Izadi Fereshteh, Sharpe Benjamin P, Breininger Stella P, Secrier Maria, Gibson Jane, Walker Robert C, Rahman Saqib, Devonshire Ginny, Lloyd Megan A, Walters Zoë S, Fitzgerald Rebecca C, Rose-Zerilli Matthew J J, Underwood Tim J
School of Cancer Sciences, Cancer Research UK Centre, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton SO16 6YD, UK.
Centre for NanoHealth, Swansea University Medical School, Singleton Campus, Swansea SA2 8PP, UK.
Cancers (Basel). 2021 Jul 6;13(14):3394. doi: 10.3390/cancers13143394.
Neoadjuvant therapy followed by surgery is the standard of care for locally advanced esophageal adenocarcinoma (EAC). Unfortunately, response to neoadjuvant chemotherapy (NAC) is poor (20-37%), as is the overall survival benefit at five years (9%). The EAC genome is complex and heterogeneous between patients, and it is not yet understood whether specific mutational patterns may result in chemotherapy sensitivity or resistance. To identify associations between genomic events and response to NAC in EAC, a comparative genomic analysis was performed in 65 patients with extensive clinical and pathological annotation using whole-genome sequencing (WGS). We defined response using Mandard Tumor Regression Grade (TRG), with responders classified as TRG1-2 ( = 27) and non-responders classified as TRG4-5 ( =38). We report a higher non-synonymous mutation burden in responders (median 2.08/Mb vs. 1.70/Mb, = 0.036) and elevated copy number variation in non-responders (282 vs. 136/patient, < 0.001). We identified copy number variants unique to each group in our cohort, with cell cycle (, ), c-Myc (), RTK/PIK3 (, ) and gastrointestinal differentiation () pathway genes being specifically altered in non-responders. Of note, mutations were exclusively present in the non-responder group with a frequency of 22%. Thus, lower mutation burden, higher chromosomal instability and specific copy number alterations are associated with resistance to NAC.
新辅助治疗后进行手术是局部晚期食管腺癌（EAC）的标准治疗方案。不幸的是，新辅助化疗（NAC）的反应较差（20%-37%），五年总生存获益同样不佳（9%）。EAC基因组复杂且患者之间存在异质性，目前尚不清楚特定的突变模式是否会导致化疗敏感性或耐药性。为了确定EAC基因组事件与NAC反应之间的关联，我们对65例具有广泛临床和病理注释的患者进行了全基因组测序（WGS）的比较基因组分析。我们使用曼德尔肿瘤消退分级（TRG）定义反应，反应者分类为TRG1-2（n = 27），无反应者分类为TRG4-5（n = 38）。我们报告反应者的非同义突变负担更高（中位数2.08/Mb vs. 1.70/Mb，P = 0.036），无反应者的拷贝数变异增加（282 vs. 136/患者，P < 0.001）。我们在队列中确定了每组特有的拷贝数变异，细胞周期（CCNE1、CCND1）、c-Myc、RTK/PIK3（EGFR、PIK3CA）和胃肠道分化（CDX2）途径基因在无反应者中发生了特异性改变。值得注意的是，KRAS突变仅在无反应者组中出现，频率为22%。因此，较低的突变负担、较高的染色体不稳定性和特定的拷贝数改变与对NAC的耐药性相关。
