FGFR4 regulates tumor subtype differentiation in luminal breast cancer and metastatic disease
Susana Garcia-Recio, … , Aleix Prat, Charles M. Perou
Susana Garcia-Recio, … , Aleix Prat, Charles M. Perou
Published June 23, 2020
Citation Information: J Clin Invest. 2020;130(9):4871-4887. https://doi.org/10.1172/JCI130323.
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Research Article Genetics Oncology

FGFR4 regulates tumor subtype differentiation in luminal breast cancer and metastatic disease

Abstract

Mechanisms driving tumor progression from less aggressive subtypes to more aggressive states represent key targets for therapy. We identified a subset of luminal A primary breast tumors that give rise to HER2-enriched (HER2E) subtype metastases, but remain clinically HER2 negative (cHER2–). By testing the unique genetic and transcriptomic features of these cases, we developed the hypothesis that FGFR4 likely participates in this subtype switching. To evaluate this, we developed 2 FGFR4 genomic signatures using a patient-derived xenograft (PDX) model treated with an FGFR4 inhibitor, which inhibited PDX growth in vivo. Bulk tumor gene expression analysis and single-cell RNA sequencing demonstrated that the inhibition of FGFR4 signaling caused molecular switching. In the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) breast cancer cohort, FGFR4-induced and FGFR4-repressed signatures each predicted overall survival. Additionally, the FGFR4-induced signature was an independent prognostic factor beyond subtype and stage. Supervised analysis of 77 primary tumors with paired metastases revealed that the FGFR4-induced signature was significantly higher in luminal/ER+ tumor metastases compared with their primaries. Finally, multivariate analysis demonstrated that the FGFR4-induced signature also predicted site-specific metastasis for lung, liver, and brain, but not for bone or lymph nodes. These data identify a link between FGFR4-regulated genes and metastasis, suggesting treatment options for FGFR4-positive patients, whose high expression is not caused by mutation or amplification.

Authors

Susana Garcia-Recio, Aatish Thennavan, Michael P. East, Joel S. Parker, Juan M. Cejalvo, Joseph P. Garay, Daniel P. Hollern, Xiaping He, Kevin R. Mott, Patricia Galván, Cheng Fan, Sara R. Selitsky, Alisha R. Coffey, David Marron, Fara Brasó-Maristany, Octavio Burgués, Joan Albanell, Federico Rojo, Ana Lluch, Eduardo Martinez de Dueñas, Jeffery M. Rosen, Gary L. Johnson, Lisa A. Carey, Aleix Prat, Charles M. Perou

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Figure 1

Comparative genetic and transcriptomic analysis of FGFR4 family members in TCGA.

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Comparative genetic and transcriptomic analysis of FGFR4 family members ...
(A) Box-and-whisker plots of FGFR family gene expression levels by mRNAseq according to molecular subtype and HER2 status by IHC. Tumors without clinical data for HER2 status and normal-like samples have been removed from the analysis, resulting in 1028 patients. Box-and-whisker plots display the median value on each bar, showing the lower and upper quartile range of the data and data outliers. The whiskers represent the interquartile range. Comparison between more than 2 groups was performed by ANOVA. Statistically significant values are highlighted in red. Each mark represents the value of a single sample. (B) Oncoprint diagram depicting high mRNA gene expression, DNA copy-number alterations, and mutations of FGFR family genes. *FGFR mRNA, high expression: high expression of genes was considered where levels exceeded the third quartile of positive values of gene expression (normalized, log2-transformed, and median-centered RNAseq data). Putative copy-number calls on 1077 cases were determined using GISTIC 2.0 (84). Deep deletion: –2 (homozygous deletion); amplification: 2 (high-level amplification). Mutation types are defined only as missense mutations (single base pair) or truncating mutations (multiple base pairs). HER2 clinical status was defined as previously described (85). LumA, luminal A; LumB, luminal B.