Some tumors contain massive DNA molecules that are undeniably reminiscent of Frankenstein: They’re stitched together from various other parts of the genome. Now researchers working on this decades-old mystery say they’ve figured out how these monsters appear in tumors. The findings, published in Cancer Cell this week, might explain how tumors safeguard their survival.
First discovered in the 1950s, neochromosomes are these giant, extra chromosomes found in up to three percent of all cancers. They’re especially common in tumors of soft tissue (sarcomas), fat tissue (liposarcomas), and some brain and blood cancers. They can be many times the size of our largest, normal chromosome, and they also contain extra copies of altered genes known to drive cancer development, called oncogenes.
By combining DNA sequencing with mathematical modeling, a large international team led by Anthony Papenfuss and David Thomas from the University of Melbourne mapped neochromosomes from liposarcomas and reconstructed the sequence of events that led up to their creation. “These cancers manipulate the normal replication process in an ingenious way, creating a monster that can selectively steal and amplify the genes it needs to grow and survive,” Thomas says in a news release.
Neochromosome formation, they found, is triggered by spontaneous chromosomal “explosions.” The shattered chromosome bits reassemble into a ring of DNA haphazardly, and then a frenzy of gene amplification and deletion takes place. And oncogenes, in particular, are massively amplified, which helps ensure that the tumor endures.
“As cells divide, and the circular chromosomes get copied and pulled into different cells, a constant abnormal morphing takes place,” Papenfuss explains. “Small circles gradually become giant circles, progressively amplifying certain genes in what appears to be a selective process.”
He adds: “The growing giant also sucks in DNA from all parts of the genome. At a certain point, the circle stops growing and becomes linear. By the time we look at tumor cells through the microscope, we see giant linear chromosomes.”
In some of the lipsarcoma cell lines, DNA from every chromosome was found in the neochromosome, and they had up to 100 copies of key oncogenes. However, when the massively amplified oncogenes were blocked, the cancer cells died -- suggesting a potential therapeutic target to explore. Furthermore, the team is also investigating the “suture lines” that keep Frankenstein stitched together. Thomas tells ABC Science: “We hope to be able to identify the patterns in the DNA at the suture lines that might give us a clue as to the mechanisms that mediate the construction of the neochromosome.”
Animation: Armando Hasudungan Faigl