Dora David, Vörös Imre, Varga Zoltán V, Takacs Peter, Teglasi Vanda, Moldvay Judit, Lohinai Zoltan
Department of Anatomy, Histology and Embryology, Faculty of Medicine, Semmelweis University, Budapest, Hungary.
Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary.
Transl Lung Cancer Res. 2023 Jan 31;12(1):27-41. doi: 10.21037/tlcr-22-449. Epub 2023 Jan 13.
BACKGROUND: BRAF is a critical member of proliferation pathways in cancer, and a mutation is present in only 2-4% of lung adenocarcinomas (LADC). There is no data available on the expression pattern of BRAF RNA that might result in enhanced signalling and drug resistance. METHODS: LADC tissue samples (n=64) were fixed and processed into paraffin blocks. Tissue microarrays (TMA) were constructed, and RNAScope hybridization (ISH) assay was performed for wild-type (WT) BRAF RNA. Apart from pathological assessment of tumor samples (grade, necrosis, vascular involvement and peritumoral infiltration), anti-programmed death ligand 1 (PD-L1) and anti-programmed death 1 (PD-1) immunohistochemistry and validation in public databases [The Cancer Genome Atlas (TCGA), Human Protein Atlas (HPA)] were carried out. RESULTS: WT BRAF RNA is expressed in LADC, with no significant expressional difference between early-stage (I-II) and advanced-stage (III-IV) patients (P=0.317). Never smokers exhibited significantly increased BRAF expression (compared to current and ex-smokers, P<0.01) and tumor necrosis correlated significantly with BRAF expression (P=0.014). PD-L1 expression was assessed on tumor cells and immune cells, PD-1 expression was evaluated on immune cells. There was no significant difference in BRAF RNA expression between tumor cell PD-L1-high low patients (P=0.124), but it was decreased in immune cell PD-L1-high patients (P=0.03). Kaplan-Meier survival analysis showed that high BRAF expression was associated with significantly decreased OS (P<0.01) and was an independent negative prognostic factor according to multivariate Cox hazard regression (P=0.024). TCGA validation cohort confirmed our findings regarding OS in early-stage patients (P=0.034). CONCLUSIONS: We found an increased expression of BRAF RNA in all stages in LADC. High BRAF expression was associated with tumor necrosis, distinct immune checkpoint biology and outcomes. We recommend further evaluating the potential of targeting overexpressed BRAF pathways in LADC.
背景：BRAF是癌症增殖通路的关键成员，仅2%-4%的肺腺癌（LADC）存在该基因突变。目前尚无关于可能导致信号增强和耐药的BRAF RNA表达模式的数据。 方法：将64例LADC组织样本固定并制成石蜡块。构建组织芯片（TMA），并对野生型（WT）BRAF RNA进行RNAscope杂交（ISH）检测。除了对肿瘤样本进行病理评估（分级、坏死、血管侵犯和肿瘤周围浸润）外，还进行了抗程序性死亡配体1（PD-L1）和抗程序性死亡1（PD-1）免疫组化检测，并在公共数据库[癌症基因组图谱（TCGA）、人类蛋白质图谱（HPA）]中进行验证。 结果：WT BRAF RNA在LADC中表达，早期（I-II期）和晚期（III-IV期）患者之间无显著表达差异（P=0.317）。从不吸烟者的BRAF表达显著增加（与当前吸烟者和既往吸烟者相比，P<0.01），且肿瘤坏死与BRAF表达显著相关（P=0.014）。在肿瘤细胞和免疫细胞上评估PD-L1表达，在免疫细胞上评估PD-1表达。肿瘤细胞PD-L1高表达与低表达患者之间的BRAF RNA表达无显著差异（P=0.124），但在免疫细胞PD-L1高表达患者中表达降低（P=0.03）。Kaplan-Meier生存分析显示，高BRAF表达与总生存期显著降低相关（P<0.01），根据多变量Cox风险回归分析，它是一个独立的阴性预后因素（P=0.024）。TCGA验证队列证实了我们关于早期患者总生存期的研究结果（P=0.034）。 结论：我们发现LADC各阶段BRAF RNA表达均增加。高BRAF表达与肿瘤坏死、独特的免疫检查点生物学特性和预后相关。我们建议进一步评估在LADC中靶向过表达BRAF通路的潜力。
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