Sotiriou Christos, Wirapati Pratyaksha, Loi Sherene, Harris Adrian, Fox Steve, Smeds Johanna, Nordgren Hans, Farmer Pierre, Praz Viviane, Haibe-Kains Benjamin, Desmedt Christine, Larsimont Denis, Cardoso Fatima, Peterse Hans, Nuyten Dimitry, Buyse Marc, Van de Vijver Marc J, Bergh Jonas, Piccart Martine, Delorenzi Mauro
Functional Genomics and Translational Research Unit, Université Libre de Bruxelles, Brussels, Belgium.
J Natl Cancer Inst. 2006 Feb 15;98(4):262-72. doi: 10.1093/jnci/djj052.
Histologic grade in breast cancer provides clinically important prognostic information. However, 30%-60% of tumors are classified as histologic grade 2. This grade is associated with an intermediate risk of recurrence and is thus not informative for clinical decision making. We examined whether histologic grade was associated with gene expression profiles of breast cancers and whether such profiles could be used to improve histologic grading.
We analyzed microarray data from 189 invasive breast carcinomas and from three published gene expression datasets from breast carcinomas. We identified differentially expressed genes in a training set of 64 estrogen receptor (ER)-positive tumor samples by comparing expression profiles between histologic grade 3 tumors and histologic grade 1 tumors and used the expression of these genes to define the gene expression grade index. Data from 597 independent tumors were used to evaluate the association between relapse-free survival and the gene expression grade index in a Kaplan-Meier analysis. All statistical tests were two-sided.
We identified 97 genes in our training set that were associated with histologic grade; most of these genes were involved in cell cycle regulation and proliferation. In validation datasets, the gene expression grade index was strongly associated with histologic grade 1 and 3 status; however, among histologic grade 2 tumors, the index spanned the values for histologic grade 1-3 tumors. Among patients with histologic grade 2 tumors, a high gene expression grade index was associated with a higher risk of recurrence than a low gene expression grade index (hazard ratio = 3.61, 95% confidence interval = 2.25 to 5.78; P < .001, log-rank test).
Gene expression grade index appeared to reclassify patients with histologic grade 2 tumors into two groups with high versus low risks of recurrence. This approach may improve the accuracy of tumor grading and thus its prognostic value.
乳腺癌的组织学分级提供了重要的临床预后信息。然而，30%-60%的肿瘤被归类为组织学2级。该分级与复发的中度风险相关，因此对临床决策没有指导意义。我们研究了组织学分级是否与乳腺癌的基因表达谱相关，以及这样的谱是否可用于改进组织学分级。
我们分析了189例浸润性乳腺癌的微阵列数据以及来自三个已发表的乳腺癌基因表达数据集的数据。通过比较组织学3级肿瘤和组织学1级肿瘤的表达谱，我们在64例雌激素受体（ER）阳性肿瘤样本的训练集中鉴定出差异表达基因，并使用这些基因的表达来定义基因表达分级指数。在Kaplan-Meier分析中，来自597例独立肿瘤的数据用于评估无复发生存率与基因表达分级指数之间的关联。所有统计检验均为双侧检验。
我们在训练集中鉴定出97个与组织学分级相关的基因；这些基因大多数参与细胞周期调控和增殖。在验证数据集中，基因表达分级指数与组织学1级和3级状态密切相关；然而，在组织学2级肿瘤中，该指数涵盖了组织学1-3级肿瘤的值。在组织学2级肿瘤患者中，高基因表达分级指数比低基因表达分级指数与更高的复发风险相关（风险比=3.61，95%置信区间=2.25至5.78；P<.001，对数秩检验）。
基因表达分级指数似乎将组织学2级肿瘤患者重新分类为复发风险高和低的两组。这种方法可能提高肿瘤分级的准确性，从而提高其预后价值。
