10 August 2022

Unravelling genetic mechanism behind tumor formation can improve targeted treatment

Genetic alterations in the FGFR2 gene occur in various cancer types and represent a promising target for therapies. However, clinical responses to available therapies remained variable and unpredictable, making it difficult to select patients who would benefit from these types of treatments. An international team of researchers led by Jos Jonkers, group leader at the Netherlands Cancer Institute and Oncode Investigator, has now elucidated the mechanism behind this variation in treatment response. Their research offers new opportunities to improve diagnostics and targeted therapy for many cancer patients. The results highlight the importance of studying the functional consequences of genetic changes in tumors.

Peter Thijssen Support Staff

In various types of cancers - including bile duct cancer, stomach cancer and breast cancer - copy number alterations and fusions in the Fibroblast Growth Factor Receptor 2 (FGFR2) gene are relatively common. But just how these genetic variations contribute to the formation of tumors was unclear. Besides this, targeting FGFR2 with therapies brought variable and unpredictable results. But now the team led by Oncode Investigator Jos Jonkers took a data driven approach to solve this puzzle presented by FGFR2.

“The story of our new findings began over a decade ago”, says Jonkers who is a group leader at the Netherlands Cancer Institute. “By using a mouse model in which we could induce genetic alterations in a controlled manner, we observed a specific variation in the last part of the FGFR2 gene leading to the presence of an incomplete FGFR2 protein. Follow up mouse experiments then showed that this truncated form of FGFR2 leads to the formation of tumors.”

Tumor formation is not caused by more of the normal protein, but by a little bit of the truncated protein

In parallel, the team started looking for evidence of the presence of this truncated form of FGFR2 in human cancer samples. With the datasets available at the Hartwig Medical Foundation and Foundation Medicine, they uncovered that many of the known alterations in the FGFR2 gene lead to the expression of the truncated protein. “We found data confirming our model at the genetic level, but also at the gene expression level”, postdoctoral fellow and first author Daniel Zingg explains. “Existing diagnostic approaches usually focus on the increased amounts of the protein in tumor samples. What we uncovered now is that it is not the amount of FGFR2 what is causing cells to become cancerous, but the expression of the truncated form. Tumor formation is not caused by more of the normal protein, but by a little bit of the truncated protein."

Clinical impact

To determine the clinical relevance of their findings, the team interrogated data from preclinical and clinical trials with FGFR inhibitors from biopharmaceutical companies Debiopharm and Incyte, respectively. “We knew that our preclinical findings had the potential to change clinical practice”, says Jonkers. “Looking into clinical trial data revealed that a good response to treatment correlates with the presence of the truncated form of FGFR2. This means that we now have a way to identify which patients can benefit from treatments targeting FGFR2.” The results should still be confirmed in a prospective clinical trial, but the team is very hopeful that their work can help to improve the clinical practice.

The results published in Nature showcase the importance of collaboration as well as a data driven approach. The team of Jos Jonkers collaborated with fellow Oncode Investigator and co-cooresponding author Lodewyk Wessels, other Oncode Investigators, colleagues at the NKI, Amsterdam UMC, Hartwig Medical Foundation, genomic profiling company Foundation Medicine, biopharmaceutical companies Incyte and Debiopharm and Rutgers Cancer Institute of New Jersey. “These findings, which go from mouse models into cancer genomics and human clinical trial data, will lay the groundwork for development of clinical trials aimed at rationally increasing the number of patients who will benefit from FGFR inhibitor therapy,” says Shridar Ganesan, MD, PhD, chief of molecular oncology and associate director for translational research at Rutgers Cancer Institute and co-senior author of the work. “This work also demonstrates the growing power of using clinical tumor sequencing data and sophisticated pre-clinical models to tackle basic questions in tumorigenesis and guide development of targeted therapeutics.”

“It’s great that through our Oncode base funding and a broad collaborative effort, we could bring this basic and data driven project towards the point where we can have a clinical impact. From a scientific perspective, our work highlights the importance of the functional analysis of mutations we find in cancer. This will allow us to better interpret the ever-growing set of genetic data from tumors, and advance our understanding of cancer biology”, Jonkers concludes.

Read the scientific article here.

Other News

PE 6
Eerste live bijeenkomst Oncode Patiënt Perspectief Programma brengt (ex-)patiënten en onderzoekers dichter bij elkaar
(Text in Dutch) Benieuwd hoe onderzoekers en (ex)patiënten elkaar kunnen helpen? Lees de highlights over Oncode's Patiënt Perspectief Programma meeting, waar onderzoekers en patiënt partners elkaar ontmoetten.


Elize is part of Oncode’s communication team. She has over 10 years of experience in the com-munication industry, both for commercial and non-profit organisations. After obtaining her bache-lor and master degree in communication at Utrecht University, Elize worked as a communication professional at a research institute, PR agency, law firm and internet company. She has a strong focus on external communications and Public Relations. At Oncode - together with her colleagues - Elize produces the monthly newsletters for Oncode Investigators & Researchers and the Oncode digital magazine. She publishes content for the Oncode website and is responsible for all social media channels. She enjoys discussing science with researchers and support them in their outreach.
Figure nature option3
Specialized immune cells carry potential for new cancer immunotherapies
Oncode Investigators Emile Voest, Ton Schumacher and Lodewyk Wessels (all NKI), together with scientists from Leiden University Medical Center (LUMC) have discovered how specialized immune cells can detect and remove cancers that are ‘invisible’ to the conventional defense mechanisms of the immune system. The findings could lead to novel cancer immunotherapies. Their work is published today in Nature.


Image t cell recognize tumor cell
New technique to detect T cells that recognize a patient’s tumor
Oncode Investigators Emile Voest and Ton Schumacher together with Wouter Scheper (all NKI) have developed a new technique that can map out molecules on the tumor cells in individual cancer patients that are recognized by T cells. This new technology is an important step toward personalized immunotherapy. Their findings were published today in Nature Biotechnology.