Beca Francisco, Pereira Miguel, Cameselle-Teijeiro Jorge F, Martins Diana, Schmitt Fernando
IPATIMUP - Institute of Molecular Pathology and Immunology of the University of Porto, Rua Dr, Roberto Frias, s/n, 4200-465 Porto, Porto, Portugal.
Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Ave., Boston, MA, 02215-5450, USA.
BMC Cancer. 2015 Apr 15;15:285. doi: 10.1186/s12885-015-1266-1.
PPP2R2A deletions were recently linked to a subgroup of luminal breast carcinoma (BC) that exhibits poor survival. This subgroup also exhibited amplification of a chromosome region containing the Cyclin D1 coding gene, CCND1. Therefore, we aimed to investigate whether a combination of PPP2R2A (B55α) and Cyclin D1 expression statuses evaluated by immunohistochemistry (IHC) could define a subgroup of luminal BC that exhibits poor survival.
First we conducted a retrospective cohort study using sequencing data from The Cancer Genome Atlas initiative to correlate PPP2R2A copy number alteration (CNA) status with its expression level and the corresponding overall survival (OS). Next, also using a retrospective cohort study design, we evaluated the PPP2R2A (B55α) expression levels by IHC in a total of 807 BC patients from two independent cohorts (discovery cohort n = 349 and validation cohort n = 458). Cyclin D1 expression was also evaluated, and the PPP2R2A (B55α)(-/low)/Cyclin D1(high) phenotype was evaluated as a predictor of disease-free survival (DFS) and OS in luminal-like BC patients.
Deletions in the PPP2R2A gene strongly correlate with lower mRNA expression and poorer OS. PPP2R2A (B55α)(-/low) carcinomas have significantly shorter DFS and OS. Furthermore, in univariate analysis, the PPP2R2A (B55α)(-/low)/Cyclin D1(high) phenotype is significantly associated with poorer DFS and OS. In a multivariate analysis, the PPP2R2A (B55α)(-/low)/Cyclin D1(high) phenotype is significantly associated with poor DFS, thus defining a group of luminal-like BC with higher risk of relapse.
We demonstrate that BCs harboring PPP2R2A deletions are associated with worse OS. Moreover, this is the first study to demonstrate that the combination of altered PPP2R2A (B55α) and high Cyclin D1 expression by IHC defines a subgroup of luminal-like BC patients with a high risk of relapse and death.
PPP2R2A缺失最近被认为与管腔型乳腺癌（BC）的一个亚组相关，该亚组患者预后较差。该亚组还表现出包含细胞周期蛋白D1编码基因CCND1的染色体区域扩增。因此，我们旨在研究通过免疫组织化学（IHC）评估的PPP2R2A（B55α）和细胞周期蛋白D1表达状态的组合是否能定义一个预后较差的管腔型BC亚组。
首先，我们利用癌症基因组图谱计划的测序数据进行了一项回顾性队列研究，以将PPP2R2A拷贝数改变（CNA）状态与其表达水平及相应的总生存期（OS）相关联。接下来，同样采用回顾性队列研究设计，我们通过IHC评估了来自两个独立队列（发现队列n = 349和验证队列n = 458）的总共807例BC患者的PPP2R2A（B55α）表达水平。还评估了细胞周期蛋白D1的表达，并将PPP2R2A（B55α）（- /低）/细胞周期蛋白D1（高）表型评估为管腔样BC患者无病生存期（DFS）和OS的预测指标。
PPP2R2A基因缺失与较低的mRNA表达及较差的OS密切相关。PPP2R2A（B55α）（- /低）癌的DFS和OS明显更短。此外，在单变量分析中，PPP2R2A（B55α）（- /低）/细胞周期蛋白D1（高）表型与较差的DFS和OS显著相关。在多变量分析中，PPP2R2A（B55α）（- /低）/细胞周期蛋白D1（高）表型与较差的DFS显著相关，从而定义了一组复发风险较高的管腔样BC。
我们证明，携带PPP2R2A缺失的BC与较差的OS相关。此外，这是第一项证明通过IHC检测到的PPP2R2A（B55α）改变与高细胞周期蛋白D1表达的组合可定义一组复发和死亡风险较高的管腔样BC患者的研究。
