‘Punctuated evolution’ drives PCa development

A new closer look at genomes in prostate cancer has revealed that genetic mutations occur in abrupt, periodic bursts, causing complex, large-scale reshuffling of DNA driving the development of the disease.

Reporting their findings in Cell (2013; 3:666-7), study authors call this process "punctuated cancer evolution," akin to the theory of human evolution that states changes in a species occur in abrupt intervals. After discovering how DNA abnormalities arise in a highly interdependent manner, the authors 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 co-lead investigator Mark Rubin, MD, of Weill Cornell Medical College and New York-Presbyterian Hospital/Weill Cornell Medical Center, New York.

"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 Dr. Rubin.

The discovery of "chromoplexy" came after the authors sequenced the entire genomes of 57 prostate tumors and compared those findings to sequences in matched normal tissue.

This study sequenced 57 prostate cancer genomes as well as the entire genomes of matched normal tissue. Researchers revealed a large number of genetic alterations in the prostate cancer cells-356,136 base-pair mutations and 5,596 rearrangements that were absent from normal DNA. Of those rearrangements, 113 were validated by re-sequencing and other methods.

"We saw wholesale rearrangements of chromosomes-the cutting up and retying of chromosomes-mutations we have never seen on that scale," said co-author Levi Garraway, MD, PhD, of the Broad Institute, Cambridge, MA, and Dana-Farber Cancer Institute, Boston. "Our research teams then charted a path of oncogenic events that appeared to drive prostate cancer."

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

"The rearrangement of chromosomes can coordinately affect specific genes, which provides a selective advantage for cancer growth," Dr. Garraway said.