A person's genetic background can strongly influence not only whether they will develop cancer but also how that cancer progresses, suggesting that genetics plays a much larger role in cancer evolution than previously understood, a study co-led by Yale researchers has found.
According to the study, published in the journal Nature, inherited DNA affects not only cancer risk, but also helps determine which mutations a tumor acquires, how quickly it grows, how genetically unstable it becomes, and even how it evolves over time.
The findings may help explain why cancers can behave differently across individuals from diverse ancestral backgrounds, even when their tumors have similar mutations, researchers say.
Although mutations play a well-established role in cancer development, these results suggest that genetic factors should also be considered when developing diagnostic tools, predicting clinical outcomes, and designing personalized treatment strategies.
"It looks like the genetics influence the ability for the cancer to arise in the first place, for the mutations to happen, and also for how a tumor then evolves in a particular individual and responds to treatment," said lead author Sarah Aitken, an assistant professor of pathology at Yale School of Medicine. She is also affiliated with the Yale Cancer Center.
For the study, the researchers administered a chemical that causes liver cancer to four genetically distinct strains of mice of the same age and under tightly controlled conditions. They then analyzed 581 resulting liver tumors in the mice using whole-genome sequencing, RNA sequencing, and microscopic pathology. The highly controlled design allowed the researchers to isolate the impacts of natural inherited genetics on how the cancer behaved, researchers said.
The analysis revealed that different genetic backgrounds send cancerous tumors down different developmental paths, even when those tumors were exposed to the same cancer-causing chemical and grown under the same conditions.
"We found that the inherited genome interacts with acquired cancer-driving mutations to alter the activity of other critical cancer pathways," Aitken said. "In other words, exactly the same mutation can have an opposite effect in different individuals. At the moment, however, we can't say exactly what in the genetic background is most responsible, because there are millions of different genetic differences that interact together, so this raises a lot of additional questions."
Still, the finding may have more immediate implications for cancer screening methods.
"We tend to target particular groups based on age or particular exposures," Aitken said. "If someone's a smoker, we might screen them for lung cancer. If someone's over a certain age, we screened them for breast cancer, whereas we don't consider people's genetics in the equation. This research indicates that perhaps we should."
Aitken's co-authors include researchers from the University of Edinburgh and from the University of Cambridge with whom she began this project more than 10 years ago. Co-lead authors are Martin Taylor, a professor of evolutionary genomics at the University of Edinburgh; and Duncan Odom, a researcher at the German Cancer Research Institute (DKFZ) and formerly of the University of Cambridge.
Researchers from the Institute for Research in Biomedicine, Barcelona, Spain; the EMBL European Bioinformatics Institute, UK; the University of Connecticut, USA; and the Liver Cancer Evolution Consortium also contributed to this study.
