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Unchecked DNA replication drives earliest steps toward cancer

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 higher mutation rate th an normal through this mechanism."

Fortunately, cells have an effective on-board damage control system, managed by the p53 gene. A protein called 53BP1, the critical role of which was reported by the same Wistar group in Nature last year, senses the DNA breaks caused by replication stress and activates the p53 pathway. That pathway shuts down the replication process, thus limiting further DNA damage. In some circumstances, p53 may even force the cell into apoptosis, or programmed death, as a way to protect against the cell developing into a tumor.

If the mutations occur in p53 itself, however, or the p53 pathway is unable to completely halt the process, further mutations will occur, leading the cell to become cancerous, with the number of mutations constantly growing. So, when p53 remains intact, it is often able to prevent cancers from developing. When it suffers damage itself, cancers commonly result, explaining why p53 mutations are so frequently seen in so many different cancers.

Halazonetis notes that the same techniques used in his experiments to monitor replications stress and DNA breaks could also be used as an effective diagnostic tool to identify precancerous cells.

"The presence of DNA breaks in precancerous and cancer cells may turn out to be the Achilles heel of cancer," Halazonetis says. "It might be possible to inhibit repair of these DNA breaks, in which case the cancer cells would die."

The lead authors on the Nature study are Vassilis G. Gorgoulis and Leandros-Vassilios F. Vassiliou at the University of Athens. In addition to senior author Halazonetis, the Wistar-based coauthors on the study are Monica Venere, Richard A. DiTullio, Jr., both also affiliated with the University of Pennsylvania, Akihiro Yoneta, and Meenhard Herlyn, D.V.M., professor and leader of the molecular and cellular oncogenesis program at Wistar. The remaining coauthors are Panagiotis Karakaidos, Panayotis Zacharatos, Athanassios Kotsinas , Nikolaos G. Kastrinakis, and Christos Kittas at the University of Athens; Triantafillos Liloglou at the University of Liverpool; Brynn Levy at Mount Sinai School of Medicine, and Dimitris Kletsas at the National Centre of Scientific Research "Demokritos" in Athens.


Source:The Wistar Institute

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