食管腺癌（OAC）是一种高度异质性癌症，生存率较差。标准治疗方法是化疗加或不加放疗，然后进行食管切除术。基因组异质性是 OAC 的一个特征，并与治疗耐药性相关。分析了来自 29 名 OAC 患者的 59 个初治样本和 18 个治疗后样本的全基因组测序数据。其中 27 人参加了由澳大利亚胃肠试验组赞助的 DOCTOR 试验。对每个未接受治疗的肿瘤进行两次活检，以定义“共享”（两个样本之间）和“私有”（存在于一个样本中）突变。突变特征 SBS2/13 (APOBEC) 和 SBS3 (BRCA) 几乎只在未经治疗的肿瘤的私人突变群体。呈现这些特征的患者的疾病特异性生存率明显较差。此外，仅在治疗后样本中检测到与铂类化疗治疗相关的突变特征以及高铂富集分数。此外，在一些未经治疗的样本中检测到了具有高推定新抗原结合分数的克隆，这表明对克隆进行了免疫编辑。这项研究证明了 OAC 的高肿瘤内异质性，以及肿瘤进化过程中治疗诱导变化的指标。肿瘤内异质性仍然是 OAC 成功治疗策略的一个问题。© 2024。作者。

Oesophageal adenocarcinoma (OAC) is a highly heterogeneous cancer with poor survival. Standard curative treatment is chemotherapy with or without radiotherapy followed by oesophagectomy. Genomic heterogeneity is a feature of OAC and has been linked to treatment resistance.Whole-genome sequencing data from 59 treatment-naïve and 18 post-treatment samples from 29 OAC patients was analysed. Twenty-seven of these were enrolled in the DOCTOR trial, sponsored by the Australasian Gastro-Intestinal Trials Group. Two biopsies from each treatment-naïve tumour were assessed to define 'shared' (between both samples) and 'private' (present in one sample) mutations.Mutational signatures SBS2/13 (APOBEC) and SBS3 (BRCA) were almost exclusively detected in private mutation populations of treatment-naïve tumours. Patients presenting these signatures had significantly worse disease specific survival. Furthermore, mutational signatures associated with platinum-based chemotherapy treatment as well as high platinum enrichment scores were only detected in post-treatment samples. Additionally, clones with high putative neoantigen binding scores were detected in some treatment-naïve samples suggesting immunoediting of clones.This study demonstrates the high intra-tumour heterogeneity in OAC, as well as indicators for treatment-induced changes during tumour evolution. Intra-tumour heterogeneity remains a problem for successful treatment strategies in OAC.© 2024. The Author(s).