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Cancer's 'Frankenstein' DNA mystery solved

Giant chromosome The creation of a 'Frankenstein' chromosome that steals the DNA it needs to grow and survive has been detailed for the first time in research led by Australian scientists.

The work, published today in the journal Cancer Cell , shows how an extra chromosome, known as a neochromosome, found in up to three per cent of all cancers, is created.

Chromosomes, found in most cells of the body, are comprised of DNA that contains specific genetic information. Human cells generally have 23 pairs. The largest chromosome contains about 249 million DNA building blocks known as base pairs.

However, neochromosomes are much bigger than normal chromosomes, in some cases containing over 700 million base pairs of nucleic acids, says co-author of the paper, Professor David Thomas, director of the Kinghorn Cancer Centre at the Garvan Institute.

Scientists have known about the presence of accessory neochromosomes in cancers such as liposarcoma (a cancer of the fatty tissues), sarcomas (soft tissue tumours), and some brain and blood cancers for decades, he says.

However, only the advent of next-generation genomic sequencing and mathematical modelling has made this latest work possible.

Thomas likens the research to that of archaeology.

"Imagine we are looking at the ruins of Troy. As archaeologists, our job is to work out exactly what the city was like when it was growing and thriving — its history essentially," he says.

"We are able to work out using mathematical modelling how [the neochromosome] originally started, how it then grew to its final form."

Neochromosomes are a unique, massive mutation inside liposarcoma cancers.

The researchers found neochromosomes that contained DNA from every chromosome in the liposarcoma cell, with between 60 and 100 copies of key genes involved in the development of cancer.

The neochromosome "provides a home to lots of genes that tell the cell to grow inappropriately", says Thomas.

Targeting Frankenstein's sutures

The finding — an international collaboration that included researchers from the Peter MacCallum Cancer Centre, Murdoch Childrens Research Institute, Walter and Eliza Hall Institute of Medical Research and Garvan Institute of Medical Research — also reveals potential targets for drug therapy.

"Imagine the neochromosome as Frankenstein, stitched together with sutures linking body parts from other chromosomes," says Thomas.

He says the "suture lines", which hold the structure together, is a key area the team is investigating.

"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," Thomas says.

"Once we understand that, potentially we have a mechanism that might be [susceptible to drugs]."

He says mathematical modelling of biological processes will be a key to future cancer research.

"We rarely get to see the original big bang that starts off the cancer," Thomas says. "To get back to those primordial events, we have to use creative bioinformatics and computational biology techniques."

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How neochromosomes form: Armando Faigl