Lesion segregation can drive complex patterns of mutations in tumor genomes

Researchers from the German Cancer Research Center, the University of Cambridge, and the University of Edinburgh have been analyzing the evolution of tumors after chemical damage.

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The researchers found that the DNA lesions induced by the chemical are not removed instantly, but are rather passed on unrepaired across many rounds of cell division. A “lesion segregation” like this can fuel surprisingly intricate patterns of mutations that occur in the tumor genome, as recently described by the researchers in the Nature Journal.

The UV radiation of sunlight, tobacco smoke, or several chemicals are various lifestyle and environmental factors that negatively affect the genetic material of human cells and can lead to cancer.

Such factors change nucleotides, which are individual DNA building blocks, such that they are no longer accurately detected when the DNA undergoes duplication. The outcome is false “counterparts” are integrated into the newly produced DNA strand.

Such defective nucleotides can be removed and substituted by a range of repair systems present in cells. However, which defective nucleotides are repaired and which ones escape repair that may eventually lead to cancer-promoting mutations? How would this impact the mutation pattern of tumor cells? How do these mutations proliferate in the clonal expansion of each cell at the time of tumorigenesis?

Responding to these questions was the aim of a collaboration between the laboratories of Duncan Odom at the German Cancer Research Center (DKFZ) and the University of Cambridge’s Cancer Research UK Cambridge Institute, Martin Taylor and Colin Semple from the MRC Human Genetics Unit in the University of Edinburgh, and also Paul Flicek from EMBL EBI, and Professor Nuria Lopez-Bigas from IRB Barcelona.

This research group employed the DNA-damaging chemical diethylnitrosamine to trigger an unlimited number of liver tumors in mice and examined the genomes of these cancers. This chemical mutagen characteristically induced around 60,000 point mutations in the genome of individual cancer cells.

During the analysis of the mutation signatures, the researchers were surprised to discover that the lesions induced by the chemical continue to remain largely unrepaired across many cell generations. The pair of DNA strands, impaired independent of one another, are isolated during cell division. The pair of resulting daughter cells subsequently develops two varying mutation profiles dubbed “lesion segregation” by the researchers.

During additional replication rounds, the lesions frequently resulted in new yet different mutations, as four different DNA nucleotides can be integrated into the defective location. Generally, cancer cells are subjected to many mutagenic events, which allow this cycle of DNA damage and lesion segregation to repeat over time and eventually lead to highly complex patterns of mutations in cancers.

The mutations have an impact on significant genes called cancer drivers. In their analysis, the researchers identified genetic defects in the cancer-promoting RAF, BRAF, and RAS signaling routes.

In the end, those cancer cells that carry the most favorable pattern of mutations will prevail. They can grow the fastest, escape the immune system and possibly survive therapies better.”

Sarah Aitken, Study Lead Author, Cancer Research UK-Cambridge Institute, University of Cambridge

Aitken is also a Cambridge-based Clinician-Scientist

According to Martin Taylor from the University of Edinburgh’s MRC Human Genetics Unit, “Persistent DNA lesions induced by chemotherapeutic agents also segregate and produce several generations of further mutations. We need to be aware of this therapeutically, and in future drug development.”

Thanks to the concept of lesion segregation, we now understand better how the surprising complexity of mutations in cancer cells can arise. This may help explain how cancer cells can react so flexibly to survival challenges, which in turn helps them to quickly develop resistance to drugs or adapt to foreign tissue environments.”

Duncan Odom, Researcher, German Cancer Research Center