Nature Communications. A CNIO study identifies new genes that predispose an individual to pancreatic cancer

Evangelina López (left) and Núria Malats. / Christian Esposito. Madmoviex. CNIO

A new study by the National Cancer Research Centre (CNIO) has identified several sets of genes related to the predisposition to develop pancreatic ductal adenocarcinoma (the most common type of pancreatic cancer), as well as the prognosis of the disease once it has appeared.

The study, which has just been published in Nature Communications, represents progress towards the development of screening programmes among the population, an essential tool for advancing early diagnosis. It is led by Núria Malats and Evangelina López de Maturana, from the Epidemiology and Molecular Genetics Group at CNIO.

Early diagnosis poses a major challenge in pancreatic cancer, since high mortality rates are associated with the fact that it is usually detected once it is very advanced.

The genes identified are part of an innate defence mechanism within the body, the complement system. When the proteins of the complement system fail, or if they are lacking or produced in excess, diseases can appear. Very few studies so far have linked the complement system with cancer.

Biomarkers for future screenings

This study, whose first author is Alberto Langtry – currently at Columbia University (USA) after completing his doctoral thesis at CNIO – has discovered that the probability of developing pancreatic cancer may increase when two specific genes in the complement system become mutated.

These genes, called FCN1 and PLAT, could become useful biomarkers for screening high-risk populations. When their presence, along with other factors, indicates susceptibility to pancreatic cancer, the individual may join a monitoring programme.

These are crucial programmes in pancreatic cancer, where high mortality rates are associated with the fact that it is often detected in the very advanced stages. However, first, it is necessary to identify those who are at higher risk of developing this tumour, and in this context, this study is of particular value, as indicated by its authors.

Working towards immunotherapy in pancreatic cancer

Other genes within the complement system are related to two types of immune cells: defenders and regulators. The team has discovered that the activity of certain groups of genes determines the infiltration of defender cells or regulatory cells in the tumour. The former increase cancer survival, while the latter have the opposite effect.

Understanding the relationship between the genes of the complement system and pancreatic cancer may also have implications for treatment. Pancreatic cancer is a ‘cold’ cancer: it manages to camouflage itself from the immune system, so it is not ‘seen’ and, therefore, the immune system does not activate to destroy it. That’s why pancreatic cancer does not respond to immunotherapy.

This new knowledge about the relationship between the complement system and pancreatic cancer allows us to consider “new immunotherapies targeted at these genes,” says Malats.

A website and an app for classifying pancreatic cancer

Another challenge of pancreatic cancer is its heterogeneity: the degree of aggressiveness of the tumours varies, as does the response to treatments. Several classification models have been previously proposed, but each one identified different subtypes.

A new study, also directed by Malats at CNIO, has compiled the information from all of these models and uses algorithms to integrate it into a new consensus classifier. In addition, the team have developed a website and an application to facilitate its use: the RNA of a tumour sample is sequenced, the data is uploaded to the website or the application, and the tumour subtype is obtained.

From the best treatment to new risk factors

The new classifier establishes two subtypes based on the information from the tumour cells, and another two based on that of the stroma, the set of healthy cells surrounding tumour cells that also influence the effectiveness of treatments. The study is published in Genome Medicine, and its first author is Pablo Villoslada, a postdoctoral researcher with Malats’ group.

The new model may indicate whether the tumour is a subtype that responds best to one of the most common treatments for this cancer. Hence its importance for clinical practice.

The classifier can also be used to study risk factors for pancreatic cancer, indicates Malats. “We know that smoking increases the risk, albeit slightly, but consistently. Perhaps what is happening is that we have studied it for pancreatic cancer in general, and it turns out that there are subtypes that increase the risk, and others that do not. Now that we are able to separate these subtypes, we can check this.”

Both the website and the app are already up and running. They are freely accessible and include the previous classifiers, to make comparisons or have that data.

Funding

The study published in Nature Communications has been largely financed using public funds provided by the Spanish Health Research Fund (FIS), the Carlos III Health Institute, the Department of Science, Innovation and Universities, and private contributions from the Scientific Foundation of the Spanish Cancer Association (AECC), and the Pancreatic Cancer Collective initiative of the Lustgarten Foundation and Stand Up To Cancer.

The study published in Genome Medicine has received funding from the Health Research Fund (FIS), the Carlos III Health Institute, the European Union’s Framework Programme for Research and Innovation (R&I), and the Pancreatic Cancer Collective initiative of the Lustgarten Foundation and Stand Up To Cancer.

About the National Cancer Research Centre (CNIO)

The National Cancer Research Centre (CNIO) is a public research centre under the Department of Science, Innovation and Universities. It is the largest cancer research centre in Spain and one of the most important in Europe. It includes around five hundred scientists, along with support staff, who are working to improve the prevention, diagnosis and treatment of cancer.

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