Sixteen-kinase gene expression identifies luminal breast cancers with poor prognosis
Sixteen-kinase gene expression identifies luminal breast cancers with poor prognosis
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DOI：
10.1158/0008-5472.can-07-5516
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发表时间：
2008-02-01
期刊：
影响因子：
11.2
通讯作者：
Bertucci, Francois
中科院分区：
文献类型：
--
作者：
Finetti, Pascal;Cervera, Nathalie;Bertucci, Francois
乳腺癌是一种由多种分子亚型组成的异质性疾病，具有不同的预后。然而，某些亚型（例如 Luminal A）的进化仍然难以预测，而且治疗也没有达到应有的程度。需要完善预后分类并确定新的治疗靶点。使用寡核苷酸微阵列，我们对 227 种乳腺癌进行了分析。我们的分析重点是预后相反的两种主要乳腺癌亚型：管腔 A (n = 80) 和基底型 (n = 58)，以及编码蛋白激酶的基因。全激酶组表达将管腔 A 肿瘤和基底肿瘤分开。编码参与有丝分裂的丝氨酸/苏氨酸激酶的 16 个基因的表达（通过激酶评分测量）区分了腔 A 肿瘤的两个亚组：Aa，预后良好，Ab，预后不良。这种分类及其预后效果在来自不同微阵列平台的三个独立系列的 276 个 luminal A 病例中得到了验证。在训练集和验证集的单变量和多变量分析中，该分类优于当前的预后因素。与管腔 Aa 肿瘤相比，管腔 Ab 亚型的特点是有丝分裂活性高，其临床特征和激酶评分介于管腔 Aa 亚型和管腔 B 亚型之间，表明管腔肿瘤存在连续体。特征的一些有丝分裂激酶代表了正在研究的治疗靶点。识别预后不良的 Luminal A 病例应有助于选择适当的治疗方法，而相关激酶组的识别则提供了潜在的靶点。
Breast cancer is a heterogeneous disease made of various molecular subtypes with different prognosis. However, evolution remains difficult to predict within some subtypes, such as luminal A, and treatment is not as adapted as it should be. Refinement of prognostic classification and identification of new therapeutic targets are needed. Using oligonucleotide microarrays, we profiled 227 breast cancers. We focused our analysis on two major breast cancer subtypes with opposite prognosis, luminal A (n = 80) and basal (n = 58), and on genes encoding protein kinases. Whole-kinome expression separated luminal A and basal tumors. The expression (measured by a kinase score) of 16 genes encoding serine/threonine kinases involved in mitosis distinguished two subgroups of luminal A tumors: Aa, of good prognosis and Ab, of poor prognosis. This classification and its prognostic effect were validated in 276 luminal A cases from three independent series profiled across different microarray platforms. The classification outperformed the current prognostic factors in univariate and multivariate analyses in both training and validation sets. The luminal Ab subgroup, characterized by high mitotic activity compared with luminal Aa tumors, displayed clinical characteristics and a kinase score intermediate between the luminal Aa subgroup and the luminal B subtype, suggesting a continuum in luminal tumors. Some of the mitotic kinases of the signature represent therapeutic targets under investigation. The identification of luminal A cases of poor prognosis should help select appropriate treatment, whereas the identification of a relevant kinase set provides potential targets.