Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China.
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
Lab Invest. 2021 Apr;101(4):463-476. doi: 10.1038/s41374-020-00517-x. Epub 2020 Dec 10.
SMAD4 is an intracellular signaling mediator of the TGF-β pathway. Its mutation was commonly observed in gastrointestinal cancers, such as pancreatic cancer. The loss of SMAD4 on immunohistochemical staining is often used to suggest a pancreaticobiliary differentiation in evaluating a metastatic adenocarcinoma with unknown origin. However, the function and molecular mechanism of SMAD4 in non-small cell lung cancer (NSCLC) development are largely unknown. Thus, we studied the correlation between SMAD4 mutations and clinico-molecular features in the patients with NSCLC. We reported the frequencies and prognostic values of SMAD4 mutations in a Chinese NSCLC cohort using next-generation sequencing. The NSCLC cases from several public databases, including The Cancer Genome Atlas and others, were also used in this study to elucidate SMAD4-related molecular partners and mechanisms. Integrated bioinformatics analyses were conducted, such as analysis of Gene Ontology enrichment analysis, gene set enrichment analysis (GSEA), and survival analysis. Immunohistochemistry showed that the tissues harboring SMAD4 mutations tended to show SMAD4 deficiency or loss, while SMAD4 expression was significantly reduced at all stages of NSCLC cases. We found that reduced SMAD4 expression was more frequent in the patients with poor disease-free survival and resistance to platinum-based chemotherapy. SMAD4 mutation was an independent risk factor for the survival of NSCLC patients. The expression of SMAD4 was associated with that of SMAD2. The GSEA showed that SMAD4 might promote NSCLC progression by regulating proliferation, adhesion, and immune response. In conclusion, these data suggest that SMAD4 mutation or loss as well as reduced expression can be used to identify the NSCLC patients with poor survival and resistance to platinum-based chemotherapy. SMAD4 may be a predictive marker or therapeutic target in NSCLC. The source code and user's guide are freely available at Github: https://github.com/wangyue77-ab/smad4 .
SMAD4 是 TGF-β 通路的细胞内信号转导介质。其突变在胃肠道癌（如胰腺癌）中较为常见。免疫组织化学染色中 SMAD4 的缺失通常用于提示在评估来源不明的转移性腺癌时存在胰胆管分化。然而，SMAD4 在非小细胞肺癌（NSCLC）发展中的功能和分子机制在很大程度上尚不清楚。因此，我们研究了 SMAD4 突变与 NSCLC 患者的临床分子特征之间的相关性。我们使用下一代测序报告了中国 NSCLC 队列中 SMAD4 突变的频率和预后价值。本研究还使用了来自多个公共数据库（包括癌症基因组图谱和其他数据库）的 NSCLC 病例，以阐明 SMAD4 相关的分子伴侣和机制。进行了综合的生物信息学分析，如基因本体论富集分析、基因集富集分析（GSEA）和生存分析。免疫组织化学显示，携带 SMAD4 突变的组织倾向于显示 SMAD4 缺乏或缺失，而 SMAD4 表达在 NSCLC 病例的所有阶段均显著降低。我们发现，SMAD4 表达降低在疾病无进展生存和对铂类化疗耐药的患者中更为频繁。SMAD4 突变是 NSCLC 患者生存的独立危险因素。SMAD4 的表达与 SMAD2 的表达相关。GSEA 显示，SMAD4 可能通过调节增殖、黏附和免疫反应来促进 NSCLC 的进展。总之，这些数据表明，SMAD4 突变或缺失以及表达降低可用于识别生存不良和对铂类化疗耐药的 NSCLC 患者。SMAD4 可能是 NSCLC 的预测标志物或治疗靶点。源代码和用户指南可在 Github 上免费获得：https://github.com/wangyue77-ab/smad4。
