It is well understood that chromosomal translocation - a process whereby pieces of two chromosomes break off and exchange places - is a hallmark of many cancers including leukemia, thyroid cancer and lymphoma and play an important part in how healthy cells become cancerous. The role spatial proximity plays in why certain chromosomal translocations happen repeatedly, however, has been a long-standing area of debate among scientists.
A new study published online in the journal Cell by lead authors Job Dekker, PhD, co-director of the Program in Systems Biology at the University of Massachusetts Medical School (UMMS) and Frederick Alt, PhD, director of the Program in Cellular and Molecular Medicine at Children's Hospital Boston, offers the first conclusive evidence that the three dimensional structure of the chromosome strongly influences patterns of chromosome rearrangements and translocations. This finding sheds light on fundamental processes related to cancer and our understanding of cancer genomics.
"Understanding how chromosome translocations happen is important if we want to understand the evolution of cancer genomes," said Rachel Patton McCord, PhD, a postdoctoral fellow at UMMS and co-first author of the study. "If certain individuals have changes in their chromosome structure it might indicate an increased risk for translocations that give rise to cancer. And, after precancerous changes have taken place in the genome of the cell, corresponding rearrangements in the 3D genome may dictate which translocations happen as cancer progresses."
In order to measure how all the sequences in the genome are organized relative to one another, McCord used a molecular technology developed in 2009 by Dekker called Hi-C to generate a three-dimensional model of a pro-B cell (white blood cell) from a mouse. At the same time, a high-throughput genome-wide translocation sequencing (HTGTS) technique developed by Dr. Alt's lab was used to map "hot spots" in the genome where chromosome breaks and translocations are more likely to occur. By combining the 3D model of the genome, the first for a mouse, with the sites of translocations in these cells, researchers were able to explore the role spatial proximity plays in the reassembly of these chromosome breaks.
What they observed is that for random, widespread, low-frequency DNA breaks, such as might occur after exposure to too much sun or chemotherapy, spatial proximity plays a dominant role in determining where in the genome these pieces of chromosome get reattached. Simply stated, the closer the breaks were to each other, the more likely they were to be incorrectly attached to a neighboring chromosome. Dekker and colleagues also observed that chromosome breaks were also more likely to be translocated along the whole chromosome where they resided, adding further evidence that spatial organization is a determining factor in chromosome translocations.
"We see the same chromosome rearrangements happening over and over again in certain cancers, but determining the role of spatial proximity in this process has been a hard question to answer," said Dekker, also professor of biochemistry & molecular pharmacology and molecular medicine at UMMS. "By generating a 3D model of the entire genome and mapping translocations from targeted chromosome breaks we can finally start to answer this question."
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