Finetti Pascal, Cervera Nathalie, Charafe-Jauffret Emmanuelle, Chabannon Christian, Charpin Colette, Chaffanet Max, Jacquemier Jocelyne, Viens Patrice, Birnbaum Daniel, Bertucci François
UMR599 Inserm, Institut Paoli-Calmettes, Laboratoire d'Oncologie Moléculaire, Centre de Recherche en Cancérologie de Marseille, Marseille, France.
Cancer Res. 2008 Feb 1;68(3):767-76. doi: 10.1158/0008-5472.CAN-07-5516.
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.
乳腺癌是一种异质性疾病，由具有不同预后的多种分子亚型组成。然而，在某些亚型（如腔面A型）中，疾病进展仍然难以预测，治疗也未达到应有的适配程度。因此，需要完善预后分类并鉴定新的治疗靶点。我们使用寡核苷酸微阵列对227例乳腺癌进行了分析。我们将分析重点放在了两种预后相反的主要乳腺癌亚型上，即腔面A型（n = 80）和基底型（n = 58），以及编码蛋白激酶的基因上。全激酶组表达区分了腔面A型和基底型肿瘤。16个编码参与有丝分裂的丝氨酸/苏氨酸激酶的基因的表达（通过激酶评分来衡量）区分出了腔面A型肿瘤的两个亚组：预后良好的Aa组和预后不良的Ab组。这一分类及其预后作用在来自三个独立队列、通过不同微阵列平台分析的276例腔面A型病例中得到了验证。在训练集和验证集的单变量和多变量分析中，该分类均优于当前的预后因素。与腔面Aa型肿瘤相比，以高有丝分裂活性为特征的腔面Ab亚组，其临床特征和激酶评分介于腔面Aa亚组和腔面B亚型之间，提示腔面型肿瘤存在连续性。该特征中的一些有丝分裂激酶是正在研究的治疗靶点。鉴定预后不良的腔面A型病例应有助于选择合适的治疗方法，而鉴定一组相关激酶则提供了潜在的靶点。
