More insights on tumor mutation susceptibility found

Scientists studied the molecular evolution of tumors after exposure to genetically damaging chemicals. They discovered that the chemical-induced defects in individual DNA building blocks are not repaired immediately but are passed on over several rounds of cell division.

Lesion segregation leads to complex patterns

Scientists from the German Cancer Research Centre (Deutschen Krebsforschungszentrum or DKFZ) and the Universities of Cambridge and Edinburgh have studied the molecular evolution of tumours after exposure to genetically damaging chemicals. They discovered that the chemical-induced defects in individual DNA building blocks are not repaired immediately but are passed on over several rounds of cell division. The two DNA strands with their independent defects are separated during cell division, resulting in two daughter cells with different mutation profiles.

During further rounds of replication, the defects repeatedly lead to new, different mutations. This "lesion segregation" leads to the complex patterns of mutations in the tumor genome. The chance that tumor-driving combinations of genetic defects will be created is high. The scientists have now published these results in the journal Nature.

Tobacco smoke, several chemicals, or sunlight UV radiation: numerous environmental and lifestyle factors damage the genetic material of our cells and can thus trigger cancer. These factors can modify individual nucleotides in such a way that they are no longer correctly recognized when the DNA is subsequently duplicated, and a false "counterpart" is incorporated into the newly synthesized strand.

Key DNA repair

Cells have a variety of repair systems that can recognise, cut and replace such defective nucleotides. But which defects are repaired and which escape repair and become potentially cancer-promoting mutations? What effects does this have on the mutation pattern of tumour cells? And how are these mutations inherited during the clonal expansion of the individual cells?

This is what Duncan Odom from the DKFZ and the Cancer Research UK Cambridge Institute at the University of Cambridge, with his colleagues Martin Taylor and Collin Semple from the University of Edinburgh wanted to find out with their current work. The study also involved scientists from EMBL and IRB Barcelona. The researchers used the DNA-damaging chemical diethylnitrosamine to induce liver tumors in mice and analysed the genetic material of the cancer cells. On average, this chemical mutagenesis resulted in about 60,000 point mutations in the genome of each cancer cell.

To their surprise, the scientists discovered during the analysis of the mutation signatures that the lesion caused by the chemical remains largely unrepaired over several cell generations. The two independently damaged DNA strands are separated during cell division. The two resulting daughter cells then develop two different mutation profiles. The researchers refer to this as "lesion segregation".

Mutations accumulate over cell generations

During further rounds of replication, the lesion repeatedly leads to new, different mutations, since four different DNA building blocks can be inserted at the defective site. Cancer cells are usually exposed to several mutagenic events, so that this process of DNA damage and segregation is repeated several times over time. This ultimately results in an extremely complex pattern of mutations in the tumor genome.

Of course, the mutations also affect important genes known as cancer drivers. In their study, the scientists found defects in genes of the BRAF, RAS and RAF signaling pathways. "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," said main author Sarah Aitken from the University of Cambridge.

"Certain chemotherapeutic agents can also induce DNA damage, which also segregates and produces further mutations over several cell generations. We need to be aware of this fact when developing future cancer drugs," added Martin Taylor from the University of Edinburgh.

"Thanks to the concept of lesion segregation, we now have a better understanding than before of how the astonishing complexity of mutations in cancer cells can arise," Duncan Odom concluded: "This explains to us how the extreme adaptability of tumors can occur. It in turn helps them to quickly develop resistance to drugs or adapt to environments in foreign tissues”.

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