E. Wik (Bergen, Norway)
University of BergenAuthor Of 1 Presentation
18P - Age-related breast cancer gene expression signature with strong prognostic value
Abstract
Background
Breast cancer (BC) diagnosed at ages <40 years is known to present more aggressive tumor phenotypes and poorer clinical outcome. To gain a better understanding of the age-related expression of BC promoting genes, we aimed to identify transcriptional alterations supporting cancer progression in BC of young women.
Methods
We studied mRNA gene expression data from two METABRIC cohorts. Differentially expressed genes (DEGs) and gene sets (Gene Set Enrichment Analysis) differentially enriched between primary BC for patients <40/≥40 years were explored. Protein-protein interaction (PPI) networks were explored by the STRING database and visualized by Cytoscape software. Hub genes were identified by MCODE and CytoHubba plugins. Drug signatures were explored by Connectivity Map (CMAP).
Results
We identified 91 and 99 commonly up- and downregulated DEGs in women <40 in the two METABRIC cohorts. Gene sets reflecting proliferation were among the top results reported (REACTOME and gene ontology; FDR <10%). Six hub genes presenting highest PPI network connectivity were identified. High signature score (sum of hub genes expression values) was significantly associated with high tumor diameter, histologic grade, lymph node metastasis, ER negativity, basal-like and HER2 enriched subtypes (P <0.001). The signature score showed strong correlation with proliferation signatures OncotypeDx and PCNA (ρ=0.90-0.96, P <0.001), and associated with reduced cancer specific survival (P <0.001), also when adjusted for traditional clinico-pathologic variables in both cohorts (HR: 1.074-1.081, 95% CI: 1.046-1.109, P ≤0.003). The signature score associated with survival when adjusting for traditional clinico-pathologic variables in OncotypeDx-low tumors in both cohorts (HR: 1.54-1.077, 95% CI: 1.034-1.251, P <0.001). By CMAP, inhibitors of CDK, PI3K and AURKA are suggested with potential relevance for BC of the young.
Conclusions
The current study provides new insights into age-related gene expression alterations in BC. We found evidence of higher tumor cell proliferation in young BC patients, and identified a gene expression signature reflecting tumor proliferation, aggressive tumor features and reduced survival, also in subsets of low OncotypeDx score.
Legal entity responsible for the study
The authors.
Funding
The study was funded by support from Centre for Cancer Biomarkers CCBIO, University of Bergen, the Research Council of Norway, and the Western Norway Regional Health Authority (Helse Vest RHF).
Disclosure
All authors have declared no conflicts of interest.