RAD21 cohesin overexpression is a prognostic and predictive marker exacerbating poor prognosis in KRAS mutant colorectal carcinomas
RAD21 cohesin overexpression is a prognostic and predictive marker exacerbating poor prognosis in KRAS mutant colorectal carcinomas
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DOI：
10.1038/bjc.2014.31
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发表时间：
2014-03-18
影响因子：
8.8
通讯作者：
Fox, S. B.
中科院分区：
文献类型：
--
作者：
Deb, S.;Xu, H.;Fox, S. B.
背景：RAD21 是内聚复合体的一个组成部分，是染色体分离和无差错 DNA 修复不可或缺的一部分。 RAD21 在肿瘤进展中具有重要的功能，但其在结直肠癌 (CRC) 中的作用尚不清楚。因此，我们评估了其在 CRC 中的临床病理学和预后意义，以及其对化疗敏感性的影响。方法：一项回顾性观察研究使用组织微阵列方法检查了 652 例 CRC 中的 RAD21 表达。进行与临床病理因素的相关性，包括性别、肿瘤分级、粘液亚型、TNM分期、疾病特异性生存（DSS）、BRAF和KRAS突变状态、肿瘤p53免疫染色、肿瘤微卫星不稳定性和肿瘤CpG岛甲基化表型。生成稳定 RAD21 敲低的结直肠癌细胞克隆，并测试细胞对常规化疗药物的敏感性。结果：RAD21 表达与男性性别（56.7% vs 43.3%，P = 0.02）、分化良好的组织学（14.4% vs 4.0%，P = 0.0001）、较高的 T 分期（36.1% vs 43.3%，P = 0.02）显着相关。在单变量和多变量分析中，存在转移（18.8% vs 12.6%，P = 0.03）和较短的 DSS（风险比 (HR) 1.4，95% CI 1.1 至 1.9，P = 0.01）。 RAD21 表达与 KRAS 突变肿瘤患者 (HR:2.6, 95% CI:1.4-4.3, P = 0.001) 和接受辅助放化疗的患者 (HR:1.9, 95% CI:1.2-3.0, P = 0.008) 的 DSS 较短相关。 RAD21 敲低的结直肠癌细胞表现出对 5-氟尿嘧啶单独使用或与奥沙利铂联合使用的敏感性增强。结论：CRC 中的 RAD21 表达与侵袭性疾病尤其是 KRAS 突变肿瘤和对放化疗的耐药性相关。 RAD21可能是一个重要的新型治疗靶点。
Background: RAD21 is a component of the cohesion complex and is integral to chromosome segregation and error-free DNA repair. RAD21 is functionally important in tumour progression but its role in colorectal carcinoma (CRC) is unclear. We therefore assessed its clinicopathological and prognostic significance in CRC, as well as its effect on chemosensitivity.Methods: A retrospective observation study examined RAD21 expression in 652 CRCs using a tissue microarray approach. Correlation with clinicopathological factors including gender, tumour grade, mucinous subtype, TNM stage, disease-specific survival (DSS), BRAF and KRAS mutation status, tumour p53 immunostaining, tumour microsatellite instability and tumour CpG island methylator phenotype was performed. Colorectal cancer cell clones with stable RAD21 knockdown were generated and tested for cellular sensitivity to conventional chemotherapeutic drugs.Results: RAD21 expression was significantly correlated with male gender (56.7% vs 43.3%, P = 0.02), well-differentiated histology (14.4% vs 4.0%, P = 0.0001), higher T-stage (36.1% vs 27.0%, P = 0.01), presence of metastasis (18.8% vs 12.6%, P = 0.03), and shorter DSS (hazard ratio (HR) 1.4, 95% CI 1.1 to 1.9, P = 0.01) in both univariate and multivariate analysis. RAD21 expression was associated with shorter DSS in patients with KRAS mutant tumours (HR:2.6, 95% CI:1.4-4.3, P = 0.001) and in patients receiving adjuvant chemoradiotherapy (HR:1.9, 95% CI:1.2-3.0, P = 0.008). Colorectal cancer cells with RAD21 knockdown exhibited enhanced sensitivity to 5-fluorouracil, either alone or in combination with oxaliplatin.Conclusions: RAD21 expression in CRC is associated with aggressive disease especially in KRAS mutant tumours and resistance to chemoradiotherapy. RAD21 may be an important novel therapeutic target.