Smart Tumors, Redux

Smart Tumors, Redux

George W. Sledge, MD, FASCO

Jan 27, 2011

I’ve spoken before about the problem of “smart” tumors, the ones that have accumulated lots of mutational changes, a fairly common event in solid tumors such as smoking-induced lung cancer, pancreatic cancer, and triple-negative breast cancer. The problem in dealing with smart tumors is partly medical and, as I suggested in a prior post, partly a systems issue: how does a clinical trials and regulatory apparatus designed for simple times deal with the complexities of genomic chaos?
Well, the plot thickens, again. The avalanche of genomic data keeps rolling on, and with it new surprises about carcinogenesis. In a recent issue of Cell (Cell 144, 27–40, January 7, 2011) , Philip Stephens and colleagues at the Sanger Institute report on what they call chromothripsis, “whereby tens to hundreds of genomic rearrangements occur in a one-off cellular crisis.” While not too common overall (2-3% of all cancers), it may account for as many as a quarter of bone tumors (osteosarcomas and chordomas).
I find this fascinating and frightening. These are manifestly “smart” tumors, with bunches of chromosomal rearrangements, which is bad enough. But the sheer suddenness of these tumors is something else again. I think of a cigarette-induced lung cancer, the product of decades of steady mutational accretion induced by tars and nicotine, and it makes sense in its own sad way. But chromothripsis seems like Pearl Harbor or 9/11, an attack out of the blue on an unsuspecting chromosome, sudden, massive and irreparable. In one case, a small cell lung cancer, the evidence suggests that “at some stage while the cancer was evolving, chromosome 8 shattered into hundreds of pieces.” Shattered! Hundreds of pieces!
How do these victims of chromothripsis act once they have undergone their malignant transformation? The paper doesn’t say, "I suspect the numbers are too small, and the tumor types too diverse, to come to any conclusions as to their eventual fate." I’m sure we’ll learn more about them in the next few years, as genomic data continues to accumulate. We are learning so much about cancer in such a short time; I have the same feeling I had as a child, watching a chain of very noisy firecrackers going off, one right after another. Chromothripsis seems a particularly noisy one: KABOOM. But almost certainly not the last firecracker in the chain.


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Anthony Frank Provenzano, MD

Feb, 03 2011 7:10 PM

i can't comment on chromothripsis but i always wondered what would happen if we kept isolating a patient's tumor cells at different times incrementally and have stem cells interact with these cells at, let's say, time A. then at a later time transfer those stem cells into a culture with tumor cells at some later time B and so on. determining whether there is some unique by product as a result of these sequential interactions might shed light on how tumor cells acquire these cumulative chromosomal rearrangements. just a thought.....

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