Multivariate exome analysis identifies CXCR5-CXCL13 signaling as a key driver in early breast cancer development and prognosis

Breast cancer (BrCa) is the most frequently diagnosed cancer and the second leading cause of cancer-related death among women worldwide despite new developments in prevention and treatment. More recently, rapid increases in BrCa incidence have been reported in countries of the Asia-Pacific region. Age of diagnosis in Asian BrCa patients is much younger than age of diagnosis in western countries, such as the United States, and Asian early BrCa patients tend to be pre-menopausal, whereas only 15-30% of western BrCas are pre-menopausal. The mechanisms responsible for early BrCa remain unknown. Furthermore, it remains controversial whether early breast cancer has unique tumor biology. The goal of this study was to characterize the molecular phenotype of early BrCa in the context of CXCL13, CXCR5 and associated gene expression. We hypothesized that CXCR5-CXCL13 signaling contributes to the aggressive phenotype of early BrCa . A bioinformatic approach was used to aid in characterizing this condition. Our patient cohort data (50 females of Korean descent, age ≤ 35 years) was obtained from The International Cancer Genome Consortium (ICGC). DESeq analysis was used to identify genes differentially expressed among normal tissue and primary tumor groups. Weighted Gene Network Co-expression (WGCNA) analysis was carried-out to identify gene networks associated with factors influencing BrCa prognosis. Finally, canonical pathway, upstream regulator, and gene interaction analysis was conducted using Ingenuity Pathway Analysis. Our data show CXCL13, CXCR5, and associated genes (LTA, LTB, IL10, IL27RA, TNFRSF13B, TNFRSF17, and TNFRSF9), which have been previously shown to drive tertiary lymphoid structure (TLS) formation, were significantly associated with the molecular phenotype of early BrCa in our patient cohort. Taken together, our findings suggest TLSs contribute to the tumor immune microenvironment and contribute to early BrCa progression. Citation Format: Courtney D. Dill, Tiara Griffen, Corey Young, Kaylin Carey, James W. Lillard. Multivariate exome analysis identifies CXCR5-CXCL13 signaling as a key driver in early breast cancer development and prognosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1975.