Cancer genetics: Learning the rules for breaking chromosomes

The chromosomes of cancer cells aren’t laid out nearly this neatly. Parts of them get broken off and reshuffled, but there are some rules for where those breaks occur, rules that Fred Alt wants to understand. (NHGRI)

In many cancers chromosomes get reshuffled, with sections breaking off and attaching to other chromosomes in what are called translocations. Fred Alt and his team are trying to better understand where chromosomes are most likely to break and where the broken pieces are most likely to attach, knowledge that could help better understand some aspects of cancer. Think of it as another set of rules layered on top of the rules (e.g., as which genes to turn on, which to turn off, and when) that govern how the genome works.

For instance, consider a set of leukemias called mixed-lineage leukemias (MLLs). These cancers all feature a translocation in which of a portion of chromosome 11 breaks off and glues itself to another chromosome, with devastating consequences.

To better understand MLL leukemias and other translocation-carrying cancers, we’d like to better understand where the genome is most likely to break and where the broken pieces are most likely to attach. “People have been characterizing translocations for the last 50 years or so,” says Alt, who directs the Immune Disease Institute (IDI) and the Program in Cellular and Molecular Medicine at Children’s Hospital Boston, “but we haven’t understood the mechanisms that form them. We know what happened, but not how it happened.”

To get to the “how,” Alt’s lab has developed a new method for mapping the “translocatome” – the total genome-wide complement of rearrangements for a particular chromosome break. The method, which Alt calls high-throughput genome-wide translocation sequencing (HTGTS), essentially maps hot spots in the genome where chromosomes are most likely to break and recombine.

An overview of some of the different translocations associated with different cancers and syndromes. (Mikael Haggstrom/Wikimedia Commons)

The breakage map they generated using the method is already giving some insights into the rules that govern when and where breaks occur. For instance, the researchers found that broken chromosome segments tend to fuse near the beginnings of genes, at locations called transcription start sites, suggesting to Alt that the process of gene transcription may itself encourage chromosome breaks.

The team also found that broken chromosomes are more likely to rearrange within themselves than to share pieces across different chromosomes.

By helping to reveal the rules of translocation, Alt thinks that HTGTS could be a boon for cancer genome researchers. Identifying translocations is a popular and effective means of unraveling the genomic havoc within cancer cells, but not all translocations are created equal. While some may play in active role in the development or persistence of a cancer, others are merely byproducts of the genomic instability common to cells once they turn cancerous. Alt’s method could help sort the bystanders from the culprits, which in turn could help pinpoint new targets for the development of new anticancer drugs.

“Childhood cancers, from leukemias and lymphomas to neuronal tumors, all have an inherent genomic instability that manifests itself in translocations,” Alt explains. “But while translocations come up very frequently across the cancer genome, it’s the ones that the cells select for that are important. Our work could help concentrate efforts to understand cancer translocations on those that are related to tumor initiation or progression and which could have some therapeutic value.”