F. Ghasemi1, J. Arima1, K. Takabe1 1Roswell Park Cancer Institute, Buffalo, NY, USA
Introduction:
Poly [ADP-ribose] polymerase (PARP) 1 and 2 enzymes play a vital role in DNA repair mechanisms. PARP inhibitors that target PARP1 and PARP2 cause synthetic lethality, and are thus indicated in BRCA1/2-mutated triple-negative breast cancer (TNBC). Given that a highly proliferative cancer requires excessive DNA replication and therefore repair, we hypothesized that PARP1 and 2 high-expression is associated with aggressive tumor biology in primary breast cancer regardless of subtype.
Methods:
The gene expression profile of the primary breast cancer from 2809 patients in 2 independent cohorts (TCGA and METABRIC) were analyzed based on PARP1 and PARP2 expression. Transcriptomics data were analyzed in luminal and basal PAM50 subtypes of breast cancer separately. PARP1 and 2 high vs low expression groups were divided by the median in each cohort.
Results:
Silent and non-silent mutation rates were higher in PARP1 and PARP2 high tumors regardless of subtypes in the TCGA cohort. In the luminal subtype, fraction of gene altered and aneuploidy scores were significantly higher in both PARP1 and PARP2 high-expression. PARP1 and PARP2 high-expression was correlated with increased KI67 gene expression across luminal and basal breast cancers in both cohorts. All the cell proliferation-related gene sets in Hallmark collection; E2F targets, Myc targets, Mitotic Spindle and G2M checkpoint were enriched in tumors with high PARP1 or PARP2 consistently in both cohorts. PARP1 and PARP2 high-expression was also associated with a significantly higher proliferation score in both luminal and basal tumors. Interferon-gamma response scores were higher with high PARP1 and PARP2 in luminal, but not in basal breast cancers. Reduced TGF-beta response scores were seen with high PARP1 and PARP2 in luminal, and only with high PARP1 in basal subtype. Progression-free survival was significantly worse in ER-positive breast cancers that over-expressed PARP1 and PARP2 (p=0.03 and 0.009 respectively) in the METABRIC dataset, but not in the TNBC group. Survival differences were not statistically significant in the TCGA cohort.
Conclusion:
Expression of PARP1 and PARP2 genes are associated with aggressive cancer biology, especially in the luminal subtype of breast cancer, supporting the potential expanded use of PARP inhibitors beyond the BRCA-mutated TNBC.