Blood Protein Signature Predicts Lung Cancer Risk More Than Five Years Before Diagnosis
核心洞察
Researchers identified a 14-protein blood signature that can predict lung cancer (搜索) risk more than five years before diagnosis using machine learning on data from over 48,000 UK Biobank participants.
The signature reflects an altered inflammatory lung environment preceding cancer and was validated across eight international datasets, including a cohort of never-smokers.
Re-analysis of the CANTOS trial showed that individuals with a high baseline protein signature who received canakinumab had their lung cancer (搜索) risk almost halved, with a number needed to treat of 55.
A landmark study published in Cell has identified a 14-protein signature in the blood that can predict lung cancer (搜索) risk more than five years before diagnosis, offering a potential path toward precision cancer prevention. The research, led by the Francis Crick Institute (搜索) and University College London (UCL) with funding from Cancer Research UK and the European Research Council, represents what one researcher called "the holy grail of cancer prevention medicine."
The team applied machine learning to blood plasma protein data from more than 48,000 UK Biobank participants, using matched cancer registry records to identify those who later developed lung cancer (搜索). Along with age, smoking status, and previous history of lung disease, the algorithm identified 14 key proteins that could predict a future lung cancer diagnosis within five years.
Validated Across Global Populations
The protein signature was validated in eight datasets from across the world, with more than 80 collaborators on four continents. In all studies, the signature was higher in patients who later developed lung cancer (搜索), including one cohort of non-smokers. This finding is particularly significant given that current lung cancer screening programs are offered only to people over a certain age who have previously smoked, missing never-smokers and individuals exposed to high levels of pollutants who may also be at risk.
Dr Clare Weeden, a corresponding author on the paper and WEHI laboratory head who conducted the research during her time at the Crick, said: "Figuring out who is at risk of developing cancer is the holy grail of cancer prevention medicine. This proof-of-concept study offers new ideas that could fill this critical knowledge gap."
A Shared Pre-Disease Inflammatory State
Analysis in patients and animal models suggested that the signature does not originate from the tumor itself, but rather reflects an altered inflammatory lung environment that precedes cancer. The signature was also increased in people who later developed idiopathic pulmonary fibrosis (搜索) or chronic obstructive pulmonary disease (搜索) (COPD), supporting the idea that it may capture a shared, pre-disease state of lung inflammation.
Charlie Swanton, Clinical Research Director and Principal Group Leader at the Crick and Professor in Cancer at UCL, explained: "Finding a signal for an inflammatory state in the lungs has given us insight into this window of opportunity, when preventative treatment could work best. This work supports a relatively new idea in the field, that some common age-related diseases, causing a high burden of disease in the community, share a common, presymptomatic state of inflammation."
The Biology of Inflammation-Driven Cancer
The study builds on the lab's earlier work showing that air pollution exposure triggers immune cells in the lung to release interleukin-1 beta (搜索) (IL-1β), which can wake up dormant cells carrying cancer-causing mutations. In the current study, the researchers demonstrated that pollution exposure simultaneously increases the signature proteins and boosts the population of 'KAC cells' — an adaptive cell state that occurs in response to injury but can become cancerous if mutations are present.
"What surprised us was that very different lung cell types all seemed to converge on the same intermediate state before becoming cancerous — suggesting KACs represent a common vulnerability in lung adenocarcinoma," said Dr Weeden. "If we can identify people in whom this process is active and intervene at that stage, we may be able to prevent cancer before it develops."
Blocking IL-1β in mice exposed to pollution reduced the number of KAC cells and slowed early tumor development, suggesting anti-IL-1β drugs could prevent lung cancer (搜索) in people whose lungs are showing this inflammatory signal.
CANTOS Trial Re-Analysis: A Precision Prevention Strategy
In 2017, Novartis's CANTOS trial tested the IL-1β blocker canakinumab to prevent cardiovascular disease and reported as an exploratory finding that the drug also reduced lung cancer (搜索) incidence. However, the benefit was modest at a population level, limiting its use as a prevention strategy in unselected people.
Re-analysing data from 4,651 CANTOS participants, the researchers found that people with a high baseline 14-protein signature were the ones who clearly benefited from canakinumab, with their lung cancer (搜索) risk almost halved. By selecting only those with a high signature, the number of people needed to treat to prevent one incidence of lung cancer was 55 — comparable to established cardiovascular prevention strategies such as statins.
Tej Pandya, Clinical PhD Student at UCL and visiting scientist at the Francis Crick Institute (搜索), said: "It's a proof of concept that, one day, we could use this signature to offer preventive treatment to people at risk of lung cancer (搜索)."
Swanton drew a parallel to cardiovascular medicine: "Drugs like statins have transformed the prevention of cardiovascular disease, used to treat individuals with a high LDL. But we don't yet have an LDL-like marker of risk or a statin for lung cancer (搜索). In the clinic, we see first-hand the impact of diagnosing lung cancer at a late stage, so being able to identify people at greater risk and intervene before the disease develops is critical."
The study involved collaboration between the Francis Crick Institute (搜索), UCL, the National Institute for Health and Care Research UCLH Biomedical Research Centre, the CRUK Lung Cancer (搜索) Centre of Excellence, Novartis, and multiple international consortia including EPIC, ARIC, TALENT, and CKB.