Prävalenz und prognostische Bedeutung der FGFR1-Genamplifikation und -Proteinexpression in humanem Lungenkrebs

von Anna-Maria Lois
Dissertation
Datum der mündl. Prüfung:2024-08-01
Erschienen:2024-08-01
Betreuer:Prof. Dr. Philipp Ströbel
Gutachter:Dr. Achim Rittmeyer
Gutachter:Prof. Dr. Thomas Meyer
Zum Verlinken/Zitieren: http://dx.doi.org/10.53846/goediss-10649

 

 

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Englisch

In the past few decades, personalized therapies have severely improved the outcome of patients with advanced-stage lung adenocarcinoma, yet so far the search for similarly druggable molecular targets in squamous cell carcinoma of the lung remains unsuccessful. FGFR1 has emerged as a potential candidate for pharmaceutical inhibition, although initial breakthroughs in pre-clinical testing could not be replicated in phase-II studies. One of the reasons for these heretofore disappointing results might be the lack of an established predictive marker for patient selection. The goal of this work was to determine the prognostic value and correlation of FGFR1 gene amplification and protein expression in lung carcinoma, as well as to determine its interaction with other, frequently dysregulated proteins in FGFR signalling, such as FRS2, FRS3 and c-Myc. To this end, a collective of more than 400 lung cancer patients was assembled and analyzed regarding clinical features. Tumor tissue from each case was transferred onto tissue microarrays and tested for FGFR1, FRS2 and FRS3 via immunohistochemistry. Finally, FGFR1 gene amplification was quantified through fluorescence in situ hybridization (FISH). To summarize, none of the proteins tested nor FGFR1 gene amplification correlated with patient outcome. Simultaneous co-expression of all three proteins FGFR1, FRS2 and FRS3 was a non-significant positive prognostic factor. As shown before, FGFR1 gene amplification does not seem to reliably coincide with FGFR1 protein expression, once again confirming that amplification is not an ideal predictive marker for successful inhibition. FGFR1 overexpression occured in 35% of adenocarcinomas, a highter rate than previously published. Furthermore, FGFR1 amplification was remarkably more frequent in male patients. Unlike previous reports, c-Myc overexpression correlated with FGFR1 amplification. To summarize, further investigation into the interactions between the above proteins is necessary to fully understand FGFR1-initiated signalling and its value in diagnostics as well as inhibition therapy. Alternative predictive markers other than gene amplification should be considered for future studies.
Keywords: FGFR1, c-Myc, FRS2, FRS3, lung cancer, biomarker; FGFR1; FRS2; FRS3; lung cancer; biomarker; c-Myc
 
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