The role of chimeric FAM72B transcripts generated by intergenic mRNA trans-splicing in breast cancer

Abstract

Family with sequence similarity 72 (FAM72) is a protein-coding gene family located on chromosome 1 (chr1) in humans, and its functional roles, particularly in cancer, remain incompletely understood. Chimeric messenger RNA (mRNA) generated by intergenic mRNA trans-splicing (CRTS) is a novel phenomenon increasingly recognized for its involvement in cancer biology. It involves the fusion of two separate mRNA transcripts from different genomic loci, resulting in a chimeric mRNA molecule with altered functions. Since aging-related diseases, including various types of cancer, are major threats to our society, we investigated the functional significance of chimeric FAM72 fusion genes and their potential role in cancer cell proliferation with a focus on intergenic mRNA trans-splicing of FAM72 in cancer. We applied biocomputational analyses to identify chimeric FAM72 fusion genes across various cancer tissues. Whole-genome sequencing (WGS) and next-generation sequencing (NGS) of mRNA (RNA-seq) analysis were applied to identify novel chimeric FAM72 fusion genes at the genome (genomic structural variants or SVs) and/or mRNA level (trans-splicing). Our data supported the occurrence of novel chimeric adiponectin receptor-2 (ADIPOR2) :: FAM72B mRNA transcripts primarily produced through an intergenic mRNA trans-splicing event. Afterwards, we set up a breast cancer tissue-specific cell system to analyze the proliferative and migratory efficacy of cancer cells expressing these novel chimeric ADIPOR2::FAM72B mRNA fusion transcripts. Our findings suggest that the novel chimeric ADIPOR2::FAM72B mRNAs, generated by intergenic mRNA trans-splicing, can act as oncogenic drivers and represent promising diagnostic and therapeutic targets in breast cancer.