Pervasive enhanced transcription in inflammatory breast cancer tumors and PBMCs impacts RNA splicing and intronic RNAs in plasma
- Dennis Wylie
- Xiaoping Wang
- Jun Yao
- Hengyi Xu
- Elizabeth A. Ferrick-Kiddie
- Toshiaki Iwase
- Savitri Krishnamurthy
- Naoto T. Ueno
- Alan M. Lambowitz
2026-05-01
Inflammatory breast cancer (IBC), an aggressive and lethal breast cancer subtype, lacks unequivocal genomic differences or robust biomarkers that differentiate it from non-IBC. Here, TGIRT-seq revealed myriad differences in tumors, PBMC, and plasma RNAs that distinguished IBC patients from non-IBC patients and healthy donors across different tested breast cancer subtypes. By mapping reads to genome and transcriptome reference sequences and quantitating intron-to-exon read depth ratios (IDRs), we developed methods for parallel analysis of transcriptional and posttranscriptional gene regulation. This analysis identified numerous protein-coding genes in IBC patient tumors and PBMCs with high IDRs, suggesting rate-limiting RNA splicing that decreases mRNA production. Mirroring gene expression differences in tumors and PBMCs, overrepresented 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 insights into IBC and should enable monitoring disease progression by liquid biopsy.