Genetic timelines: determining cancer’s path

In many aspects of our lives, we find meaning in the order in which events occur. We buy into myths about ‘middle child syndrome’, talk of calm before storms, and consider it strange to start a meal with dessert.  

Whether these things really matter is largely constructed by society, when it comes to biology, it’s becoming clear that there’s an undeniable biological order driving diseases like cancer. In fact, the sequence of molecular events leading to the disease can shape a patient’s future, often long before they’ve even been diagnosed.

No two people’s cancers are the same. Each tumour is a unique patchwork of cells carrying different genetic mutations, evolving and changing over time. It is why people diagnosed with the same type of cancer can experience wildly different outcomes.  

This can sometimes be explained by the presence or absence of certain mutations, but that’s not always the case. Modern DNA sequencing technologies are allowing researchers to uncover a crucial additional layer of complexity; it’s not just the presence of particular mutations in a tumour that affect its behaviour, it’s the order in which they occur.  

Take for example a class of genes called tumour suppressor genes. These biological safeguards prevent cells from growing without control, meaning that if a tumour suppressor gene is lost or mutated, cells can grow unchecked.  

But new research suggests that if tumour suppressor loss occurs at a particular time in a tumour’s development, it can paradoxically have an unexpected protective effect.

“It can be tempting to look at cancer mutations as good or bad, black or white,” says Francesca Ciccarelli, who leads a research team at the Crick and Queen Mary University of London. “But that’s not always the case.”  

Sequence shapes survival

In a recent study, her team focused on a tumour suppressor gene called CDKN2A, which is commonly mutated in a pre-cancerous condition of the oesophagus known as Barrett's oesophagus.  

Unexpectedly, they found losing this gene doesn’t always trigger cancer, and under certain circumstances, can actually prevent Barrett’s progressing. This, they discovered, is because cells that lose CDKN2A cannot tolerate subsequent loss of another key gene TP53, which is essential for Barrett’s to progress.

However, this all changes if the order is swapped, and CDKN2A is lost after the cancer has already lost TP53. In such cases, CDKN2A loss fuels growth of more aggressive tumours in the oesophagus.  

“Our findings challenge the simplistic perception that cells with mutations are ticking time bombs and show that, in some cases, they can even be protective,” says Francesca.

This dynamic shift highlights how tracing the evolutionary history of cancers is key to identifying vulnerabilities in the course of disease – the moments when treatments may be most effective or, ideally, when doctors could intervene to stop cancer developing in the first place.