Big bang theory of cancer development

[Joan M]

From The New York Times, January 11:

Cancer Can Develop in Catastrophic Burst

New rapid methods of decoding DNA have brought to light a catastrophe that can strike human cells: a whole chromosome may suddenly shatter into pieces.

If the cell survives this disaster, something worse may ensue: the cell becomes cancerous.

The finding marks a striking exception to the current theory of how cancer develops. Cells are thought to become cancerous over many years as they collect, one by one, the mutations required to override the many genetic restraints on a cell’s growth. It now seems that a cell can gain all or most of these cancerous mutations in a single event.

The discovery is reported in the current issue of Cell by a team led by Peter J. Campbell of the Sanger Institute near Cambridge, England.

The institute is part of a consortium with the National Institutes of Health in the United States to study the genomes of different types of cancer cells, a task now brought within reach because of fast and cheap methods for decoding DNA. The hope is to identify the causative mutations that drive each type of cancer.

As part of this project Dr. Campbell, a hematologist, was scanning the genome of 10 patients with a certain kind of leukemia. Cancer cells lose control of their chromosomes, and their genomes are often a chaotic hodgepodge in which the chromosomes are rearranged, with some segments duplicated and others lost. In one of his patients, Dr. Campbell noticed an unusual feature: almost all of the damage was confined to a single chromosome.

By reconstructing the exact pattern of chromosomal rearrangements, he and colleagues found it could not be explained by the standard process in which one mutation is acquired after another in a protracted series. Rather, the chromosome must have shattered into pieces in a single event; the cell then knitted them together as best it could, but in the wrong order.

Usually a cell that suffers this much damage will destroy itself, either immediately or after it has tried unsuccessfully to repair its chromosomes. But in certain cases, the self-destruct mechanism evidently fails, leaving a cell like Frankenstein’s monster, with badly patched-up chromosomes but a survival advantage that leads to unrestrained growth.

Dr. Campbell’s group reports that about 2 percent to 3 percent of all cancers, and 25 percent of bone cancers, originate in this kind of chromosome-shattering crisis.

“It’s very hard to explain why the damage is so catastrophic but so localized,” Dr. Campbell said, referring to the fact that almost all the damage occurs in a single chromosome or chromosome region. His best guess is that the damage is caused by a pulse of radiation.

Bone cancer is sometimes treated with radioactive isotopes that home in on the bone, which might explain why so many cases of bone cancer arise this way.

But Matthew Meyerson and David Pellman, two cancer biologists at the Harvard Medical School, say in a commentary that the chromosomes could shatter accidentally when they condense, a process that happens before the cell divides. Whatever the cause of the shattering, the finding “reveals a new way that cancer genomes can evolve,” they write.

The discovery has no immediate implications for therapy. But it could explain why a few cancers, contrary to the usual rule, appear very suddenly. “There are clearly examples where someone has had a normal mammogram, then presents shortly after with an aggressive tumor,” Dr. Campbell said.

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This theory does make me wonder. One year my mammogram was okay. The following year I had two tumors in one breast (DCIS and infiltrating) that were HER2+ and 7 positive lymph nodes.

Joan