Zhu Xi, Kao Xiaoming, Liu Leilei, Wang Xuan, Li Yang, Li Qiurong
Research Institute of General Surgery, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China.
Research Institute of General Surgery, Jinling Hospital, Nanjing Medical University, Nanjing, China.
Cancer Med. 2025 Mar;14(6):e70815. doi: 10.1002/cam4.70815.
The response to neoadjuvant chemoradiotherapy (NACRT) for locally advanced rectal cancer (LARC) varies from achieving a complete pathological response to encountering resistance to treatment. Therefore, biomarkers for predicting the NACRT responses should be identified. This prospective study aimed to identify key genomic biomarkers as the predictors of the NACRT response with LARC.
Overall, 67 patients with LARC treated with NACRT and proctectomy were divided into two groups based on the tumor regression grade (TRG) for identifying key biomarkers. Patients with a TRG of 0 or 1 were assigned to the sensitive response group, and patients with a TRG of 2 or 3 were the resistant response group. Twenty-nine postsurgical tumor samples were collected for whole exome sequencing (WES) to identify genomic variation biomarkers. The other 38 pairs of tumor specimens from pretreatment and postsurgery samples were evaluated by immunohistochemistry (IHC) to examine the biomarker features.
In the WES subcohort, 11 genes showed copy number variation, including FNKBIA, ARID1A, CCND2, CDK4, LYN, MDM2, RAD51B, RARA, SPEN, STAT3, and Daxx, which has the highest copy number variation. For the IHC subcohort, Daxx was initially highly expressed in the nuclei of tumor cells, particularly in the sensitive response group, while varying its expression after NACRT, demonstrating that Daxx levels were related to treatment responses and the survival benefit, especially a better disease-free survival (DFS).
We identified multiple genomic variations between sensitive and resistant responders and verified that Daxx is a potential predictive biomarker of the response to NACRT in LARC.
局部晚期直肠癌（LARC）对新辅助放化疗（NACRT）的反应各不相同，从实现完全病理缓解到出现治疗抵抗。因此，应确定预测NACRT反应的生物标志物。这项前瞻性研究旨在确定关键的基因组生物标志物，作为LARC对NACRT反应的预测指标。
总体而言，67例接受NACRT和直肠切除术治疗的LARC患者根据肿瘤退缩分级（TRG）分为两组，以确定关键生物标志物。TRG为0或1的患者被分配到敏感反应组，TRG为2或3的患者为抵抗反应组。收集29份术后肿瘤样本进行全外显子组测序（WES），以识别基因组变异生物标志物。另外38对治疗前和术后肿瘤标本通过免疫组织化学（IHC）进行评估，以检查生物标志物特征。
在WES亚组中，11个基因显示出拷贝数变异，包括FNKBIA、ARID1A、CCND2、CDK4、LYN、MDM2、RAD51B、RARA、SPEN、STAT3和Daxx，其中Daxx的拷贝数变异最高。对于IHC亚组，Daxx最初在肿瘤细胞核中高表达，尤其是在敏感反应组中，而在NACRT后其表达发生变化，表明Daxx水平与治疗反应和生存获益相关，尤其是无病生存期（DFS）更好。
我们确定了敏感和抵抗反应者之间的多种基因组变异，并证实Daxx是LARC对NACRT反应的潜在预测生物标志物。
