Department of Oncology and Pathology, Karolinska Institutet and University Hospital, Stockholm, Sweden.
Department of Biosciences and Nutrition, Karolinska Institutet and University Hospital, Stockholm, Sweden.
Breast Cancer Res. 2019 Feb 28;21(1):34. doi: 10.1186/s13058-019-1121-4.
Use of cyclin D1 (CCND1) gene amplification as a breast cancer biomarker has been hampered by conflicting assessments of the relationship between cyclin D1 protein levels and patient survival. Here, we aimed to clarify its prognostic and treatment predictive potential through comprehensive long-term survival analyses.
CCND1 amplification was assessed using SNP arrays from two cohorts of 1965 and 340 patients with matching gene expression array and clinical follow-up data of over 15 years. Kaplan-Meier and multivariable Cox regression analyses were used to determine survival differences between CCND1 amplified vs. non-amplified tumours in clinically relevant patient sets, within PAM50 subtypes and within treatment-specific subgroups. Boxplots and differential gene expression analyses were performed to assess differences between amplified vs. non-amplified tumours within PAM50 subtypes.
When combining both cohorts, worse survival was found for patients with CCND1-amplified tumours in luminal A (HR = 1.68; 95% CI, 1.15-2.46), luminal B (1.37; 1.01-1.86) and ER+/LN-/HER2- (1.66; 1.14-2.41) subgroups. In gene expression analysis, CCND1-amplified luminal A tumours showed increased proliferation (P < 0.001) and decreased progesterone (P = 0.002) levels along with a large overlap in differentially expressed genes when comparing luminal A and B-amplified vs. non-amplified tumours.
Our results indicate that CCND1 amplification is associated with worse 15-year survival in ER+/LN-/HER2-, luminal A and luminal B patients. Moreover, luminal A CCND1-amplified tumours display gene expression changes consistent with a more aggressive phenotype. These novel findings highlight the potential of CCND1 to identify patients that could benefit from long-term treatment strategies.
使用细胞周期蛋白 D1（CCND1）基因扩增作为乳腺癌生物标志物一直受到细胞周期蛋白 D1 蛋白水平与患者生存之间关系的相互矛盾的评估的阻碍。在这里，我们旨在通过全面的长期生存分析来阐明其预后和治疗预测潜力。
使用来自两个队列的 SNP 阵列评估 CCND1 扩增，这两个队列分别有 1965 名和 340 名患者，具有匹配的基因表达阵列和超过 15 年的临床随访数据。使用 Kaplan-Meier 和多变量 Cox 回归分析来确定在临床上相关的患者组、PAM50 亚型内和特定治疗亚组内，CCND1 扩增与非扩增肿瘤之间的生存差异。箱线图和差异基因表达分析用于评估 PAM50 亚型内扩增与非扩增肿瘤之间的差异。
当结合两个队列时，在 luminal A（HR=1.68；95%CI，1.15-2.46）、luminal B（1.37；1.01-1.86）和 ER+/LN-/HER2-（1.66；1.14-2.41）亚组中，CCND1 扩增肿瘤患者的生存情况更差。在基因表达分析中，与 luminal A 和 B 非扩增肿瘤相比，CCND1 扩增的 luminal A 肿瘤显示出增殖增加（P<0.001）和孕激素减少（P=0.002），并且差异表达基因有很大重叠。
我们的结果表明，CCND1 扩增与 ER+/LN-/HER2-、luminal A 和 luminal B 患者的 15 年生存率较差相关。此外，luminal A CCND1 扩增肿瘤显示出与更具侵袭性表型一致的基因表达变化。这些新发现强调了 CCND1 识别可能受益于长期治疗策略的患者的潜力。
