Gene Expression Profiling of PDGFRA Mutant GIST Reveals Immune Signatures as a Specific Fingerprint of D842V Exon 18 Mutation
Gene Expression Profiling of PDGFRA Mutant GIST Reveals Immune Signatures as a Specific Fingerprint of D842V Exon 18 Mutation
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DOI：
10.3389/fimmu.2020.00851
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发表时间：
2020-06-02
影响因子：
7.3
通讯作者：
Nannini, Margherita
中科院分区：
文献类型：
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作者：
Indio, Valentina;Ravegnini, Gloria;Nannini, Margherita
血小板衍生生长因子受体α（PDGFRA）突变仅发生在约5-7%的胃肠道间质瘤（GIST）中，特别是外显子12/14/18的改变。最常见的PDGFRA突变是外显子18 D842 V，这与特定的临床病理特征相关，如原发性伊马替尼耐药和较高的无痛性。在这里，我们提出了一个基因表达谱（GEP）比较D842 V与PDGFRA与突变以外的D842 V（非D842 V）。GEP后进行生物信息学分析，旨在评估差异表达，肿瘤微环境组成和途径富集。我们发现了一个大的致癌基因，转录因子和核受体下调D842 V突变。相反，D842 V显示出免疫和干扰素相关基因特征的显著富集。还强调了肿瘤微环境组成的差异，包括更高丰度的CD 8 + T细胞和D842 V突变亚组中T细胞炎症特征的过表达，这是免疫治疗反应的预测。PDGFRA D842 V与非D842 V GIST显示出不同的表达谱，具有突出的免疫学特征，这可以代表在GIST的这种药物孤儿亚组中测试免疫策略的原理证明。
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 byin silicobioinformatic 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.