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 NSD1 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, in silico 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.

中文翻译：

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基于 SOX2 和 SOX9 相关基因组在头颈部鳞状细胞癌中建立可塑性相关风险模型

最近的研究强调 SOX2 和 SOX9 是癌细胞可塑性的关键决定因素，并证明顺铂诱导的口腔鳞状细胞癌 (SCC) 适应是通过两种转录因子的反向调节获得的。然而，SOX2/SOX9 相关遗传程序与风险因素和原发性头颈部 SCC (HNSCC) 的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是未知的。在这里，我们在癌症基因组图谱 (TCGA)-HNSC 中鉴定了与 SOX2 和 SOX9 转录相关的差异表达基因 (DEG)，这使得将患者聚集成具有不同临床特征和存活率的组。基于 TCGA-HNSC（训练队列）中 DEG 的表达模式，通过 LASSO Cox 回归建立预后风险模型，并在独立的 HNSCC 验证队列以及 TCGA 的其他癌症队列中得到证实。TCGA-HNSC 风险组之间突变景观的差异证明了低风险组截断 NSD1 突变的丰富性，并阐明了 DNA 甲基化作为 SOX2 表达的调节剂。基因组变异分析 (GSVA) 揭示了风险组之间几种致癌途径的差异，包括与高风险组的致癌 KRAS 信号传导相关的基因组的上调。最后，计算机药物筛选分析揭示了许多靶向 EGFR 信号传导的化合物对具有较高风险表型的癌细胞系的功效显着降低，但也表明了潜在的脆弱性。启示：已建立的风险模型可识别原发性 HNSCC 患者，