Objectives Oesophageal squamous cell carcinoma (OSCC) and adenocarcinoma (OAC) are distinct cancers in terms of a number of clinical and epidemiological characteristics, complicating the design of clinical trials and biomarker developments. We analysed 1048 oesophageal tumour-germline pairs from both subtypes, to characterise their genomic features, and biological and clinical significance. Design Previously exome-sequenced samples were re-analysed to identify significantly mutated genes (SMGs) and mutational signatures. The biological functions of novel SMGs were investigated using cell line and xenograft models. We further performed whole-genome bisulfite sequencing and chromatin immunoprecipitation (ChIP)-seq to characterise epigenetic alterations. Results OSCC and OAC displayed nearly mutually exclusive sets of driver genes, indicating that they follow independent developmental paths. The combined sample size allowed the statistical identification of a number of novel subtype-specific SMGs, mutational signatures and prognostic biomarkers. Particularly, we identified a novel mutational signature similar to Catalogue Of Somatic Mutations In Cancer (COSMIC)signature 16, which has prognostic value in OSCC. Two newly discovered SMGs, CUL3 and ZFP36L2, were validated as important tumour-suppressors specific to the OSCC subtype. We further identified their additional loss-of-function mechanisms. CUL3 was homozygously deleted specifically in OSCC and other squamous cell cancers (SCCs). Notably, ZFP36L2 is associated with super-enhancer in healthy oesophageal mucosa; DNA hypermethylation in its super-enhancer reduced active histone markers in squamous cancer cells, suggesting an epigenetic inactivation of a super-enhancer-associated SCC suppressor. Conclusions These data comprehensively contrast differences between OSCC and OAC at both genomic and epigenomic levels, and reveal novel molecular features for further delineating the pathophysiological mechanisms and treatment strategies for these cancers.

中文翻译：

---

食管鳞状细胞癌和腺癌中不同突变模式和新驱动基因的鉴定

目的 食管鳞状细胞癌 (OSCC) 和腺癌 (OAC) 在许多临床和流行病学特征方面是不同的癌症，使临床试验的设计和生物标志物的开发变得复杂。我们分析了这两种亚型的 1048 对食管肿瘤-种系对，以表征它们的基因组特征以及生物学和临床意义。设计 重新分析之前的外显子组测序样本以识别显着突变基因 (SMG) 和突变特征。使用细胞系和异种移植模型研究了新型 SMG 的生物学功能。我们进一步进行了全基因组亚硫酸氢盐测序和染色质免疫沉淀 (ChIP)-seq 以表征表观遗传改变。结果 OSCC 和 OAC 显示出几乎互斥的驱动基因集，表明他们遵循独立的发展路径。合并的样本量允许对许多新的亚型特异性 SMG、突变特征和预后生物标志物进行统计识别。特别是，我们发现了一种新的突变特征，类似于癌症体细胞突变目录 (COSMIC) 特征 16，它在 OSCC 中具有预后价值。两个新发现的 SMG，CUL3 和 ZFP36L2，被验证为特定于 OSCC 亚型的重要肿瘤抑制因子。我们进一步确定了它们额外的功能丧失机制。CUL3 在 OSCC 和其他鳞状细胞癌 (SCC) 中被纯合删除。值得注意的是，ZFP36L2 与健康食管黏膜中的超级增强剂有关；其超级增强子中的 DNA 高甲基化降低了鳞状癌细胞中的活性组蛋白标志物，表明超增强子相关的 SCC 抑制因子的表观遗传失活。结论 这些数据全面对比了 OSCC 和 OAC 在基因组和表观基因组水平上的差异，并揭示了新的分子特征，以进一步描述这些癌症的病理生理机制和治疗策略。