Jumppanen Mervi, Gruvberger-Saal Sofia, Kauraniemi Päivikki, Tanner Minna, Bendahl Pär-Ola, Lundin Mikael, Krogh Morten, Kataja Pasi, Borg Ake, Fernö Mårten, Isola Jorma
Department of Pathology, Seinäjoki Central Hospital, Hanneksenrinne 7, FIN-60220 Seinäjoki, Finland.
Breast Cancer Res. 2007;9(1):R16. doi: 10.1186/bcr1649.
Basal-phenotype or basal-like breast cancers are characterized by basal epithelium cytokeratin (CK5/14/17) expression, negative estrogen receptor (ER) status and distinct gene expression signature. We studied the clinical and biological features of the basal-phenotype tumors determined by immunohistochemistry (IHC) and cDNA microarrays especially within the ER-negative subgroup.
IHC was used to evaluate the CK5/14 status of 445 stage II breast cancers. The gene expression signature of the CK5/14 immunopositive tumors was investigated within a subset (100) of the breast tumors (including 50 ER-negative tumors) with a cDNA microarray. Survival for basal-phenotype tumors as determined by CK5/14 IHC and gene expression signature was assessed.
From the 375 analyzable tumor specimens, 48 (13%) were immunohistochemically positive for CK5/14. We found adverse distant disease-free survival for the CK5/14-positive tumors during the first years (3 years hazard ratio (HR) 2.23, 95% confidence interval (CI) 1.17 to 4.24, p = 0.01; 5 years HR 1.80, 95% CI 1.02 to 3.15, p = 0.04) but the significance was lost at the end of the follow-up period (10 years HR 1.43, 95% CI 0.84 to 2.43, p = 0.19). Gene expression profiles of immunohistochemically determined CK5/14-positive tumors within the ER-negative tumor group implicated 1,713 differently expressed genes (p < 0.05). Hierarchical clustering analysis with the top 500 of these genes formed one basal-like and a non-basal-like cluster also within the ER-negative tumor entity. A highly concordant classification could be constructed with a published gene set (Sorlie's intrinsic gene set, concordance 90%). Both gene sets identified a basal-like cluster that included most of the CK5/14-positive tumors, but also immunohistochemically CK5/14-negative tumors. Within the ER-negative tumor entity there was no survival difference between the non-basal and basal-like tumors as identified by immunohistochemical or gene-expression-based classification.
Basal cytokeratin-positive tumors have a biologically distinct gene expression signature from other ER-negative tumors. Even if basal cytokeratin expression predicts early relapse among non-selected tumors, the clinical outcome of basal tumors is similar to non-basal ER-negative tumors. Immunohistochemically basal cytokeratin-positive tumors almost always belong to the basal-like gene expression profile, but this cluster also includes few basal cytokeratin-negative tumors.
基底型或基底样乳腺癌的特征是基底上皮细胞角蛋白(CK5/14/17)表达、雌激素受体(ER)阴性以及独特的基因表达特征。我们研究了通过免疫组织化学(IHC)和cDNA微阵列确定的基底型肿瘤的临床和生物学特征,特别是在ER阴性亚组中。
使用IHC评估445例II期乳腺癌的CK5/14状态。在一部分(100例)乳腺肿瘤(包括50例ER阴性肿瘤)中,用cDNA微阵列研究CK5/14免疫阳性肿瘤的基因表达特征。评估通过CK5/14 IHC和基因表达特征确定的基底型肿瘤的生存率。
在375份可分析的肿瘤标本中,48例(13%)CK5/14免疫组化呈阳性。我们发现CK5/14阳性肿瘤在最初几年的远处无病生存率较差(3年风险比(HR)2.23,95%置信区间(CI)1.17至4.24,p = 0.01;5年HR 1.80,95%CI 1.02至3.15,p = 0.04),但在随访期末这种显著性消失了(10年HR 1.43,95%CI 0.84至2.43,p = 0.19)。在ER阴性肿瘤组中,免疫组化确定的CK5/14阳性肿瘤的基因表达谱涉及1713个差异表达基因(p < 0.05)。对这些基因中排名前500的基因进行层次聚类分析,在ER阴性肿瘤实体中也形成了一个基底样簇和一个非基底样簇。可以用已发表的基因集(Sorlie的内在基因集,一致性90%)构建高度一致的分类。两个基因集都确定了一个基底样簇,其中包括大多数CK5/14阳性肿瘤,但也包括免疫组化CK5/14阴性的肿瘤。在ER阴性肿瘤实体中,通过免疫组化或基于基因表达的分类确定的非基底样和基底样肿瘤之间没有生存差异。
基底细胞角蛋白阳性肿瘤与其他ER阴性肿瘤在生物学上具有不同的基因表达特征。即使基底细胞角蛋白表达可预测未选择肿瘤中的早期复发,但基底型肿瘤的临床结局与非基底型ER阴性肿瘤相似。免疫组化基底细胞角蛋白阳性肿瘤几乎总是属于基底样基因表达谱,但这个簇中也包括少数基底细胞角蛋白阴性肿瘤。