliest steps toward cancer

(Philadelphia, PA) Although not widely appreciated as a disease of the genes, cancer is always rooted in genetic errors or problems in gene regulation. Scientists have identified some of the first genetic triggers for cancer as mutations in specific oncogenes or tumor suppressor genes. Full-blown tumors and metastatic cancers, however, often exhibit many genetic mutations, sometimes dozens in a given tumor. An important scientific question, and one with significant clinical implications, has been what happens after the initial mutation that leads to dangerous later-stage cancers with multiple damaged genes.

In a new study, researchers at The Wistar Institute answer this vital question and suggest why mutations in a certain few genes, such as the p53 tumor suppressor gene, are found in so many different cancers. Mutations in p53 are found in the majority of human cancers, for example. The Wistar team's primary observation is that an initiating genetic error can push a cell to divide relentlessly, leading to conditions of DNA replication stress. This stress leads to random errors in the DNA duplication process breaks in the DNA that disrupt genes, for example. Unless halted, this error-generating process leads to an accumulation of mutant genes in the cell and, eventually, cancer.

A report on the new findings appears in the April 14 issue of Nature and is featured on the journal's cover.

"Cancer progression is driven by these mutations," explains Thanos D. Halazonetis, D.D.S., Ph.D., professor in the molecular and cellular oncogenesis program at Wistar and senior author on the Nature study. "Once you have the initiating event, you will have constant DNA breaks. These DNA breaks create more mutations, leading to tumor progression.

"Scientists have debated for a long time whether very early precancerous cells are genetically unstable, whether they have an unusually high mutation rate. What we show in this study is that they do have a
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Contact: Marion Wyce
wyce@wistar.org
215-898-3943
The Wistar Institute
13-Apr-2005


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