Exploring Shootin1's oncogenic role within FGFR2 gene fusions

Area of Science:

• Oncology
• Molecular Biology
• Genomics

Background:

• Fibroblast Growth Factor Receptor (FGFR) gene fusions are key drivers of cancer initiation and progression.
• FGFR fusions are significant therapeutic targets, especially in difficult-to-treat cancers such as cholangiocarcinoma.

Purpose of the Study:

• To characterize the novel FGFR2::SHTN1 fusion.
• To identify it as a de novo chimeric protein.
• To elucidate its oncogenic mechanism.

Main Methods:

• Identification of FGFR2::SHTN1 fusions using cancer genomics databases.
• Structural modeling with AlphaFold and HADDOCK, including membrane embedding.
• Assessment of SHTN1 oligomerization and fusion protein activity via coimmunoprecipitation and gel electrophoresis.

Main Results:

• The FGFR2::SHTN1 fusion is an in-frame joining of FGFR2 exons 1-17 and SHTN1 exons 7-17.
• The chimeric protein retains the intact FGFR2 tyrosine kinase domain.
• Shootin1's coiled-coil domains mediate ligand-independent dimerization and constitutive FGFR2 activation.

Conclusions:

• FGFR2::SHTN1 is a potent oncogenic driver, particularly in cholangiocarcinoma, via constitutive FGFR2 activation.
• This study provides the first molecular characterization of the FGFR2::SHTN1 fusion.
• The findings advance understanding of FGFR2 fusion biology and identify a target for future diagnostics and therapies.