Prostate cancer driven by periodic bursts of genetic mutations

Sequencing of 57 prostate cancer genomes found that cancer gains a powerful advantage with abrupt intervals of complex, large-scale DNA reshuffling. This process has been dubbed punctuated cancer evolution, akin to the theory of human evolution that states that changes in a species occur in abrupt intervals. After discovering how DNA abnormalities arise in a highly interdependent manner, researchers named these periodic disruptions in cancer cells that lead to complex genome restructuring chromoplexy.

"We believe chromoplexy occurs in the majority of prostate cancers, and these DNA shuffling events appear to simultaneously inactivate genes that could help protect against cancer," said the study's co-lead investigator Mark Rubin, MD, of Weill Cornell Medical College and New York-Presbyterian Hospital/Weill Cornell Medical Center in New York, New York. The study was published in Cell (2013; doi: 10.1016/j.cell.2013.03.021).

"Knowing what actually happens over time to the genome in cancer may lead to more accurate diagnosis of disease and, hopefully, more effective treatment in the future," said Rubin. "Our findings represent a new way to think about cancer genomics as well as treatment in prostate and, potentially, other cancers."

The discovery of chromoplexy came after the research team worked collaboratively to sequence the entire genomes of 57 prostate tumors and compare those findings to sequences in matched normal tissue. An astonishing number of genetic alterations in the prostate cancer cells were revealed, with 356,136 base-pair mutations and 5,596 rearrangements found. Of these rearrangements, 113 were validated by resequencing and other methods.

Using advanced computer techniques that modeled the genomic rearrangements and copy number alterations, the scientists inferred that the chromosomal disarray in a typical tumor might accumulate over a handful of discrete events during tumor development.

"Chromoplexy is a common process by which geographically distant genomic regions may be disrupted at once, in a coordinated fashion," said Rubin. "The unifying feature is that these alterations seem to occur in a sequential, punctuated pattern which is designed to eliminate cancer-fighting genes. This suggests that genes that are active at the end of these events may drive progression of the cancer."

The study required the development of special computational tools to go beyond the pure detection, meaning presence or absence, of any particular aberration, and to quantify the dosage of the mutation; meaning, how many tumor cells have that specific mutation in the patient's tumor.

"The punctuated changes we see occur in a single cycle of cell growth, and we believe this leads to tumor cells that have a growth advantage," said Rubin. "This new model of cancer growth tells us that cells gain an advantage mutating multiple genes simultaneously as opposed to gradually."

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