Pervasive Enhanced Transcription in Inflammatory Breast Cancer Tumors and PBMCs Impacts RNA Splicing and Intronic RNAs in Plasma

Inflammatory breast cancer (IBC), the most aggressive and lethal breast cancer subtype, lacks unequivocal genomic differences or robust biomarkers that differentiate it from non-IBC. Here, Thermostable Group II Intron Reverse Transcriptase sequencing of RNA samples revealed myriad differences in tumors, PBMCs, and plasma that distinguished IBC from non-IBC patients and healthy donors across all tested non-IBC subtypes. By mapping reads to genome and transcriptome reference sequences and quantitating intron-to-exon read depth ratios, we developed methods for parallel analysis of transcriptional and post-transcriptional gene regulation. This analysis identified numerous protein-coding genes in IBC patient tumors and PBMCs with high intron-to-exon read depths, suggesting rate-limiting RNA splicing that negatively impacts mRNA production. Mirroring gene expression differences in tumors and PBMCs, over-represented protein-coding gene RNAs in IBC patient plasma were largely intron RNA fragments, while those in non-IBC patient and healthy donor plasma were largely mRNA fragments. Our findings provide new insights into IBC and should enable monitoring disease progression by liquid biopsy.