Cancer’s madness

by Richard Saltus (HHMI Bulletin, Spring 2014)

Computational approaches reveal that massive chromosome alterations give cancer an edge.

Cancer cells are known for the rampant disorder in their genomes: extra or absent chromosomes or parts of chromosomes, long stretches of DNA gone missing or present in too many copies. “It looks like someone threw a stick of dynamite into the nucleus,” says HHMI Investigator Stephen Elledge of Harvard Medical School and Brigham and Women’s Hospital.

This chaotic state is called aneuploidy. It stems from errors during cell division causing the daughter cells to have abnormal numbers of chromosomes or chromosome fragments. Aneuploidy affects hundreds or thousands of genes and can wreak all kinds of havoc, including miscarriages, lethal birth defects, and disorders like Down syndrome.

Based on his group’s latest research, Elledge says these massive alterations have evolved because they give malignant cells an edge in the “brutal competition” to win out over normal cells.

Because chromosomes exist in pairs, the loss of single chromosomes affects only one copy of a given gene. The second copy on the partner chromosome remains intact. As a result, these “hemizygous” losses have a weaker effect on cancer growth than the mutation of both copies of a tumor suppressor gene. But the additive combination of groups of hemizygous losses can have a large impact.

We have basically answered the question: Does aneuploidy drive cancer? We believe it does” says Stephen Elledge.

To those familiar with the “two-hit” model of cancer, it may come as a surprise that loss of a single gene copy can have an effect. According to this model, a mutation in a single copy of a tumor suppressor gene does nothing because the second copy compensates, and only if that second copy is subsequently “hit,” or mutated, does the cell begin its malignant journey.

However, Elledge cites evidence that a large proportion of cancer-suppressing genes are “haploinsufficient”—loss of even one copy can contribute to cancer development. In fact, Elledge estimates that 30 percent of all genes in humans are haploinsufficient, which has important implications for human development and disease.

“Losing or gaining single copies of genes on their own may have small effects, but altering many at the same time gives the cancer cell an advantage,” says Angelika Amon, a biologist and HHMI investigator at the Massachusetts Institute of Technology who studies aneuploidy. “Once you see [Elledge’s findings], you realize these losses and gains are not random noise in tumors, and we can begin to understand them.” 

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