Role of FGF Receptors and Their Pathways in Adrenocortical Tumors and Possible Therapeutic Implications

Iuliu Sbiera, Stefan Kircher, Barbara Altieri, Kerstin Lenz, Constanze Hantel, Martin Fassnacht, Silviu Sbiera, Matthias Kroiss, Iuliu Sbiera, Stefan Kircher, Barbara Altieri, Kerstin Lenz, Constanze Hantel, Martin Fassnacht, Silviu Sbiera, Matthias Kroiss

Abstract

Adrenocortical carcinoma (ACC) is a rare endocrine malignancy and treatment of advanced disease is challenging. Clinical trials with multi-tyrosine kinase inhibitors in the past have yielded disappointing results. Here, we investigated fibroblast growth factor (FGF) receptors and their pathways in adrenocortical tumors as potential treatment targets. We performed real-time RT-PCR of 93 FGF pathway related genes in a cohort of 39 fresh frozen benign and malignant adrenocortical, 9 non-adrenal tissues and 4 cell lines. The expression of FGF receptors was validated in 166 formalin-fixed paraffin embedded (FFPE) tissues using RNA in situ hybridization (RNAscope) and correlated with clinical data. In malignant compared to benign adrenal tumors, we found significant differences in the expression of 16/94 FGF receptor pathway related genes. Genes involved in tissue differentiation and metastatic spread through epithelial to mesechymal transition were most strongly altered. The therapeutically targetable FGF receptors 1 and 4 were upregulated 4.6- and 6-fold, respectively, in malignant compared to benign adrenocortical tumors, which was confirmed by RNAscope in FFPE samples. High expression of FGFR1 and 4 was significantly associated with worse patient prognosis in univariate analysis. After multivariate adjustment for the known prognostic factors Ki-67 and ENSAT tumor stage, FGFR1 remained significantly associated with recurrence-free survival (HR=6.10, 95%CI: 1.78 - 20.86, p=0.004) and FGFR4 with overall survival (HR=3.23, 95%CI: 1.52 - 6.88, p=0.002). Collectively, our study supports a role of FGF pathways in malignant adrenocortical tumors. Quantification of FGF receptors may enable a stratification of ACC for the use of FGFR inhibitors in future clinical trials.

Keywords: FGF-pathway; FGFR; RNA Expression; RNAScope; adrenocortical tumors; normal adrenal glands; patient survival; unsupervised clustering.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2021 Sbiera, Kircher, Altieri, Lenz, Hantel, Fassnacht, Sbiera and Kroiss.

Figures

Figure 1
Figure 1
An example of RNAScope signal detection using the ImageScope software. The first image (A) is the original image; in the square is the selected area for detection. (B) the same image with the detected mRNA molecules marked in red by the software, while (C) is the same image with the detected cells marked in blue (nuclei) and yellow (cytoplasm).
Figure 2
Figure 2
Unsupervised clustering of RT-PCR data of the FGF pathway genes. Unsupervised hierarchical matrix based on FGF pathway expression. On the left side is a graphical representation of the log 2 transformed normalized expression data arranged vertically by tissue name, and horizontally by gene name in the order that they were arranged on the PCR plate. To the right side is the data rearranged through the unsupervised similarity matrix clustering. The colored bar under the tissue names is encoding the different types of tissues analyzed: NAG=normal adrenal glands, ACA, adrenocortical adenomas; ACC1+2, ACC in ENSAT stages I and II; ACC3, ACC in ENSAT stage III; ACC4, ACC in ENSAT stage IV; EPTN, normal (non-neoplastic) classical epithelial tissues; EPTC, malignant tumors of classical epithelial tissues/carcinomas; MESC, malignant tumors of classical mesenchymal tissues/sarcomas and CELL, cell-lines.
Figure 3
Figure 3
Examples of expression RNAScope staining in ACC. (A) an example of house keeping gene, PPIB, staining, while (B–D) show various levels of FGFR4 expression, from low to high.
Figure 4
Figure 4
Expression of FGF receptors 1, 2 and 4 in adrenocortical tissues as assessed by RNAScope. Expression levels in ACA vs ACC (A), in ACC ENSAT stages 1 + 2 vs 3 + 4 (B) and in ACC primary tumor samples vs local or distant recurrences (C). Statistical significance: *p<0.05, **p<0.01, ***p<0.001.
Figure 5
Figure 5
Association between expression of FGF receptors 1, 2 and 4 with patient survival. (A, C, E) overall survival (B, D, F) recurrence-free survival. *p < 0.05 and **p < 0.01.

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