Almost 10 years to the day after the human genome sequence was completed, a group of researchers has unveiled the first whole genome sequences of prostate tumors. Their results, published online today in Nature, may lead to the development of more efficient, less invasive ways to diagnose and treat this cancer.
Sequencing the whole genome of a prostate tumor, says co-author Levi Garraway, a physician and biologist at Harvard Medical School in Boston, allowed the researchers to see "biology that would have been invisible with any other method." Most genetic analyses of tumors have focused on figuring out which mutations turn normal cells cancerous and how these "spelling errors" foster tumor growth.
But by sequencing the entire genomes of seven prostate tumors and comparing them with genomes from the patients' normal cells, the researchers discovered an unexpected phenomenon. Rather than single spelling errors, the tumors had long "paragraphs" of DNA that appeared to have broken off and moved to another part of the genome.
These migrations were not random. The chunks of DNA that broke off all contained genes that help drive cancer progression, and they moved to prime locations in the genome where they would be most active. In the prostate, these areas are often controlled by testosterone and other male hormones. How these self-promoting genes jump to these prime locations remains a mystery, but the researchers believe it may have to do with the DNA's three-dimensional structure in particular areas that allows for genetic rearrangement when the genome is being copied or when certain genes are active. Then natural selection takes over to pick out the most rapidly growing cells in the prostate.
Several of the relocated genes hadn't previously been linked to cancer. One, MAGI2, appears to interact with a known cancer pathway. That's exciting, says co-author Mark Rubin, a pathologist at Weill Cornell Medical College in New York City, because this pathway may be a "druggable" target in prostate cancer.
Alexis Borisy, CEO of Foundation Medicine, a cancer diagnostics company in Cambridge, Massachusetts, that studies how genetics can be translated into therapies, says that the study is "an excellent example of a coming wave of information from cancer genomes" that he expects to be sequenced in the future through the Cancer Genome Atlas and other projects. With the decreasing cost and increasing efficiency of genome sequencing, he predicts that sequencing a cancer genome in a patient will soon become a standard of care, similar to an magnetic resonance imaging scan before surgery.
Once researchers learn which genes may be markers for cancer, Rubin says, this type of sequencing technology is so powerful that it might be able to detect them in a blood or urine test, replacing an invasive prostate exam or biopsy. "We're right at the cusp of being able to do sequence-based diagnosis," he says.
In the short term, says Borisy, one of the most important things to learn from a genome would be how to distinguish an aggressive prostate tumor from a nonaggressive one. The prostate-specific antigen (PSA) test, the only prostate cancer test currently used in the clinic, has been controversial as it tends to diagnose cancer in men who don't have aggressive tumors, often leading to unnecessary surgeries.
Sudhir Srivastava, chief of the Cancer Biomarkers Research Group at the National Cancer Institute in Bethesda, Maryland, says that the prostate cancer genome could lead to a "companion diagnosis" test for the PSA test and spur the search for new drug targets. He adds that the current study is not there yet. Seven tumors, he says, is not a large enough sample to see the entire spectrum of mutations in prostate cancer.
The authors agree that the findings need to be validated in more patients. They're continuing to sequence prostate tumors to learn how frequently different mutations occur, as well as studying which of the rearranged genes are actually driving cancer.
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