Gene Expression Profiling of PDGFRA Mutant GIST Reveals Immune Signatures as a Specific Fingerprint of D842V Exon 18 Mutation
Valentina Indio, Gloria Ravegnini, Annalisa Astolfi, Milena Urbini, Maristella Saponara, Antonio De Leo, Elisa Gruppioni, Giuseppe Tarantino, Sabrina Angelini, Andrea Pession, Maria A. Pantaleo, Margherita Nannini
Abstract
PDGFRA mutations occur in in only about 5–7 % of gastrointestinal stromal tumors (GIST), notably with alterations on exon 12/14/18. The most frequent PDGFRA mutation is the exon 18 D842V, which is correlated to specific clinical-pathological features as the primary imatinib resistance and the higher indolence. Here, we present a gene expression profile (GEP) comparison of D842V versus PDGFRA mutant other than D842V (non-D842V). GEP was followed by in silico bioinformatic analysis aimed to evaluate differential expression, tumor microenvironment composition and pathway enrichment. We found a large set of oncogenes, transcription factors and nuclear receptors downregulated in D842V mutant. Conversely, D842V showed significant enrichment of immune- and interferon- related gene signatures. Differences in tumor microenvironment composition were also highlighted, including a higher abundance of CD8+ T-cells and an overexpression of the T cell-inflamed signature in D842V mutant subgroup, that is predictive of immunotherapy response. PDGFRA D842V versus non-D842V GIST display a different expression profile, with a prominent immunological signature, that could represent a proof of principle for testing immunotherapeutic strategies in this drug-orphan subset of GIST.