Explaining the Complexity of Tumor Genome Mutations

In a study published today in Nature, researchers investigated the evolution of tumors following chemical damage. The findings suggest that DNA lesions are not eliminated immediately but are passed on, unrepaired, over several rounds of cell division. This leads to a variety of mutation combinations in cells, providing many chances to find the best combination for tumor growth.

DNA mutations occur due to numerous environmental factors such as tobacco smoke, chemicals, or UV radiation from sunlight. These factors modify individual nucleotides in such a way that they are no longer correctly recognized when the DNA is duplicated. The consequence is that false counterparts are incorporated into the newly synthesized DNA strand.

Cells have a variety of repair systems that can remove and replace defective nucleotides. But how do we know which defects will be repaired and which will escape repair? To answer this question, the researchers used the DNA-damaging chemical diethylnitrosamine to induce hundreds of liver tumors in mice and analyzed the genomes of these cancers. On average, this chemical mutagen caused about 60,000 point mutations in the genome of each cancer cell.

To their surprise, the scientists discovered that the lesions caused by diethylnitrosamine remain largely unrepaired over several cell generations. The two DNA strands, which were damaged independently of each other, are separated during cell division. The two resulting daughter cells then develop two different mutation profiles. The researchers refer to this as “lesion segregation.”

During further replication rounds, the lesions repeatedly lead to new, different mutations since four different DNA nucleotides can be incorporated at the defective site. Cancer cells are usually exposed to several mutagenic events, so this cycle of DNA damage and lesion segregation repeats over time, ultimately resulting in extremely complex patterns of mutations in cancers.

The mutations affect important genes known as cancer drivers. In their study, the scientists found defects in genes of the cancer-promoting BRAF, RAS, and RAF signaling pathways. “In the end, those cancer cells that carry the most favorable pattern of mutations will prevail,” says first author Sarah Aitken of the University of Cambridge. “They can grow the fastest, escape the immune system, and possibly survive therapies better.”

“Thanks to the concept of lesion segregation, we now understand better how the surprising complexity of mutations in cancer cells can arise,” says coauthor Duncan Odom of DKFZ. “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.”