NEW CLUES TO LONG-STANDING CANCER MYSTERY
- Why cancer-triggering damage, like smoking, may cause disease in some people but not others
- Scottish researchers funded by Cancer Research UK help answer a long-standing mystery of cancer – why some people get the disease while others don’t.
An international team of leading scientists has discovered that inherited genetic differences play a crucial role in shaping how cancers develop and evolve after DNA damage to the body occurs.
The findings could help explain why some people exposed to major cancer risks, such as smoking, never develop disease while others do.
The research, published in Nature, carried out in mice by researchers at Edinburgh, Cambridge, Heidelberg and Yale universities, shows that genetic ancestry can directly influence how cancer-causing mutations behave and how the resulting cancers grow and interact within the body.
Study co-lead Professor Martin Taylor, of the Institute of Genetics and Cancer at the University of Edinburgh, said: “Cancer doesn’t develop in a vacuum. Our research has shown that inherited genetics can fundamentally shape how tumours grow and evolve.
“Understanding this interaction between an individual’s inherited genetics and new cancer-driving mutations caused by DNA damage brings us a step closer to truly personalised cancer care.”
Personalised medicine is a growing area of cancer research which aims to tailor treatment to a specific patient but more information, such as this study, is needed to understand why and how cancer behaves in different people.
In the UK, more than 403,000* people are diagnosed with cancer each year (34,800 in Scotland***) with around 170,000** people (16,400 in Scotland****) dying from the disease annually, so finding new ways to tackle the disease is vital.
DNA damage through normal ageing and environmental exposures like sunlight, tobacco smoke or processed meat can lead to cancer however, the process is far from predictable.
Many smokers, for example, never develop lung cancer, while some people who have never smoked do. The reasons for this are not fully understood as studies of human cancers are limited by the complexity of real life such as differences in lifestyle, environment, and the role genetics plays.
To understand the role genetics plays, the research team recreated cancer development under controlled conditions.
Using four genetically distinct groups of mice, representing levels of genetic variation similar to those in human populations, the team exposed each group to the same DNA-damaging chemical comparable to those found in some processed meats.
They then tracked how tumours developed in remarkable detail, analysing whole genomes, gene activity, and tumour structure.
Despite identical exposure, the cancers that emerged followed strikingly different paths depending on genetic background.
The study found that most tumours shared a common feature: disruption of a key cancer-driving pathway known as MAPK. However, how this disruption occurred and what happened next, varied widely.
Researchers observed differences in which genes were mutated, how tumours grew, the number of additional cancer-driving mutations and whether entire genomes were duplicated – a major step in cancer progression.
Even more striking, the same cancer-causing mutation could have different effects depending on genetic background, influencing critical pathways such as the body’s key tumour suppressor system.
Study co-lead, clinician scientist pathologist Dr Sarah Aitken, Assistant Professor at the Centre of Molecular and Cellular Oncology, Yale University, said: “Our findings have important implications for cancer screening, diagnosis, and prognostication as well as profound implications for precision medicine.
“Even when tumours arise from the same type of damage and look nearly identical under the microscope, they can acquire distinct molecular changes depending on inherited genetics which shape how the cancer behaves.
“Treatments are often designed to target specific mutations (identified by genomic pathology tests) but this research suggests that patients with the same mutation may respond differently depending on their genetic background.”
By better understanding how inherited DNA influences cancer evolution, future approaches could improve prediction of cancer risk, allow medics to tailor treatments more effectively to individuals and help address disparities in cancer outcomes across populations.
Senior author Professor Duncan Odom, who led the research while at the Cancer Research UK Institute and the University of Cambridge, now based at the German Cancer Research Centre (DKFZ)in Heidelberg, Germany, said: “Cancer does not arise entirely by chance. Although tumours often reach the same biological endpoint, the path to that endpoint is determined by an individual’s genetic background.
“We’ve been able to show for the first time the extent to which genetic background influences both the mutation processes and the pathways leading to tumour development.”
The study is the result of years of international collaboration between the Universities of Edinburgh, Yale and Cambridge and forms part of the Liver Cancer Evolution consortium led by Professor Duncan Odom, Dr Sarah Aitken and Professor Martin Taylor.
Along the way, the team uncovered unexpected patterns in how DNA damage is processed; insights that ultimately enabled them to track cancer development with unprecedented precision.
Cancer Research UK research information lead, Dr Sam Godfrey, said: “This study gives us a fascinating hint that our inherited genes might have a big influence on the way that cancers develop after DNA damage.
“We still need to see more research before we can understand what this means in humans, but this finding could change our understanding of how cancer starts, and lead to more powerful and precise ways of tackling cancer.”
By releasing this dataset to the wider scientific community, the researchers hope to accelerate discoveries in cancer evolution and treatment.
