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Researchers Unearth New Clues About How Prostate Cancer Evolved

Published: Thursday, May 16, 2013
Last Updated: Thursday, May 16, 2013
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With the help of a computational model, Broad researchers were able to reconstruct the genomes of prostate cancer cells.

Imagine you’re visiting the Acropolis. You tour the ruins, taking snapshots as you go. Later, at home, you tell your family and friends about your visit and someone, noticing the building’s advanced deterioration, asks: well, how did it get that way? Now, say you knew nothing about the Acropolis, and could only rely on your photos and memory to describe the place. What would you say? Without the rich archeological history of the Acropolis, you’d be missing a huge part of the story.

Now imagine a cancer cell as a similar kind of ruin. Over time mutations accumulate, pushing the cell further and further from its original shape and function, eventually overwhelming its ability to control growth. When scientists sequence a cancer genome, the resulting data is essentially a snapshot of the tumor and its mutations at the time it was sampled. But what stories would emerge if we knew the order in which those mutations occurred?

In the case of prostate cancer — the second most lethal cancer in American men — research has demonstrated that structural genomic alterations, such as broken and rearranged chromosomes, are key to tumor development and progression. With no evidence to suggest a chronology for these breaks and repairs, researchers generally assumed that they accumulated gradually over time, often as a result of cell division. But new research is suggesting the deterioration isn’t gradual at all.

For the first time, a team of scientists from the Broad, Dana-Farber Cancer Institute, and Weill Cornell Medical Center has revealed the “cellular archeology” of prostate cancer cells. Using a computational model, the team was able to track how mutations accumulated in the genomes of 55 prostate cancer tumors. The results of the study, recently published in Cell, revealed that mutations often occur in abrupt, interconnected bursts, resulting in large-scale rearrangement of DNA.

“We’ve known for a long time that the rearrangement of certain chromosomes is key to the development of prostate cancer and we suspected they were the result of some very complex DNA-damaging events,” says Sylvan Baca, the study’s first author and cellular Indiana Jones. As a researcher in Broad senior associate member Levi Garraway’s lab and part of the Broad/Dana-Farber/Weill Cornell team, Baca had observed how the genomes of prostate cancer cells appeared as if they’d been taken apart and put back together the wrong way. In an attempt to fill in the gaps in the story, Baca developed ChainFinder — a modeling algorithm that was able to reconstruct the shattered genomes and determine the chronology of the alterations.

“Interestingly, our findings indicate that many of these rearrangements arise in a highly interdependent fashion, and may often occur together within a single cell,” said Baca, who along with the other members of the team, dubbed these damaging events “chromoplexy” from the Greek word to interweave or integrate. Similar to the idea of punctuated evolution in the population sciences — which suggests that that major genetic changes can happen to select populations in a relatively small window of time — chromoplexy indicates that sets of mutations may originate together, drastically altering cells.

“While we can’t yet say much about the timing of the events, or what the events are, the study suggests that just a few of these events may be enough to lead to the changes we know result in prostate cancer,” says Baca. A major goal of prostate cancer research is to identify new drug targets, as well as genetic characteristics that could distinguish aggressive forms of the disease. While researchers are currently working to further understand the initiating source of these events, Baca speculates that in the future profiling cells for chromoplexy may be a way to identify certain “linchpin” mutations in particular cancers.

The idea that periodic bursts of genetic upheaval, resulting in a cascade of changes eventually leading to tumor growth, has been hinted at in other cancers — but the identification of chromoplexy suggests this sort of genomic derangement may be far more common than previously thought.

“The complex genomic restructuring we discovered is a unique and important model of carcinogenesis which likely has relevance for other tumor types,” said Garraway, a co-senior author of the study. The team is now using ChainFinder to study other cancers known for containing complex genetic rearrangements, including lung adenocarcinoma, melanoma, and breast cancer, to see if those changes are also the result of chromoplexy.


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