A novel age-related gene expression signature associates with proliferation and disease progression in breast cancer.

Background And Objective: Breast cancer (BC) diagnosed at ages <40 years presents with more aggressive tumour phenotypes and poorer clinical outcome compared to older BC patients. Here, we explored transcriptional BC alterations to gain a better understanding of age-related tumour biology, also subtype-stratified.

Methods: We studied publicly available global BC mRNA expression (n = 3999) and proteomics data (n = 113), exploring differentially expressed genes, enriched gene sets, and gene networks in the young compared to older patients.

Results: We identified transcriptional patterns reflecting increased proliferation and oncogenic signalling in BC of the young, also in subtype-stratified analyses. Six up-regulated hub genes built a novel age-related score, significantly associated with aggressive clinicopathologic features. A high 6 Gene Proliferation Score (6GPS) demonstrated independent prognostic value when adjusted for traditional clinicopathologic variables and the molecular subtypes. The 6GPS significantly associated also with disease-specific survival within the luminal, lymph node-negative and Oncotype Dx intermediate subset.

Conclusions: We here demonstrate evidence of higher tumour cell proliferation in young BC patients, also when adjusting for molecular subtypes, and identified a novel age-based six-gene signature pointing to aggressive tumour features, tumour proliferation, and reduced survival-also in patient subsets with expected good prognosis.