New chromosomal mechanism contributes to cancer evolution

The existence of new fragile genomic sites responsible for chromosomal alterations in tumors has been demonstrated by a new study. Cancer arises from the accumulation of mutations and structural changes in chromosomes, which in some cases give rise to combinations that favor the growth or expansion of the disease. In this context, chromosomes tend to lose or duplicate entire regions, although the mechanisms that initiate these chromosomal abnormalities are not fully understood.

Collisions between the machinery responsible for duplicating the DNA and for transferring this genomic information to the RNA for protein synthesis, which is transcription, are the cause of a very high proportion of the chromosomal alterations found in tumors. Until now, the majority of these problems were believed to originate in areas of the genome that were difficult to duplicate and which, therefore, required the completion of the entire S phase of the cell cycle; this is the stage in which cells duplicate their DNA. Due to this episode, these regions were especially exposed to breaks or aberrations.

This study, led by the group of André Nussenzweig, PhD, at the National Cancer Institute, with the participation of Óscar Fernández-Capetillo, PhD, of the Spanish National Cancer Research Centre, reveals that other areas of the genome also exist that are prone to breakages. These areas are those that replicate quickly in S phase. In particular, breakages occur when these DNA regions that replicate have surrounding genes that are being actively copied to RNA.

"In these cases, the collision between the two machineries, the duplication machine and the transcription machine, can be responsible for generating chromosomal alterations that are deadly for cells," said Fernández-Capetillo.

This study moves us a step closer to understanding the mechanisms that explain the chromosomal alterations in tumor cells most common in tumors. "This new mechanism can even explain up to 50% of the abnormalities associated with some types of leukemia,” stated Fernández-Capetillo.

Furthermore, this work defines a new class of genomic fragile sites that might contribute to our understanding of the changes that took place in the genome throughout evolution. This study was published in Cell (2013;152[3]:620-632).

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