Altered PPP2R2A and Cyclin D1 expression defines a subgroup of aggressive luminal-like breast cancer

Abstract

BackgroundPPP2R2A 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.MethodsFirst 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 D1high phenotype was evaluated as a predictor of disease-free survival (DFS) and OS in luminal-like BC patients.ResultsDeletions 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 D1high phenotype is significantly associated with poorer DFS and OS. In a multivariate analysis, the PPP2R2A (B55α)-/low/Cyclin D1high phenotype is significantly associated with poor DFS, thus defining a group of luminal-like BC with higher risk of relapse.ConclusionWe 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-1266-1) contains supplementary material, which is available to authorized users.

Associating lncRNAs with small molecules via bilevel optimization reveals cancer-related lncRNAs

“…LY294002, which was reported to be related to breast cancer cell apoptosis [46], was associated with BRCAT64.1 through the ALACD model ( Fig 4B). Three out of the five genes that were associated with LY294002 and BRCAT64.1 were linked to breast cancer, as supported by the literature [47][48][49]. In addition, BRCAT64.1 was associated with breast cancer in MiTranscriptome with a confidence score larger than 0.5, and was specifically expressed in breast cancer (Fig 4D).…”

Overexpression of miR-222-3p promotes proliferation and inhibits apoptosis in diffuse large B-cell lymphoma cells via suppressing PPP2R2A

“…16 A previous study shows that the PPP2R2A deletions were recently linked to a subgroup of luminal breast carcinoma that exhibits poor survival. 27 Down-regulation of PPP2R2A is proved to inhibit homologous recombination DNA repair and predict tumor sensitivity to PARP inhibition. 28 Wang et al showed that the levels of PPP2R2A was lower in giant cell tumor of bone tissues than that in normal tissues.…”

Pan-cancer computational histopathology reveals mutations, tumor composition and prognosis

“…The deletion of a segment on cytoband 8p23.2 containing CSMD1 , which has been previously reported as a candidate tumor suppressor gene that is frequently lost in many carcinomas 22 , was identified in 6 cancer types such as ovarian serous carcinoma (AUC=0.62, CI=[0.53-0.71]), esophageal carcinoma (AUC=0.79, CI=[0.65-0.93]) and liver hepatocellular carcinoma (AUC=0.70, CI=[0.60-0.81]). A proximal deletion of PPP2R2A , located on 8p21.2, which was commonly deleted in cancers and was shown to be associated with a worse prognosis 23,24 , was identified in 5 cancers including esophageal carcinoma (AUC=0.8, [0.65-0.94]), hepatocellular carcinoma (AUC=0.67, CI=[0.57-0.78]) and breast invasive carcinoma (AUC=0.67, CI=[0.59-0.75]). As these 2 deletions frequently co-occur (Cohen's κ=0.88), it is possible that these histological associations reflect the same underlying alteration.…”