Department of Otorhinolaryngology, Head and Neck Tumors, Heidelberg University Hospital, Heidelberg, Germany.
Division of Radiooncology/Radiobiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Mol Cancer Res. 2021 Oct;19(10):1676-1687. doi: 10.1158/1541-7786.MCR-21-0066. Epub 2021 Jul 20.
Recent studies highlighted SOX2 and SOX9 as key determinants for cancer-cell plasticity and demonstrated that cisplatin-induced adaptation in oral squamous cell carcinoma (SCC) is acquired by an inverse regulation of both transcription factors. However, the association between SOX2/SOX9-related genetic programs with risk factors and genetic or epigenetic alterations in primary head and neck SCC (HNSCC), and their prognostic value is largely unknown.Here, we identified differentially-expressed genes (DEG) related to SOX2 and SOX9 transcription in The Cancer Genome Atlas (TCGA)-HNSC, which enable clustering of patients into groups with distinct clinical features and survival. A prognostic risk model was established by LASSO Cox regression based on expression patterns of DEGs in TCGA-HNSC (training cohort), and was confirmed in independent HNSCC validation cohorts as well as other cancer cohorts from TCGA. Differences in the mutational landscape among risk groups of TCGA-HNSC demonstrated an enrichment of truncating mutations for the low-risk group and elucidated DNA methylation as modulator of SOX2 expression. Gene set variation analysis (GSVA) revealed differences in several oncogenic pathways among risk groups, including upregulation of gene sets related to oncogenic KRAS signaling for the high-risk group. Finally, drug screen analysis revealed numerous compounds targeting EGFR signaling with significantly lower efficacy for cancer cell lines with a higher risk phenotype, but also indicated potential vulnerabilities. IMPLICATIONS: The established risk model identifies patients with primary HNSCC, but also other cancers at a higher risk for treatment failure, who might benefit from a therapy targeting SOX2/SOX9-related gene regulatory and signaling networks.
最近的研究强调了 SOX2 和 SOX9 作为癌细胞可塑性的关键决定因素，并表明口腔鳞状细胞癌（SCC）中顺铂诱导的适应性是通过这两种转录因子的反向调节获得的。然而，SOX2/SOX9 相关遗传程序与原发性头颈部 SCC（HNSCC）中的危险因素以及遗传或表观遗传改变之间的关联及其预后价值在很大程度上尚不清楚。在这里，我们在癌症基因组图谱（TCGA）-HNSC 中确定了与 SOX2 和 SOX9 转录相关的差异表达基因（DEG），这些基因能够将患者聚类为具有不同临床特征和生存的组。通过基于 TCGA-HNSC 中 DEG 表达模式的 LASSO Cox 回归建立了预后风险模型（训练队列），并在独立的 HNSCC 验证队列以及来自 TCGA 的其他癌症队列中得到了验证。TCGA-HNSC 风险组之间的突变景观差异表明低风险组中截断突变的富集，并阐明了 DNA 甲基化作为 SOX2 表达的调节剂。基因集变异分析（GSVA）揭示了风险组之间几种致癌途径的差异，包括高风险组中与致癌 KRAS 信号相关的基因集上调。最后，药物筛选分析表明，针对 EGFR 信号的许多化合物对具有更高风险表型的癌细胞系的疗效明显降低，但也表明了潜在的脆弱性。意义：所建立的风险模型可识别原发性 HNSCC 患者，但也可识别其他癌症患者，这些患者因治疗失败而面临更高的风险，他们可能受益于针对 SOX2/SOX9 相关基因调控和信号网络的治疗。
