Abstract 2695: Identification of an age-related breast cancer gene expression signature with strong prognostic value
Authors: Ingebriktsen Lise Martine , Akslen Lars Andreas , Wik Elisabeth 
Published: July 2021

Abstract
Background and Objective: Breast cancer (BC) diagnosed at ages &lt;40 years is known to present more aggressive tumor phenotypes and poorer clinical outcome compared to older BC patients. To gain a better understanding of the possible age-related expression difference in BC promoting genes, we aimed to identify transcriptional alterations supporting cancer progression in BC of the young.
Methods: We studied mRNA gene expression data from METABRIC discovery (n=997), and validation cohort (n=995), and explored the transcriptional patterns associated with BC of the young. We investigated differentially expressed genes (DEGs) between primary BC for patients below and above 40 years at time of diagnosis and explored gene sets (by Gene Set Enrichment Analysis) enriched in BC of the young. Protein-protein interaction (PPI) networks were explored by the STRING database and visualized in Cytoscape software. Hub genes were identified by MCODE and CytoHubba plugins.
Results: Among genes differentially expressed between BC of the young and older, 91 DEGs were commonly (for the two cohorts) upregulated and 99 commonly downregulated in the young (Fold change ≥1.5/≤ -1.5). Oncogenic- and proliferation associated signatures were enriched in the young BC, including signatures reflecting KRAS, MTOR and MYC. Proliferation and cell cycle processes were the dominating enriched gene ontology categories (FDR &lt;10%). Six hub genes presenting highest PPI network connectivity were identified, described to be associated with the cell cycle and cell proliferation. A signature score was made by summarizing the hub genes expression values. High signature score was significantly associated with high tumor size, high histologic grade, lymph node metastasis, ER negativity, basal-like, and HER2 enriched subtypes (P &lt;0.001). The signature score showed strong correlation with the proliferation signatures OncotypeDx and PCNA (ρ=0.90-0.96, P &lt;0.001). Our signature score associated with reduced cancer specific survival (P &lt;0.001), also when adjusted for tumor size, histologic grade, and lymph node status in multivariate analyses in both cohorts (HR: 1.074-1.081, 95% CI: 1.046-1.109, P ≤0.003). The signature score maintained independent, significant association with survival when adjusting for the traditional clinico-pathologic variables in OncotypeDx-low tumors in discovery (HR: 1.077, 95% CI: 1.034-1.122) and validation cohort (HR: 1.154, 95% CI: 1.065-1.251), both P &lt;0.001.
Conclusion: By genome-wide gene expression analyses, the current study provides new insights into age-related gene expression alterations in breast cancer. We demonstrate enrichment of oncogenic signaling and evidence of higher tumor cell proliferation in young BC patients, and identify a gene expression signature reflecting tumor proliferation, aggressive tumor features and reduced survival, also in subsets of low OncotypeDx score.
Citation Format: Lise Martine Ingebriktsen, Lars Andreas Akslen, Elisabeth Wik. Identification of an age-related breast cancer gene expression signature with strong prognostic value [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2695.