Abstract P4-07-02: A large integrated-gene profiling analysis identifies prognostic microRNAs and correlated DNA repair genes in estrogen receptor positive and negative breast cancers
Authors: Gyorffy Balazs , Kormos Mate , Bottai Giulia , Kleivi Kristine , Calin George A , Borresen-Dale Anne-Lise , Santarpia Libero 
Published: May 2015

Abstract
Background: MicroRNAs (miRNAs) are small non-coding RNAs involved in the pathogenesis of breast cancer (BC). Estrogen receptor (ER) is one of the most important factors influencing BC outcome. In this study we aim to assess the prognostic value in a cross-project analysis for all known miRNAs in ER-positive (ER+) and ER-negative (ER-) BC separately.
Materials and Methods: We assessed the prognostic value of miRNA expression in three independent BC datasets: TCGA (n=782), Metabric [M] (n=1,293) and GSE40267 (n=181) including 472, 853, and 475 miRNAs, respectively. Overall survival (OS) data was available for all patients. Statistical analysis was performed with R software. Survival analysis was performed using Cox proportional hazards regression in each dataset separately. To define an mRNA expression fingerprint for each miRNA, correlation between miRNA and mRNA expressions was computed using Spearman rank correlation in the Metabric dataset. Subsequently, specific metagenes were established using significant correlated mRNAs ("Metabric mRNA", M-mRNA) for each miRNA. Metagenes were also used in the Cox regression analysis. The entire analysis was performed for each miRNA in ER-positive and ER-negative BCs separately.
Results: In the ER+ BC, 283 miRNAs reached statistical significance in at least one dataset. The best performing and significant miRNAs in all datasets were miR-195 (M: HR=1.73, p=3.5E-06; TCGA: HR=2.17, p=3.5E-06, M-mRNA: HR=0.54, p=2.0E-10), miR-199b (M: HR=1.74, p=3.8E-06; TCGA: HR=0.46, p=0.028, M-mRNA: HR=0.56, p=2.8E-09), and miR-210 (M: HR=0.7, p=0.003; TCGA: HR=0.45, p=0.014, Metabric mRNA: HR=1.34, p=0.002). These 3 miRNAs retained their prognostic significance also in a multivariate analysis paired with HER2 status, lymph node status, size, grade and MKI67 expression. In the ER- group 73 significant miRNAs were identified. The best performing miRNAs in at least two datasets were miR-155 (GSE40267: HR=2.21, p=0.034, M: HR=1.67, p=0.008) and miR-381 (GSE40267: HR=0.41, p=0.026; M: HR=0.67, p=0.038). However, the miRNAs in ER- BC in a multivariate analysis were not independent from tumor size. The metagenes identified were significantly enriched in DNA repair genes (e.g. AURKB, TEK) and exhibited an inverse correlation to survival as compared to miRNA expression.
Conclusions: This is the first large-scale miRNA expression analysis demonstrating different prognostic miRNAs in ER+ and ER- BCs. Correlated miRNA-metagenes are involved in the regulation of DNA repair and genomic stability.
Citation Format: Balazs Gyorffy, Mate Kormos, Giulia Bottai, Kristine Kleivi, George A Calin, Anne-Lise Borresen-Dale, Libero Santarpia. A large integrated-gene profiling analysis identifies prognostic microRNAs and correlated DNA repair genes in estrogen receptor positive and negative breast cancers [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-07-02.