Orozco-Castaño Carlos, Mejía-Garcia Alejandro, Tsao Hsuan Megan, Bonilla Diego A, Bruges-Maya Ricardo, Combita Alba, Parra-Medina Rafael
Instituto Nacional de Cancerología, Bogotá, Colombia.
McGill University, Montreal, Canada.
J Egypt Natl Canc Inst. 2025 Jun 9;37(1):25. doi: 10.1186/s43046-025-00284-0.
Pleural mesothelioma (PM) is an aggressive cancer with poor prognosis, often driven by asbestos exposure. Mutations in the NF2 gene, a key regulator of the Hippo signaling pathway, are frequently observed in PM. However, their impact on tumor biology, immune infiltration, cytokine signaling, and therapeutic response remains poorly understood.
Using data from The Cancer Genome Atlas, we analyzed 82 PM cases to assess the prevalence and consequences of NF2 mutations. Logistic regression was used to evaluate associations with clinical variables, while transcriptomic differences were examined through differential expression and functional enrichment analyses. Immune and stromal infiltration were inferred via the xCell algorithm, cytokine signaling analyzed with Cytosig, and chemotherapeutic sensitivity predicted using the pRRophetic R package. Single-cell RNA sequencing data provided further insights into transcriptional patterns in NF2-mutated tumors.
NF2 mutations were present in 22% of cases, with no significant correlations to histological subtype, stage, or age. NF2-mutated tumors exhibited increased infiltration of basophils, naïve B cells, and pericytes, along with altered cytokine profiles, including NRG1, TGFB3, and reduced FGF2. Differentially expressed genes, such as MYL7 and HOXA11, were linked to poorer survival. Chemotherapy modeling indicated higher sensitivity to camptothecin and vinblastine in NF2-mutated tumors.
NF2 mutations influence the tumor microenvironment, transcriptional landscape, and predicted therapeutic response in PM, underscoring their potential as prognostic biomarkers. These findings support tailored therapeutic strategies targeting NF2-related pathways, including Hippo signaling and cytokine modulation.
胸膜间皮瘤（PM）是一种侵袭性癌症，预后较差，通常由接触石棉引起。NF2基因是Hippo信号通路的关键调节因子，其突变在PM中经常被观察到。然而，它们对肿瘤生物学、免疫浸润、细胞因子信号传导和治疗反应的影响仍知之甚少。
利用来自癌症基因组图谱的数据，我们分析了82例PM病例，以评估NF2突变的发生率和后果。采用逻辑回归评估与临床变量的关联，同时通过差异表达和功能富集分析检查转录组差异。通过xCell算法推断免疫和基质浸润，用Cytosig分析细胞因子信号传导，并用pRRophetic R包预测化疗敏感性。单细胞RNA测序数据进一步深入了解了NF2突变肿瘤中的转录模式。
22%的病例存在NF2突变，与组织学亚型、分期或年龄无显著相关性。NF2突变的肿瘤表现出嗜碱性粒细胞、幼稚B细胞和周细胞浸润增加，以及细胞因子谱改变，包括NRG1、TGFB3和FGF2减少。差异表达基因，如MYL7和HOXA11，与较差的生存率相关。化疗模型表明，NF2突变的肿瘤对喜树碱和长春碱更敏感。
NF2突变影响PM中的肿瘤微环境、转录格局和预测的治疗反应，强调了它们作为预后生物标志物的潜力。这些发现支持针对NF2相关途径的定制治疗策略，包括Hippo信号传导和细胞因子调节。
