The arrival of summer may bring long days in the sun, perhaps at the beach or pool, and the constant reminder that environmental insults can cause cancer. It’s not just UV radiation, of course, but also chemicals—like those found in tobacco smoke—that damage the genetic material of our cells and can trigger cancer. These carcinogens modify nucleotides so that they are no longer correctly recognized when the DNA is duplicated.
Now, scientists from the German Cancer Research Center and the Universities of Cambridge and Edinburgh have tracked the impact of the DNA-damaging chemical diethylnitrosamine to better understand how chemicals cause mutations in our cells’ DNA. The work is published in Nature in a paper titled, “Pervasive lesion segregation shapes cancer genome evolution.”
The researchers analyzed the genomes of hundreds of liver tumors in mice that were induced by diethylnitrosamine. On average, this chemical mutagen caused about 60,000 point mutations in the genome of each cancer cell. The team went on to study the evolution of tumors following chemical damage.
The scientists discovered during the analysis of the mutation signatures that the lesions caused by the chemical remains 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. During further rounds of replication, the lesions repeatedly generated new combinations of mutations, providing many chances to find the best combination for tumor growth. The researchers refer to this as “lesion segregation,” which can drive unexpectedly complex patterns of mutations in the tumor genome.
Their model of “lesion segregation” is explained as follows: 1) mutagens generate lesions on each DNA strand, and segregate during replication, 2) daughter cells have non-overlapping lesions, which are then resolved into full mutations, and 3) lineages with drivers undergo clonal expansion.
“Thanks to the concept of lesion segregation, we now understand better how the surprising complexity of mutations in cancer cells can arise,” summarized Duncan Odom, PhD, research group leader at the German Cancer Research Center. “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.”
Sarah Aitken, PhD, NIHR clinical lecturer at Cancer Research UK Cambridge Institute and lead author on the paper, tweeted that the team “found something really unexpected,” referring to the “chromosome-scale, strand-asymmetric distribution of mutations.” Here are ~60,000 mutations identified in a single tumor, she noted, and “we find similar Watson-versus-Crick-strand asymmetry of mutations in all 371 tumor genomes.”
Cancer cells are usually exposed to several mutagenic events, so that this cycle of DNA damage and lesion segregation repeats over time, ultimately resulting in extremely complex patterns of mutations in cancers.
They found that lesion segregation is a pervasive feature of all exogenous mutagens and is evident in human cancers and, as Aitken noted, “profoundly revises our understanding of how the architecture of DNA repair and clonal proliferation can conspire to shape the cancer genome.”
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. They can grow the fastest, escape the immune system and possibly survive therapies better,” said Aitken.
“Persistent DNA lesions induced by chemotherapeutic agents also segregate and produce several generations of further mutations,” said Martin Taylor, PhD, group leader from the University of Edinburgh’s MRC Human Genetics Unit. “We need to be aware of this therapeutically, and in future drug development.”
