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Stitching shattered chromosomes

By Robert Aboukhalil (June 23 2011)

In each one of our cells is stored a copy of our DNA, the instructions used by the cell to manufacture its components. The instructions are divided into chromosomes and written in an alphabet of only four letters: A, C, T and G. When our DNA undergoes changes in its instructions, and when these changes—known as mutations—accumulate over time, cells can replicate uncontrollably and form tumors. This uncontrolled cell division is known as cancer.

Although cancer is usually the result of years of erratic mutations, scientists have discovered instances of mutations that arise on a much larger scale than previously thought possible, where entire chromosomes are shattered and glued back together, but shuffled. A study led by Philip J. Stephens (http://dx.doi.org/10.1016/j.cell.2010.11.055) suggests that chromothripsis, which is Greek for shattering chromosomes, occurs as a single event.

This has important consequences, since we typically think of cancer as the gradual accumulation of so-called point mutations and chromosomal aberrations. A point mutation occurs when a single letter of DNA mutates into another. Although there are 3 billion letters in a single DNA molecule, point mutations alone are sometimes important contributors to disease. We only need to consider sickle-cell anemia patients, whose red blood cells have unusual shapes due to a change in a single letter of their DNA. Another way in which DNA is modified is by chromosomal abberations, where segments of DNA are deleted, inverted, moved to other regions, or duplicated.

But why do such mutations cause cancer? Aren't there mechanisms that prevent cells from replicating uncontrollably? There are two major kinds of genes that act as protection mechanisms: proto-oncogenes and tumor-suppressor genes. A great way of visualizing their roles is to use a car analogy: The proto-oncogenes form the gas pedal since they encourage cells to replicate, whereas tumor-suppressor genes form the brake pedal, since they inhibit replication. In a nutshell, mutations cause our car to break down: When proto-oncogenes undergo mutations, the gas pedal no longer works and we can no longer stop the cells from replicating. Conversely, if tumor-supressor genes become dysfunctional due to mutations, the brake pedal stops working and cell division once again cannot be stopped.

In their study published in the Cell journal, scientists witnessed hundreds to thousands of localized mutations happening as a result of a single event. To demonstrate that, they sequenced the tumor DNA of patients diagnosed with various cancers. By comparing a patient's tumor DNA to a reference genome, they could identify regions of DNA where rearrangements had occurred. In nearly 3% of cancer samples and in 25% of bone cancers, they found entire chromosomes shuffled around that could be explained by several point mutations happening in parallel. Rather, this is likely the result of "a single catastrophic event": When an entire chromosome (or part of it) is shattered, the cell's DNA repair apparatus stitches some of the bits back together, in the hopes of saving the cell from eminent death (or apoptosis, in biologists' parlance). Even if the cell survives, however, this is unlikely to be good news: the stitching back is mostly done ad-hoc and several tumor-suppressor genes can be deleted in the process, which may cause uncontrolled cell replication (i.e. cancer) as discussed earlier.

Dr. Stephens and his colleagues believe that chromosome shattering occurs while the cell is replicating. Although they remain unsure of what exactly causes the shattering, they speculate that it might be due to a pulse of ionizing radiation, but further studies are needed to confirm this hypothesis. As with all new scientific discoveries, it is perhaps too early to be certain of its impact. Regardless, it offers us a clearer understanding of the mechanisms of cancer. And if we are to improve diagnostic tools and treatments, this is but a first step in the right direction.

Given that 2011 is the International Year of Chemistry, it should come as no surprise that scientists are increasingly eager to better grasp the molecular basis of cancer

Author Bio

Hello there, I'm Robert, co-founder of Technophilic Magazine. I'm fascinated by, and mostly write about, computation, biology and physics.