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Genomic Chaos And Cellular Evolution Lead To Colorectal Cancer

BUFFALO, NY - Cellular evolution, at a vastly accelerated rate and guided by natural selection, transforms normal cells into malignant cells. Results of new research on colorectal cancer tumors and premalignant polyps published in the December 21 issue of the Proceedings of the National Academy of Sciences, show that cancer arises from a decade or more of cellular changes arising from a profound loss of DNA stability.

"We have found that in colorectal cancer in the general population (sporadic colorectal cancer), malignancy is not the end result of a few mutations, but rather the consequence of exceptionally unstable cells that have had years to evolve into cancer," said Garth R. Anderson, PhD, Department of Cancer Genetics at Roswell Park Cancer Institute (RPCI) and senior author of this paper. "We estimate that at least 11,000 individual genomic events have occurred in each tumor cell."

The team of seven geneticists, molecular biologists and surgeons from RPCI and the University of Montreal Hospital Center used a technique called inter-(simple sequence repeat) PCR (polymerase chain reaction} to sample a number of diverse regions of the genome simultaneously. They compared tumor DNA to normal tissue DNA from 58 consecutive sporadic colorectal cancer and 12 premalignant polyp patients. By determining the number of events that had occurred within the sampled segments of the genome, and defining what fraction of the entire genome was being sampled, the investigators were able to compute the approximate total number of genomic events that had occurred in each tumor.

"A comparison of products amplified from tumor DNA and normal tissue DNA from the same patient reveals a unique pattern of bands. Most products are identical, although in cases where tumor-specific rearrangements occurred, new products are seen and other products disappear," said Daniel Stoler, PhD, Department of Experimental Pathology, RPCI.

The authors point out that the results of this research have relevance at both clinical and therapeutic levels, beyond providing a clearer picture of what cancer fundamentally is. "Being able to quantitate the degree of genomic instability in early-stage tumors should provide insights as to prognosis; particularly in breast and prostate cancers, which are widely detected in early-stage disease, but where only a fraction progress," notes Dr. Anderson. "More attractive therapeutic approaches, in view of our findings, appear to include cancer prevention in the form of stabilizing the genome before progression to cancer can be completed. Once cancer exists, the numerous events and evolved nature of the disease cause each tumor to contain a diverse population of cells, which are unlikely to respond to therapy in an uniform manner. Thus, for patients with cancer, targeting genomically stable non-tumor cells essential for the tumor's survival, such as disrupting the blood supply, offers great promise. Of course, early detection and surgical removal of the entire tumor remains the best treatment of all.

Roswell Park Cancer Institute, founded in 1898, is the nation's first and one of its largest cancer research, treatment and education centers and is the only National Cancer Institute-designated comprehensive cancer center in Western New York.

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