“Frankenstein” Chromosomes Amplify Cancer Genes
Australian researchers have discovered how massive DNA molecules called neochromosomes that appear in some tumours are stitched together from other parts of the genome “like Frankenstein’s monster”.
Neochromosomes are giant extra chromosomes found in up to 3% of all cancers, most commonly in liposarcomas (tumours of fatty tissue), soft tissue tumours and some brain and blood cancers. They are large and harbour extra copies of cancer-causing “oncogenes”.
The research, published in Cancer Cell, showed that neochromosome formation is triggered by spontaneous and catastrophic “explosions” of chromosomes. The shattered relics reassemble haphazardly, followed by a genetic frenzy of amplification and deletion. Genes that are important for cancer development become massively amplified, assuring the cancer’s survival.
“We showed that chromosome 12 shatters and its remnants form a ring of DNA in a haphazard fashion,” said A/Prof Tony Papenfuss of the Walter and Eliza Hall Institute and the Peter MacCallum Cancer Centre. “As cells divide, and the circular chromosomes get copied and pulled into different cells, a constant abnormal morphing takes place. Small circles gradually become giant circles, progressively amplifying certain genes in what appears to be a selective process.
“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 tumour cells through the microscope we see giant linear chromosomes.”
Prof David Thomas of the Garvan Institute said the extent of the genetic rearrangement was truly astonishing. “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,” he said.
“In some liposarcoma cell lines, DNA from every chromosome in the cell was found in the neochromosome, with between 60 and 100 copies of key oncogenes. Patient tumours also exhibited similar gene rearrangement.”
The study also identified a potential therapeutic target for the treatment liposarcomas. “When the key oncogenes that were massively amplified in the cancer cells were blocked, the cancer cells died,” Thomas said.
