Friday, September 30, 2011

Early steps in tumour formation made more clear

A new technique has given us more insights in how cells start to become cancerous. Scientists observed a process called translocation, where one piece of a chromosome breaks off, and promptly gets tied to another one. By discovering in which way the pieces of DNA reconnect, we now have more information in how these rearrangements can induce cellular events that promote uncontrolled growth. For their experiments, scientists of  The Rockefeller University induced DNA breakdown in chromosomes by a specific enzyme that only cuts the DNA at known locations. Thereafter, they observed which pieces of DNA were able to reconnect with the parts that were broken off. The experiments revealed several aspects of this translocation process, that we may use to prevent the onset of cancer, instead of trying to cure it afterwards.

The researchers used B lymphocytes for their experiments, cells that can form lymphomas when they become cancerous. By constantly inducing the same form of DNA breakdown on the chromosome in many cells, they were able to make observations in how cellular repair mechanisms reconnect the pieces of genetic code. The results showed that the DNA that is reconnected to a broken piece is often part of a gene, instead of genetic code that lies in between genes. This is an important observation, as the rearrangement of DNA that codes for genes that are important for our cellular functions, can dysregulate our cells whereafter they become cancerous. For example, if a growth-inducing gene would be translocated to an area where it is made much more active than normal, it can induce uncontrolled cell growth and thus start the process of developing a tumour.

In addition, from the experiments can be concluded that active genes are more often translocated compared to their silent counterparts. For rearranging genes across the chromosomes, a clear preference for breaking off a gene at the start of the genetic code was found, as opposed to the middle or end part of the gene. This may explain why genes are still able to function much like the way they did before they were moved around: much of the original genetic code is still intact if it is broken off at the start.

The observations were based on about 180.000 translocations. For this, the researchers used about 400 million B cells. They were able to analyze such vast amounts of genetic rearrangements by setting up a new technique called high troughput genomic translocation screening, which can be used to screen the whole genome with all chromosomes for anomalies caused by translocation.

Our genetic code is organized by packing it into chromosomes: large strings of genetic code, that lie in the centre of the cell, the nucleus. Humans possess a total of 46 chromosomes, which include two sex chromosomes that are different for men and women. Men have an X and a Y chromosomes, while women have two X chromosomes. The 44 remaining chromosomes pack all our genes, for both men and women. Chromosomes come in duos that are identical, which means that there are 22 unique chromosomes.

By revealing how DNA rearranges itself after a piece breaks off, we may be able to develop countermeasures to prevent certain cancerous translocations from happening. However, gene therapies are still far from being used in the clinic. The experiments from the Rockefeller University focused specifically on B cells: it remains to be seen how other cells respond to DNA breakdown. However, the cellular preferences in how to reconnect DNA that were discovered might be part of a universal concept that can be used to explain the onset of many cancers, and not just lymphoma.

Translocation is just one process that gives rise to the formation of tumours. Cancer can also be caused by 'simple' mutations in the DNA, that have a profound impact in the activity or function of a gene. There are a number of different forms: individual DNA bases can be mutated, parts of genes can be accidentally cut out or be re-inserted in the wrong direction.

Changes in DNA can not be prevented, but we might be able to strengthen our DNA by protecting ourselves from harmful rearrangements of chromosomes.

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