Chen Chih-I, Kao Yi-Kai, Yang Po-Wen, Chen Pin-Chun, Yang Ching-Chieh, Li Wan-Shan, Tsai Hsin-Hwa, Wang Yu-Jen, Lai Hong-Yue
Division of Colon and Rectal Surgery, Department of Surgery, E-DA Hospital, Kaohsiung, Taiwan.
Divsiion of General Medicine Surgery, Department of Surgery, E-DA Hospital, Kaohsiung, Taiwan.
Radiat Oncol. 2025 Aug 9;20(1):126. doi: 10.1186/s13014-025-02709-5.
In individuals presenting with locally advanced rectal cancer, the therapeutic strategy of neoadjuvant concurrent chemoradiotherapy (CCRT) aims to enhance tumor downstaging; however, only a subset of patients exhibit a favorable response. Molecular stratification, combined with the traditional tumor staging system (TNM), is a promising approach for predicting treatment efficacy and patient outcomes. Therefore, we intend to better grasp the molecular basis of CCRT resistance and guide therapeutic strategies with greater precision.
We utilized a public rectal cancer transcriptomic dataset (n = 46) to predict responsiveness to neoadjuvant CCRT by analyzing signal transduction-related genes. In our well-characterized rectal cancer cohort (n = 343), we assessed correlations between membrane-spanning 4-domains A12 (MS4A12) immunostaining and clinicopathological characteristics using Pearson's chi-squared test. To calculate survival rates, we employed the Kaplan-Meier method with a log-rank test. Additionally, we conducted multivariate analyses with the Cox proportional hazards model to identify independent prognostic biomarkers.
We identified that the MS4A12 gene is highly expressed in rectal cancer resistant to CCRT. Elevated MS4A12 expression, confirmed by immunohistochemical staining, is significantly associated with advanced tumor status after CCRT (p < 0.001), positive node status both before and after CCRT (p = 0.01 and p = 0.004), the presence of perineural and vascular invasion (p = 0.006 and p = 0.001), and low or no response to CCRT (p < 0.001). Notably, high MS4A12 immunoexpression is strongly correlated with reduced patient survival in rectal cancer. Mechanically, high MS4A12 expression is significantly associated with aberrant glycosylation and B-cell infiltration.
MS4A12 expression may offer a helpful predictive and prognostic indicator for identifying patients who could gain advantages from neoadjuvant CCRT.
在局部晚期直肠癌患者中，新辅助同步放化疗（CCRT）的治疗策略旨在提高肿瘤降期效果；然而，只有一部分患者表现出良好的反应。分子分层结合传统肿瘤分期系统（TNM）是预测治疗效果和患者预后的一种有前景的方法。因此，我们旨在更好地掌握CCRT耐药的分子基础，并更精确地指导治疗策略。
我们利用一个公开的直肠癌转录组数据集（n = 46），通过分析信号转导相关基因来预测对新辅助CCRT的反应性。在我们特征明确的直肠癌队列（n = 343）中，我们使用Pearson卡方检验评估跨膜4结构域A12（MS4A12）免疫染色与临床病理特征之间的相关性。为了计算生存率，我们采用Kaplan-Meier方法和对数秩检验。此外，我们使用Cox比例风险模型进行多变量分析，以确定独立的预后生物标志物。
我们发现MS4A12基因在对CCRT耐药的直肠癌中高表达。免疫组化染色证实，MS4A12表达升高与CCRT后肿瘤进展状态显著相关（p < 0.001），CCRT前后淋巴结阳性状态（p = 0.01和p = 0.004），神经周围和血管侵犯的存在（p = 0.006和p = 0.001），以及对CCRT低反应或无反应（p < 0.001）。值得注意的是，MS4A12高免疫表达与直肠癌患者生存率降低密切相关。从机制上讲，MS4A12高表达与异常糖基化和B细胞浸润显著相关。
MS4A12表达可能为识别能从新辅助CCRT中获益的患者提供有用的预测和预后指标。
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