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Researchers sequence the genome of prostate cancer, a step toward identifying aggressive tumors

Boston researchers have sequenced the genomes of prostate tumors from seven men, a “landmark event” that promises eventually to help clinicians learn how to differentiate between those tumors that will be highly aggressive and require immediate treatment and those that are essentially benign and that can be simply observed.

“This is a transforming moment in understanding the underlying biology of prostate cancer,” said geneticist Michael F. Berger of the Broad Institute of MIT and Harvard University, lead author of the paper appearing online Wednesday in the journal Nature.

Geneticists have been sequencing a variety of tumors of different types, but the effort on prostate tumors introduces a new level of complexity. For each of the tumors, the researchers sequenced not only the genome of the tumor itself, but also the genome obtained from white blood cells of the patient so they they could identify any changes that had occurred. That produced a tremendous amount of data. If the data for each genome were presented in the form of a printed telephone book, noted Dr. Jonathan W. Simons, president and chief executive of the Prostate Cancer Foundation in Santa Monica, it would form a book 35 feet high.

The team found a median of 3,866 so-called point mutations in each tumor -- that is, single base changes in the roughly 3 billion bases that make up the human genome. That is about the same number that appear in acute myeloid leukemia and breast cancer, but only about one-tenth of the number found in small cell lung cancer and melanoma. Many of these single-gene changes are undoubtedly simply “passenger” changes that play no role in tumor formation, but others are likely to be driving forces in tumor growth. Identifying which are which will become more easy when more tumors are sequenced, Berger said.

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But what really surprised the researchers, said geneticist Levi Garraway, a co-author from the Dana-Farber Cancer Institute, was the wholesale shuffling of large segments of the genomes, with relatively big chunks of DNA broken out from one site and reinserted elsewhere. The team found more than 100 such rearrangements, far more than had been observed in any other form of cancer studied so far. “Not only were they much more common than one might have imagined, but there were certain patterns,” Garraway said. “It’s important for prostate cancer, but it might be telling us something fundamental about how cancer genomes become messed up in the first place.”

Several of the tumors, for example, contained rearrangements that interfered with the activity of genes that are known to suppress tumor formation. Drugs that replace the activity of these genes are now under study and might be appropriate in prostate cancer therapy. Several other rearrangments also suggest potential therapies that have not yet been tried for prostate cancer.

Each genome took less than three months to sequence and cost about $25,000, Berger said, a far cry from the years and billions of dollars that were required to sequence the first human genome a decade ago. In a best case now, he said, the analysis could be performed in two to three weeks and cost less than $20,000, and he thinks the cost could come down to less than $5,000 in a couple of years. Moreover, as researchers sequence more tumor genomes and identify what they call hotspots of genetic variation, it may not be necessary to sequence the whole genome of a patient’s tumor, but only selected regions, which would reduce the cost even further.

All of the tumors sequenced so far have been from patients with high-risk tumors, so the team is not yet able to differentiate between aggressive and benign tumors. “It may well be that indolent tumors have much quieter genomes,” Garraway said. “It raises the intriguing possibility that, if we were to apply this more widely, given the richness of the patterns we are seeing, there might be features we could sort out that would tell us [which tumors] are going to remain quiet and which are going to be bad actors.”


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