Authors of the study. From the left: Núria Malats, Evangelina López de Maturana, Sagrario Ortega, Cristina Bodas, Irene Felipe, Ana Cayuela, Jaime Martínez and Francisco X. Real. / Pilar Gil. CNIO
A group at the Spanish National Cancer Research Centre (CNIO) has found the mechanism that leads a genetic variant to increase the risk for pancreatic cancer.
“This enables us to identify a high-risk population, for whom prevention strategies could be developed”, according to Francisco X. Real, lead researcher of the study.
It has been published in the GUT journal.
Pancreatic cancer is on the rise and could become the second leading cause of cancer-related deaths worldwide in less than a decade. One reason is that it is not known how to detect it early, therefore the diagnosis often comes when the disease is already in advanced stages. Oncology seeks to “understand what precedes pancreatic cancer in order to try to prevent it or diagnose it in very early stages”, according to Francisco X. Real, Head of the Epithelial Carcinogenesis Group at the Spanish National Cancer Research Centre (CNIO).
Together with his team, he has presented a finding that could help to identify pancreatic cancer risk groups, that is, people on whom to focus prevention and early detection efforts, as well as to understand how to do so. The study has been published in the GUT journal.
Present in 17% of the population
More specifically, the CNIO group has identified a new mechanism that could help explain how a genetic variant in the gene that encodes chemotrypsinogen 2, CTRB2, increases the risk of developing the tumour.
This variant is present in 17% of the population and the increased risk it confers is not high in itself. However, the increase could be significant if the mutation is combined with other factors, such as smoking, obesity, alcohol consumption or diabetes, which are already known to favour pancreatic cancer (like the vast majority of tumours, pancreatic cancer is caused by a combination of environmental and hereditary factors).
“When this genetic variant appears along with other factors, such as diabetes or pancreatitis, or with other genetic variants, the risk could increase”, explains Real. “This enables us to identify a high-risk population, for which prevention strategies could be developed”.
In pancreatic cancer there are to date no tests that are specific, sensitive and non-invasive enough to screen the population – due to its location in the body, it is difficult to access the pancreas. This explains the importance of identifying high-risk groups.
Lesions in the pancreas that can be identified early
This mutation in the CTRB2 gene had already been identified in previous studies by the CNIO group and other collaborators. The new study, whose first authors are Cristina Bodas and Irene Felipe, confirms its causal role.
The group created a mouse animal model with the same mutation found in humans, and observed that it dramatically alters key aspects of how pancreatic cells function. “The damage in the pancreas of animals with the mutation could be seen in very young mice, using genomic techniques”, according to Real.
The authors, in collaboration with the CNIO’s Genetic and Molecular Epidemiology Group, led by Núria Malats, found that the same phenomenon occurred in humans with the mutation: alterations in the pancreas before cancer developed.
Preventive treatments
The next steps of the CNIO group focus on investigating how the new mutation in the CTRB2 gene collaborates with other factors associated with pancreatic cancer. Not only with the aforementioned pathologies, such as diabetes or pancreatitis, but also with mutations in the KRAS gene, which is known to be mutated in more than 90% of cases of pancreatic ductal adenocarcinoma (the most common subtype of pancreatic cancer).
The aim is to identify “a population with a much higher risk of developing the disease, for which preventive strategies can be proposed”, points out Real.
About the Spanish National Cancer Research Center (CNIO)
The Spanish National Cancer Research Center (CNIO) is a public research center under the Ministry of Science, Innovation and Universities. It is the largest cancer research center in Spain and one of the most important ones in Europe. It integrates half a thousand scientists, plus support staff, who work to improve cancer prevention, diagnosis and treatment.
Reference article
Bodas C, Felipe I, Chanez B, Lafarga M, Lopez de Maturana E, Martinez de Villarreal J, Del Pozo N, Malumbres M, Vargiu P, Cayuela A, Peset I, Connelly K, Hoskins J, Méndez R, Amundadottir L, Malats N, Ortega S, Real FX. A Common CTRB misfolding variant associated with pancreatic cancer risk causes ER stress and inflammation in mice. Gut. 2025 Apr 29:gutjnl-2024-333406. doi: 10.1136/gutjnl-2024-333406.