Prognostic significance of Werner syndrome protein in BRCA-mutated breast cancers


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Arvind Arora, Constantinos Savva, Srinivasan Madhusudan

Abstract

Background

Werner protein (WRN) plays an important role in DNA repair, replication, transcription, and consequently genomic stability via its DNA-helicase and exonuclease activity. Loss of function of WRN is associated with Werner syndrome (WS) which is characterised by premature aging and cancer predisposition. WRN and BRCA1 facilitate DNA damage response in a coordinated manner as BRCA1 binds directly to WRN by stimulating its exonuclease and helicase activity. PARP1 inhibits both WRN exonuclease and helicase activities, an interaction that is influenced by the poly (ADP-ribosyl)ation status of PARP1. Currently, the clinicopathological significance of WRN in BRCA-mutated breast cancer is largely unknown.

Method

We investigated the clinicopathological and prognostic significance of WRN protein expression in a cohort of clinically annotated series of BRCA-mutated invasive breast cancers (n=75). We correlated WRN protein expression to clinicopathological characteristics and clinical outcomes. Statistical analysis was performed using SPSS (SPSS, version 22 Chicago, IL). Where appropriate, Pearsons Chi-square was used. Fishers exact test was used to obtain p values where one or more cells have an expected frequency of five or less. Adjusted p values were calculated using the Benjamini-Hochberg false discovery rate method to adjust for multiple testing. Cumulative survival probabilities were estimated using the Kaplan–Meier method, and differences between survival rates were tested for significance using the log-rank test.

 

Results

In the whole cohort, low WRN cytoplasmic expression conferred the shortest BCSS (p<0.05). Although low WRN nuclear expression showed a trend towards worse BCSS, this was not statistically significant (p>0.05). Subgroup analysis showed that low nuclear and cytoplasmic WRN expression confer worse BCSS in the BRCA1-mutated tumours (p<0.05). In the BRCA2-mutated tumours, low nuclear WRN expression was associated with poor BCSS (p<0.05). Interestingly, WRN protein expression was not associated with clinicopathological parameters (p>0.05).

Conclusion

Low WRN protein expression is associated with poor BCSS in patients with BRCA-mutated breast cancer. 

Impact statement

Further understanding of the functional interaction between WRN and PARP1 in BRCA-mutated tumours may lead to novel therapeutic approaches which can be used to optimise the risk stratification for personalised treatment.