Departments of Obstetrics and Gynecology, University Hospital, Mainz, Germany.
Clin Cancer Res. 2012 May 1;18(9):2695-703. doi: 10.1158/1078-0432.CCR-11-2210. Epub 2012 Feb 20.
Although the central role of the immune system for tumor prognosis is generally accepted, a single robust marker is not yet available.
On the basis of receiver operating characteristic analyses, robust markers were identified from a 60-gene B cell-derived metagene and analyzed in gene expression profiles of 1,810 breast cancer; 1,056 non-small cell lung carcinoma (NSCLC); 513 colorectal; and 426 ovarian cancer patients. Protein and RNA levels were examined in paraffin-embedded tissue of 330 breast cancer patients. The cell types were identified with immunohistochemical costaining and confocal fluorescence microscopy.
We identified immunoglobulin κ C (IGKC) which as a single marker is similarly predictive and prognostic as the entire B-cell metagene. IGKC was consistently associated with metastasis-free survival across different molecular subtypes in node-negative breast cancer (n = 965) and predicted response to anthracycline-based neoadjuvant chemotherapy (n = 845; P < 0.001). In addition, IGKC gene expression was prognostic in NSCLC and colorectal cancer. No association was observed in ovarian cancer. IGKC protein expression was significantly associated with survival in paraffin-embedded tissues of 330 breast cancer patients. Tumor-infiltrating plasma cells were identified as the source of IGKC expression.
Our findings provide IGKC as a novel diagnostic marker for risk stratification in human cancer and support concepts to exploit the humoral immune response for anticancer therapy. It could be validated in several independent cohorts and carried out similarly well in RNA from fresh frozen as well as from paraffin tissue and on protein level by immunostaining.
尽管免疫系统在肿瘤预后中的核心作用已被普遍接受，但目前仍缺乏一种稳健的单一标志物。
基于受试者工作特征分析，从 60 个基因的 B 细胞衍生的元基因中确定了稳健的标志物，并在 1810 例乳腺癌、1056 例非小细胞肺癌（NSCLC）、513 例结直肠癌和 426 例卵巢癌患者的基因表达谱中进行了分析。在 330 例乳腺癌患者的石蜡包埋组织中检测了蛋白和 RNA 水平。使用免疫组织化学双重染色和共聚焦荧光显微镜鉴定细胞类型。
我们鉴定出免疫球蛋白κC（IGKC），作为单一标志物，其预测和预后能力与整个 B 细胞元基因相似。在淋巴结阴性乳腺癌（n=965）的不同分子亚型中，IGKC 始终与无转移生存相关，并预测了蒽环类药物为基础的新辅助化疗（n=845）的反应（P<0.001）。此外，IGKC 基因表达在 NSCLC 和结直肠癌中具有预后意义。在卵巢癌中未观察到相关性。IGKC 蛋白表达在 330 例乳腺癌患者的石蜡包埋组织中与生存显著相关。鉴定出肿瘤浸润性浆细胞是 IGKC 表达的来源。
我们的研究结果提供了 IGKC 作为人类癌症风险分层的新型诊断标志物，并支持利用体液免疫反应进行抗癌治疗的概念。它可以在几个独立的队列中进行验证，并且在新鲜冷冻和石蜡组织的 RNA 以及免疫染色的蛋白水平上同样有效。
