'Frankenstein' DNA keeps tumours alive

Australian researchers have discovered how the massive DNA molecules that appear in some tumours are stitched together from other parts of the genome, making them similar to Frankenstein’s monster. This explains how these tumours ensure their own survival.

The research, published in the journal Cancer Cell, showed that spontaneous and catastrophic chromosomal ‘explosions’ trigger the formation of neochromosomes. These giant, extra chromosomes, found in up to 3% of all cancers, are well known to harbour many extra copies of oncogenes - altered genes known to drive cancer development.

Following the explosions, the shattered relics reassemble haphazardly, followed by a genetic frenzy of amplification and deletion. Genes known to be important for cancer development are massively amplified, assuring the cancer’s survival. The discovery was a collaborative venture between the Peter MacCallum Cancer Centre, the Walter and Eliza Hall Institute of Medical Research (WEHI) and the Garvan Institute of Medical Research.

The researchers, led by Professor David Thomas and Associate Professor Tony Papenfuss, mapped the neochromosomes from liposarcomas (tumours of fat tissue) using next-generation DNA sequencing. Next, the team used mathematical modelling to reconstruct the sequence of events that caused the neochromosome to form, deducing that only chromosomal shattering could be to blame.

“We showed that chromosome 12 shatters and its remnants form a ring of DNA in a haphazard fashion,” said Associate Professor Papenfuss, from WEHI 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.”

Professor Thomas, the director of The Kinghorn Cancer Centre at 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 to explore for treating liposarcomas, which are well known to harbour neochromosomes. Associate Professor Papenfuss said, “When we blocked the activity of key oncogenes that were massively amplified in the cancer cells, they died, which opens up new avenues of research to combat their ability to survive and thrive.”

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