New Research Offers Insights Into Genetic Changes Causing Cancer

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Highlights:

• Recent experiments on the nematode worm C. Elegans offer insights into the mechanisms operating in the MMR (mismatch repair) pathway that are key to repairing the DNA damage occurring during cell division.
• Cancer is caused by damage and alteration in the DNA, however, the precise details of pathways operating in repair of damaged DNA (eg: MMR to prevent cancer) remain unclear.
• Improved knowledge of the sequence of these genetic changes or mutations taking place in the cell, will aid in understanding the origins of cancer and may open up newer avenues for cancer treatment.

Controlled tests on the worm model C. Elegans to delineate mechanisms operating in the mismatch repair (MMR) pathways may be relevant to humans as well and this knowledge could pave the way for newer approaches to cancer therapy according to a group of scientists from European Bioinformatics Institute (EMBL-EBI), the University of Dundee and the Wellcome Sanger Institute.

The results of the study appear in the journal Genome Research.

Details of Study - Nematode Worm Model to Analyze Mismatch Repair Pathway

• The study team hoped to assess in detail how the DNA repair mechanisms operate, in particular the DNA mismatch repair (MMR) pathway to prevent DNA damage and therefore reduce risk of cancer.
• Previous research has shown that one of the first DNA repair pathways affected, resulting in increased risk of cancer is DNA mismatch repair (MMR).
• The team proceeded to analyze the MMR pathway in greater detail using the nematode worm model C. Elegans.
• What makes the nematode worm the model of choice is that it requires only three days for these worms to be propagated from one generation to the next, greatly expediting the process of analyzing how DNA alterations are passed on from one generation to the next.

"The DNA mutations we see in cancer cells were caused by a yin and yang of DNA damage and repair," explains Moritz Gerstung, Research Group Leader at EMBL-EBI.

‘Similar DNA mutational processes take place in nematodes and humans and studying the nematode worm will help in providing more insight into the origins of cancer.’

"When we study a patient's cancer genome we're looking at the final outcome of multiple mutational processes that often go on for decades before the disease manifests itself. The reconstruction of these processes and their contributions to cancer development is a bit like the forensic analysis of a plane crash site, trying to piece together what's happened. Unfortunately, there's no black box to help us. Controlled experiments in model organisms can be used to mimic some of the processes thought to operate on cancer genomes and to establish their exact origins."

• The team found that DNA mismatch repair was passed down for many generations (in worms) and this enabled them to determine a distinct mutational pattern.

Can DNA Changes In Nematode Worm Apply to Humans?

• The million dollar question that begged to be answered now was, whether the same processes operated in humans as well.
• To answer this question, EMBL-EBI PhD student Nadia Volkova compared theC. Elegans findings with molecular data from 500 human cancer genomes.

"We found a resemblance between the most common signature associated with mutations in MMR genes in humans and the patterns found in nematode worms," explains Volkova. This suggests that the same mutational process operates in nematodes and humans.

The findings of the study could, therefore aid in better understanding of the processes involved in carcinogenesis and create fresh research opportunities to develop novel treatments.

DNA Damage and Inbuilt Repair Mechanisms to Prevent Cancer

Cancer is caused by genetic changes or DNA mutations triggered by a range of external factors such as exposure to UV radiation, certain chemicals and smoking. However, errors occurring during the course of cell division also are known to play an important role in carcinogenesis. A cell recognizes most of these errors and corrects them through various repair mechanisms.

However, DNA repair is not a perfect process, so it could still leave certain mutations unrepaired or repair them inaccurately leading to persisting changes in DNA.

Understanding the sequential changes of these mutational processes is key in identifying the reasons for cancer and showing the way for potential avenues for new treatments.

DNA Mismatch Repair and Mismatch Repair Deficiency

In DNA mismatch repair, errors (base mismatching) that occur during DNA replication are recognized, removed and replaced. The mismatch repair pathway maintains the stability of the genome during repeated cell division.

The MLH1, MSH2, MSH6 and PMS2 genes are involved in the process of "mismatch repair" or MMR. In persons with constitutional mismatch repair deficiencysyndrome, this innate repairing process is affected. Such children are more prone to develop brain tumors, gastrointestinal polyps, lymphomas, hematological cancers and rare childhood.

Studies such as these show the way for further research into these pathways, details of the processes involved and how to address defective repair pathways.

Reference:

1. Constitutional Mismatch Repair Deficiency Syndrome - (https:www.stjude.org/disease/constitutional-mismatch-repair-deficiency.html)

Source: Medindia

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