Toomey Sinead, Gunther Jillian, Carr Aoife, Weksberg David C, Thomas Valentina, Salvucci Manuela, Bacon Orna, Sherif El-Masry, Fay Joanna, Kay Elaine W, Sheehan Katherine M, McNamara Deborah A, Sanders Keith L, Mathew Geena, Breathnach Oscar S, Grogan Liam, Morris Patrick G, Foo Wai C, You Yi-Qian N, Prehn Jochen H, O'Neill Brian, Krishnan Sunil, Hennessy Bryan T, Furney Simon J
Medical Oncology Group, Department of Molecular Medicine, Royal College of Surgeons in Ireland, Dublin, Dublin 9, Ireland.
Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Cancers (Basel). 2020 Jul 6;12(7):1808. doi: 10.3390/cancers12071808.
Standard treatment for locally advanced rectal cancer (LARC) is neoadjuvant chemoradiotherapy (NACRT), followed by surgical resection. However, >70% of patients do not achieve a complete pathological response and have higher rates of relapse and death. There are no validated pre- or on-treatment factors that predict response to NACRT besides tumour stage and size. We characterised the response of 33 LARC patients to NACRT, collected tumour samples from patients prior to, during and after NACRT, and performed whole exome, transcriptome and high-depth targeted sequencing. The pre-treatment LARC genome was not predictive of response to NACRT. However, in line with the increasing recognition of microbial influence in cancer, RNA analysis of pre-treatment tumours suggested a greater abundance of in intermediate and poor responders. In addition, we investigated tumour heterogeneity and evolution in response to NACRT. While matched pre-treatment, on-treatment and post-treatment tumours revealed minimal genome evolution overall, we identified cases in which microsatellite instability developed or was selected for during NACRT. Recent research has suggested a role for adaptive mutability to targeted therapy in colorectal cancer cells. We provide preliminary evidence of selection for mismatch repair deficiency in response to NACRT. Furthermore, pre-NACRT genomic landscapes do not predict treatment response but pre-NACRT microbiome characteristics may be informative.
局部晚期直肠癌（LARC）的标准治疗方法是新辅助放化疗（NACRT），随后进行手术切除。然而，超过70%的患者未实现完全病理缓解，复发率和死亡率更高。除了肿瘤分期和大小外，尚无经过验证的预测NACRT反应的治疗前或治疗中因素。我们对33例LARC患者对NACRT的反应进行了特征分析，在NACRT之前、期间和之后收集患者的肿瘤样本，并进行了全外显子组、转录组和高深度靶向测序。治疗前的LARC基因组无法预测对NACRT的反应。然而，随着对微生物在癌症中影响的认识不断增加，治疗前肿瘤的RNA分析表明，中等反应者和低反应者中 的丰度更高。此外，我们研究了肿瘤异质性以及对NACRT的反应演变。虽然配对的治疗前、治疗中和治疗后肿瘤总体上显示出最小的基因组进化，但我们发现了在NACRT期间微卫星不稳定性出现或被选择的病例。最近的研究表明，适应性突变在结直肠癌细胞的靶向治疗中起作用。我们提供了因应NACRT而选择错配修复缺陷的初步证据。此外，NACRT前的基因组图谱无法预测治疗反应，但NACRT前的微生物组特征可能具有参考价值。
