Aberrant activation of FAM168B via chimeric PLEKHB2::FAM168B mRNA promotes breast invasive cancer progression

Abstract

Fusion genes have emerged as pivotal oncogenic drivers across diverse cancer types. The predominant mechanisms underlying fusion gene formation include chromosomal aberrations and intergenic mRNA trans-splicing. With advances in cancer genomics and transcriptomics, the identification, prevalence, and functional characterization of fusion genes have become major areas of investigation. In this study, we performed a comprehensive analysis of fusion events involving the family with sequence similarity 168B (FAM168B) and pleckstrin homology domain–containing B2 (PLEKHB2) in breast invasive carcinoma (BRCA). Integrated DNA and RNA sequencing analyses revealed that the chimeric PLEKHB2::FAM168B mRNA transcript is generated through an intergenic mRNA trans-splicing mechanism. This chimeric transcript leads to elevated FAM168B protein expression via long intergenic non-coding RNA 02228 (LINC02228)–mediated activation of DEAD-box helicase 3 X-linked (DDX3X). This, in turn, activates the DAZ-associated protein 2 (DAZAP2)/homeodomain-interacting protein kinase 2 (HIPK2)/tumor protein 53 (TP53) signaling cascade, resulting in enhanced cell cycle progression and increased BRCA cell proliferation. In summary, our findings suggest that chimeric PLEKHB2::FAM168B mRNA may serve as a potential biomarker in BRCA.