Department of Clinical Radiology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Department of Surgery, Kyushu University Beppu Hospital, Beppu, Japan.
Cancer Res. 2021 Oct 1;81(19):4926-4938. doi: 10.1158/0008-5472.CAN-21-0653. Epub 2021 Aug 19.
Esophageal squamous cell carcinoma (ESCC) often recurs after chemoradiotherapy, and the prognosis of ESCC after chemoradiotherapy has not improved over the past few decades. The mutation process in chemoradiotherapy-resistant clones and the functional relevance of genetic alterations remain unclear. To address these problems, we performed whole-exome sequencing of 52 tumor samples from 33 patients with ESCC who received radiotherapy combined with 5-fluorouracil/platinum. In multiregion analyses of pretreatment and locally recurrent lesions from five cases, most driver gene-altered clones remained under chemoradiotherapy selection pressure, while few driver gene alterations were acquired at recurrence. The mutation signatures of recurrent ESCC, including increased deletion frequency and platinum dose-dependent base substitution signatures, were substantially different from those of primary ESCC and reflected the iatrogenic impacts of chemoradiotherapy. Single-region analysis of 28 pretreatment tumors indicated that focal copy-number gain at the locus was significantly associated with poor progression-free survival and overall survival after chemoradiotherapy. gain remained throughout the chemoradiotherapy course and potentially contributes to intrinsic resistance to chemoradiotherapy. Consistent with these findings, copy number and mRNA and protein levels in ESCC cell lines correlated positively with resistance to radiotherapy, and knockdown improved sensitivity to radiotherapy. Overall, these data characterize the clonal evolution process induced by chemoradiotherapy and clinically relevant associations for genetic alterations in ESCC. These findings increase our understanding of therapeutic resistance and support the rationale for precision chemoradiotherapy. SIGNIFICANCE: Whole-exome sequencing reveals the genetic evolution of ESCC during chemoradiotherapy, highlighting gain in pretreatment tumors as a potential marker of therapy resistance.
食管鳞状细胞癌（ESCC）在放化疗后常复发，且近几十年来放化疗后 ESCC 的预后并未改善。放化疗耐药克隆中的突变过程以及遗传改变的功能相关性仍不清楚。为了解决这些问题，我们对 33 名接受放疗联合 5-氟尿嘧啶/铂类化疗的 ESCC 患者的 52 个肿瘤样本进行了全外显子组测序。在对 5 例患者的预处理和局部复发性病变进行的多区域分析中，大多数驱动基因改变的克隆在放化疗选择压力下仍然存在，而在复发时很少获得驱动基因改变。复发性 ESCC 的突变特征，包括删除频率增加和铂类依赖性碱基取代特征，与原发性 ESCC 有很大不同，反映了放化疗的医源性影响。对 28 个预处理肿瘤的单区域分析表明， 基因座的局灶性拷贝数增益与放化疗后无进展生存期和总生存期显著相关。 增益在放化疗过程中持续存在，可能导致对放化疗的内在耐药。这些发现与以下发现一致，即 ESCC 细胞系中的 拷贝数和 mRNA 及蛋白水平与对放疗的耐药性呈正相关，而 敲低可提高对放疗的敏感性。总的来说，这些数据描绘了放化疗诱导的克隆进化过程以及 ESCC 中遗传改变的临床相关关联。这些发现增加了我们对治疗抵抗的理解，并支持精准放化疗的合理性。意义：全外显子组测序揭示了 ESCC 在放化疗过程中的遗传演变，突出了预处理肿瘤中 的增益，作为潜在的治疗抵抗标志物。
