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First Look at Prostate Cancer Genome Yields Insights
Date:2/9/2011

By Jenifer Goodwin
HealthDay Reporter

WEDNESDAY, Feb. 9 (HealthDay News) -- Genetic sequencing of the entire prostate cancer cell genome revealed never-before-seen changes in DNA that may contribute to tumor growth, new research finds.

By mapping the full genetic blueprint of the tumor, researchers hope the information will eventually lead to the development of more targeted drugs and a better understanding of which prostate cancers are likely to spread, one of the biggest challenges for physicians and patients.

"With additional studies and as we sequence more prostate cancer genomes, we may be able to distinguish benign from more aggressive prostate cancers and prevent unnecessary surgeries and treatments," said lead study author Michael Berger, now an assistant professor of pathology at Memorial Sloan-Kettering Cancer Center in New York City.

In the study, researchers mapped the complete genome of prostate cancer -- that is, all genetic material, including more than 20,000 genes and other DNA material surrounding the genes, for seven patients with advanced disease. The researchers then compared the cancer genome in the tumors to the normal genome in white blood cells taken from the same patients.

The investigators found various types of genetic alterations, some of which had previously been identified and others that had never been seen before. Of particular note were structural rearrangements in which relatively large chunks of DNA from one chromosome move to another location, or swap places with other pieces of DNA. These rearrangements can create "fusion genes," prevent genes from working or let the gene operate unchecked, leading to out-of-control cell growth and cancer, the authors noted.

The sequencing revealed nearly 100 such rearrangements in each patient, said Berger.

DNA rearrangements tend to happen more as cancer progresses and the cells become more fragile and damaged, but some of the rearrangements may turn out to be important to the development of the cancer in the first place, he added.

"We are doing whole genome sequencing as opposed to more targeted sequencing because it's really necessary to identify these rearrangements which are so important in prostate cancer," Berger said.

The study, conducted by researchers from the Broad Institute, Dana-Farber Cancer Institute and Weill Cornell Medical College, appears in the Feb. 10 issue of Nature.

Until recently, such DNA rearrangements were known to be important in blood cancers such as lymphoma and leukemia, said William Phelps, program director for Translational and Preclinical Cancer Research at the American Cancer Society. However, it's only more recently that researchers have started uncovering the importance of that type of genetic alteration in solid tumors such as breast and now, prostate cancers, he said.

Here's one way to conceptualize the alteration, Phelps said: "If the genome was a book, instead of just looking for out-of-place letters or misspelled words, whole genome sequencing looks for whole paragraphs that are in the wrong place.

"Because [the researchers] sequenced everything, they were able to map not only individual base changes but also how whole genes or segments of the chromosomes had moved around," Phelps said. "By sequencing everything and comparing the normal DNA (in white blood cells), they could see that not only were there individual base changes in the genes, but the genes themselves had been reshuffled in the tumor as part of the process of becoming cancer," he explained.

"If we could use those changes as a diagnostic tool that would be tremendously valuable," he added.

Whole genome sequencing also enables scientists to look not only at "coding" genes, but also "noncoding" DNA around the genes that was once thought to be "junk" but is now known to play an important regulatory role within cells, Phelps said.

Prostate cancer causes more than 30,000 deaths in the United States annually, according to background information in the article. More than 200,000 men are diagnosed each year.

Currently, it's difficult for physicians to know if prostate cancer is going to be slow-growing, in which case doctors may monitor but not treat it, or if it will be aggressive, in which case surgery and chemotherapy may be needed, said Dr. Anna Ferrari, director of the Genitourinary Cancer Program at the NYU Cancer Institute.

The researchers "have done a complete sequencing of the genome in prostate cancers that are very aggressive, and they found in addition to the already established alterations, new genes and new pathways that may influence the progression of the disease," Ferrari said. "This may point to new targets for drug development and treatment strategies."

More information

The U.S. National Cancer Institute has more on prostate cancer.

SOURCES: Michael F. Berger, Ph.D., assistant professor, pathology, Memorial Sloan-Kettering Cancer Center, New York City; William Phelps, Ph.D., program director, Translational and Preclinical Cancer Research, American Cancer Society, Atlanta; Anna C. Ferrari, M.D., director, Genitourinary Oncology Program, NYU Cancer Institute, New York City; Feb. 10, 2011, Nature


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