Gene Expression Profiling of PDGFRA Mutant GIST Reveals Immune Signatures as a Specific Fingerprint of D842V Exon 18 Mutation

Abstract

Platelet Derived Growth Factor Receptor Alpha (PDGFRA) mutations occur in only about 5–7% of gastrointestinal stromal tumors (GIST), notably with alterations on exons 12/14/18. The most frequent PDGFRA mutation is the exon 18 D842V, which is correlated to specific clinico-pathological features, such as primary imatinib resistance and higher indolence. Here, we present a gene expression profile (GEP) comparison of D842V vs. PDGFRA with mutations other than D842V (non-D842V). GEP was followed by in silico bioinformatic analysis aimed at evaluating differential expression, tumor microenvironment composition and pathway enrichment. We found a large set of oncogenes, transcription factors and nuclear receptors downregulated in the D842V mutant. Conversely, D842V showed a 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 the D842V mutant subgroup, which is predictive of immunotherapy response. PDGFRA D842V vs. 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.

Gastrointestinal Stromal Tumors (GISTs): Novel Therapeutic Strategies with Immunotherapy and Small Molecules

“…The D842V mutation is the most common mutation associated with primary resistance to imatinib because it alters the kinase domain formation and, therefore, negatively affects imatinib association [ 40 , 41 ]. In fact, the progression free survival (PFS) of patients treated with imatinib carrying the D842V mutation compared to non-D842Vs is statistically significant (2.8 vs. 28.5 months, respectively) [ 42 ].…”

“…In another study of a cohort of patients with PDGFRA D842V-mutated GIST, imatinib resulted in progressive disease for most patients (58.9%), with PFS up to 8 months [ 43 ]. Moreover, resistance occurs due to this mutation in the sunitinib [ 40 , 41 ].…”

“…Many studies indicate that D824V mutation displays more immune cells with increased cytolytic activity [ 40 , 41 , 44 , 45 , 46 , 47 ]. In particular, express higher interferon levels and several chemokines, such as CXCL14; demonstrates additional driver-derived neoepitope-HLA binding proteins; and has more PD-1 and PD-L1 expressing tumors [ 40 , 41 , 47 ]. Differences in tumor microenvironment composition were also highlighted between the D824 mutation and the other GIST molecular subtypes.…”

The Identity of PDGFRA D842V-Mutant Gastrointestinal Stromal Tumors (GIST)

“…Finally, the authors found that the D842V mutation produces more high-affinity neoepitopes, binding with many prevalent HLA types, which suggests that the presence of this mutation could be involved in immune responses in a wide variety of patients [37]. [36][37][38]. Abbreviations: GIST: gastrointestinal stromal tumors; n: number; PDGFRA: platelet-derived growth factor receptor A; WT: wild type.…”

“…Given the known heterogeneity within PDGFRA-mutant GIST, the differential immunological profile of PDGFRA D842V-mutant GIST in comparison with other PDGFRA mutants was subsequently investigated in order to better understand if the previously observed prominent immune features belong to all PDGFRA-mutant GIST or if they represent a specific peculiar fingerprint of the D842V mutant subgroup [36]. [36][37][38]. Abbreviations: GIST: gastrointestinal stromal tumors; n: number; PDGFRA: platelet-derived growth factor receptor A; WT: wild type.…”