Department of Obstetrics and Gynecology, JW Goethe-University, Frankfurt, Germany.
Eur J Cancer. 2012 Jan;48(1):12-23. doi: 10.1016/j.ejca.2011.06.025. Epub 2011 Jul 7.
Molecular markers displaying bimodal expression distribution can reveal distinct disease subsets and may serve as prognostic or predictive markers or represent therapeutic targets. Oestrogen (ER) and human epidermal growth factor receptor 2 (HER2) receptors are strongly bimodally expressed genes in breast cancer.
We applied a novel method to identify bimodally expressed genes in 394 triple negative breast cancers (TNBC). We identified 133 bimodally expressed probe sets (128 unique genes), 69 of these correlated to previously reported metagenes that define molecular subtypes within TNBC including basal-like, molecular-apocrine, claudin-low and immune cell rich subgroups but 64 probe sets showed no correlation with these features.
The single most prominent functional group among these uncorrelated genes was the X chromosome derived Cancer/Testis Antigens (CT-X) including melanoma antigen family A (MAGE-A) and Cancer/Testis Antigens (CTAG). High expression of CT-X genes correlated with worse survival in multivariate analysis (HR 2.02, 95% CI 1.27-3.20; P=0.003). The only other significant variable was lymph node status. The poor prognosis of patients with high MAGE-A expression was ameliorated by the concomitant high expression of immune cell metagenes (HR 1.87, 95% CI 0.96-3.64; P=0.060), whereas the same immune metagene had lesser prognostic value in TNBC with low MAGE-A expression.
MAGE-A antigen defines a very aggressive subgroup of TNBC; particularly in the absence of immune infiltration in the tumour microenvironment. These observations suggest a therapeutic hypothesis; TNBC with MAGE-A expression may benefit the most from further augmentation of the immune response. Novel immune stimulatory drugs such as (anti-cytotoxic T-lymphocyte antigen-4 CTLA-4) directed therapies provide a realistic opportunity to directly test this hypothesis in the clinic.
表现出双峰表达分布的分子标志物可以揭示不同的疾病亚群，并且可以作为预后或预测标志物，或者代表治疗靶点。雌激素（ER）和人表皮生长因子受体 2（HER2）受体在乳腺癌中是强烈双峰表达的基因。
我们应用一种新方法来鉴定 394 例三阴性乳腺癌（TNBC）中的双峰表达基因。我们鉴定出 133 个双峰表达探针集（128 个独特基因），其中 69 个与先前报道的定义 TNBC 内分子亚型的基因元相关，包括基底样、分子大汗腺样、 Claudin-low 和免疫细胞丰富亚组，但 64 个探针集与这些特征没有相关性。
在这些不相关的基因中，最突出的功能组群是来自 X 染色体的癌症/睾丸抗原（CT-X），包括黑色素瘤抗原家族 A（MAGE-A）和癌症/睾丸抗原（CTAG）。在多变量分析中，CT-X 基因的高表达与生存不良相关（HR 2.02，95%CI 1.27-3.20；P=0.003）。唯一其他显著变量是淋巴结状态。在伴有免疫细胞基因元高表达的情况下，高 MAGE-A 表达患者的预后较差（HR 1.87，95%CI 0.96-3.64；P=0.060），而在 MAGE-A 表达低的 TNBC 中，相同的免疫基因元的预后价值较小。
MAGE-A 抗原定义了 TNBC 中非常侵袭性的亚组；特别是在肿瘤微环境中没有免疫浸润的情况下。这些观察结果提出了一个治疗假设；表达 MAGE-A 的 TNBC 可能最受益于进一步增强免疫反应。新型免疫刺激药物，如（抗细胞毒性 T 淋巴细胞抗原-4 CTLA-4）靶向治疗，为在临床上直接测试这一假设提供了现实机会。
