More shattering news about cancer chromosomes

    Glioblastoma. drug discovery.com

Back in 2011, in the journal Cell, Philip Stephens and a host of colleagues drawn mainly from the University of Cambridge and the Sanger Institute, published a dramatic account of extreme cancer evolution in a paper they titled “Massive Genomic Rearrangement Acquired in a Single Catastrophic Event during Cancer Development”. The massive event they documented had come from cell samples collected from a 62 year-old woman with chronic lymphocytic leukaemia. They counted a massive 42 genomic rearrangements that had occurred, in one fell crisis, in the long arm of chromosome 4. Detailed sequencing of the chromosome revealed that these break points had been healed by DNA repair enzymes but in a random way where bits of chromosome were re-attached together such that the new conjoined fragments of DNA had originally been separated by megabases of DNA. They concluded that chromosome 4 had literally blown itself apart, some time before the patient had been diagnosed, and had been repaired, extraordinarily, to form a new “hodge-podge” chromosome which bore little structural resemblance to the original chromosome. They coined a name for the phenomenon – chromothripsis – which literally means “chromosome shattering into pieces”. The patient had subsequently declined rapidly – her cancer relapsed because it had acquired resistance to alemtuzumab – the drug being used to treat her.

So, had they discovered an extremely rare extreme form of cancer evolution – a one in a trillion random event that had, against all odds, proved fortuitous – for the cancer – or is chromothripsis more commonplace? Ever since 2011, cases of chromothripsis have been appearing regularly in the scientific literature. As a mechanism for cancer evolution, and occasionally as a method to rectify a disease process, it is now becoming treated as a mainstream, if extreme, form of evolution. So much so that scientists from the College of Life Sciences at Sichuan University in China have created an online database of chromothripsis examples called ChromothripsisDB. Now Robert Rennert and Clark Chen, from UC San Diego, have added another dramatic case of chromothripsis to this growing pile – this time involving a particularly nasty type of brain cancer called glioblastoma.

Rennert’s case involved an unfortunate patient who suffered from a widely metastatic glioblastoma, in the cells of which chromosome 6 had blown itself to pieces and reassembled. They proposed that the chromothripsis had silenced key genes that protect against metastatic potential – creating the selective advantage for this cancer. As they cautiously put it: “While the interpretation of “N of 1” studies warrants extreme caution, thoughtful consideration of these studies has yielded insights that that have led to significant scientific advances. It is in this context that we present our finding of chromosome 6 chromothripsis in a metastatic glioblastoma specimen”. Although glioblastomas are extremely aggressive, they say, cases of metastasis to sites in the body outside the central nervous system are rare – but here they documented spread to skin and soft tissue.

By 2011, Stephens’ group had already examined a further 746 cancer cell lines and discovered evidence for chromothripsis in about 100 of them. It was particularly common in bone cancers and they argue that it occurs in 2-3% of all cancers. They further argued that this was a poke in the eye to the gradualist model of evolution, where mutations accumulate at a slow, steady rate, and more accurately resembled the “punctuated equilibrium” model of evolution, characterised by long periods of stasis interrupted by dramatic bursts of evolutionary change. They cited a case of chromothripsis in chromosome 8 of a small cell lung cancer line where chromosome 8 had shattered into hundreds of pieces. Many of these, they said, were stitched together into a derivative chromosome 8, but 15 other fragments were joined to create an bizarre circular so-called double minute chromosome which contained multiple copies of the cancer susceptibility gene MYC. This massive amplification of gene copy number, allied to over replication of the double minute, they argued, had conferred huge selective advantage to daughter cancer cells bearing it.

All these dramatic – and traumatic – bursts of chromosome reassembly, cutting across genes and inactivating them, or bringing DNA from formerly distant parts of the chromosome into novel contact, very occasionally throw up cancer cells with huge selective potential in the horrible place in the body where cancer cell lines battle it out with the body’s immune system, each other, and the toxic drugs we throw at them. Cancer cells that undergo chromothripsis, and other forms of dramatic and gross structural change, remind Professor Charlie Swanton, of the Crick Institute in London, of the evolutionary heretic Richard Goldschmidt, who believed that evolutionary change in organisms required huge leaps, rather than the steady plodding preferred by the dominant gradualist school of Neo-darwinism. His theory was haughtily branded the “hopeful monster” theory and immediately thrown in the trash. But Swanton believes that in the harsh world of cancer cells (and some bacteria) Goldschmidt’s idea can work, and that cancer cells are indeed hopeful monsters.