Adélaïde José, Finetti Pascal, Bekhouche Ismahane, Repellini Laetitia, Geneix Jeannine, Sircoulomb Fabrice, Charafe-Jauffret Emmanuelle, Cervera Nathalie, Desplans Jérôme, Parzy Daniel, Schoenmakers Eric, Viens Patrice, Jacquemier Jocelyne, Birnbaum Daniel, Bertucci François, Chaffanet Max
Marseille Cancer Research Center, Department of Molecular Oncology, Institut Paoli-Calmettes and UMR599 Institut National de la Santé et de la Recherche Médicale, Marseille, France.
Cancer Res. 2007 Dec 15;67(24):11565-75. doi: 10.1158/0008-5472.CAN-07-2536.
Basal and luminal are two molecular subtypes of breast cancer with opposite histoclinical features. We report a combined, high-resolution analysis of genome copy number and gene expression in primary basal and luminal breast cancers. First, we identified and compared genomic alterations in 45 basal and 48 luminal tumors by using 244K oligonucleotide array comparative genomic hybridization (aCGH). We found various genome gains and losses and rare high-level gene amplifications that may provide therapeutic targets. We show that gain of 10p is a new alteration in basal breast cancer and that a subregion of the 8p12 amplification is specific of luminal tumors. Rare high-level amplifications contained BCL2L2, CCNE, EGFR, FGFR2, IGF1R, NOTCH2, and PIK3CA. Potential gene breaks involved ETV6 and FLT3. Second, we analyzed both aCGH and gene expression profiles for 42 basal and 32 luminal breast cancers. The results support the existence of specific oncogenic pathways in basal and luminal breast cancers, involving several potential oncogenes and tumor suppressor genes (TSG). In basal tumors, 73 candidate oncogenes were identified in chromosome regions 1q21-23, 10p14, and 12p13 and 28 candidate TSG in regions 4q32-34 and 5q11-23. In luminal breast cancers, 33 potential oncogenes were identified in 1q21-23, 8p12-q21, 11q13, and 16p12-13 and 61 candidate TSG in 16q12-13, 16q22-24, and 17p13. HORMAD1 (P = 6.5 x 10(-5)) and ZNF703 (P = 7 x 10(-4)) were the most significant basal and luminal potential oncogenes, respectively. Finally, among 10p candidate oncogenes associated with basal subtype, we validated CDC123/C10orf7 protein as a basal marker.
基底样型和管腔型是具有相反组织临床特征的两种乳腺癌分子亚型。我们报告了对原发性基底样型和管腔型乳腺癌的基因组拷贝数和基因表达进行的联合高分辨率分析。首先，我们使用244K寡核苷酸阵列比较基因组杂交（aCGH）技术，鉴定并比较了45例基底样型肿瘤和48例管腔型肿瘤中的基因组改变。我们发现了各种基因组的增加和缺失以及罕见的高水平基因扩增，这些可能提供治疗靶点。我们表明10p的增加是基底样型乳腺癌中的一种新改变，并且8p12扩增的一个亚区域是管腔型肿瘤所特有的。罕见的高水平扩增包含BCL2L2、CCNE、EGFR、FGFR2、IGF1R、NOTCH2和PIK3CA。潜在的基因断裂涉及ETV6和FLT3。其次，我们分析了42例基底样型和32例管腔型乳腺癌的aCGH和基因表达谱。结果支持基底样型和管腔型乳腺癌中存在特定的致癌途径，涉及多个潜在的致癌基因和肿瘤抑制基因（TSG）。在基底样型肿瘤中，在染色体区域1q21 - 23、10p14和12p13中鉴定出73个候选致癌基因，在区域4q32 - 34和5q11 - 23中鉴定出28个候选TSG。在管腔型乳腺癌中，在1q21 - 23、8p12 - q21、11q13和16p12 - 13中鉴定出33个潜在致癌基因，在16q12 - 13、16q22 - 24和17p13中鉴定出61个候选TSG。HORMAD1（P = 6.5×10⁻⁵）和ZNF703（P = 7×10⁻⁴）分别是最显著的基底样型和管腔型潜在致癌基因。最后，在与基底样型亚型相关的10p候选致癌基因中，我们验证了CDC123/C10orf7蛋白作为一种基底样型标志物。
