Homologous recombination mRNAs (RAD21, RAD50 and BARD1) have a potentially poor prognostic role in ERBB2-low bladder cancer patients

Abstract

Human epidermal growth factor receptor 2 (HER2/ERBB2) factor is known to be implicated in many malignancies and the potential of it as a prognostic biomarker was reported years ago. Molecular subtypes of HER2/ERBB2 negative and positive with distinct clinical outcomes have been identified in recent years; however, it is still under investigation for bladder cancer. This study evaluates the biological and prognostic significance of RAD21, RAD50 and BARD1 (homologous recombination biomarkers) mRNA levels with ERBB2 low and high expression to explore their impact on bladder cancer patient survival and cancer aggressiveness. The expression of ERBB2, RAD21, RAD50 and BARD1 mRNA levels was assessed in The Cancer Genome Atlas (TCGA) bladder cancer dataset along with four validation cohorts. Outcome analysis was evaluated using disease-free survival (DFS) and overall survival (OS). Univariate and multivariate analysis were used to evaluate the relationship between RAD21, RAD50, BARD1 and ERBB2 expression and clinicopathological variables. A significant increase in mRNA expression levels of RAD21, RAD50 and BARD1 was noticed in ERBB2-low patients compared to ERBB2-high patients. This overexpression of the homologous recombination repair transcripts was associated with poor outcome in ERBB2-low tumors, not in ERBB2-high tumors. Furthermore, the combined expression of high RAD21/RAD50, high RAD21/BARD1 or high RAD50/BARD1 were significantly associated with worse DFS and a better outcome for those with low co-expression in the ERBB2-low cohort. High expression of either RAD21/RAD50 or RAD21/BARD1 in ERBB2-low cohort associated with higher chance of metastasis. In addition, gene expression of BARD1 alone or in combination with RAD50 acted as an independent prognostic factor for worst survival. The data presented in this study reveal a connection between RAD21, RAD50, BARD1 and ERBB2 and patient survival. Importantly, it provided novel findings and potential prognostic markers, particularly in ERBB2-low bladder cancer.