Towards resolution of the intron retention paradox in breast cancer

Abstract

Background After many years of neglect in the field of alternative splicing, the importance of intron retention (IR) in cancer has come into focus following landmark discoveries of aberrant IR patterns in cancer. Many solid and liquid tumours are associated with drastic increases in IR, and such patterns have been pursued as both biomarkers and therapeutic targets. Paradoxically, breast cancer (BrCa) is the only tumour type in which IR is reduced compared to adjacent normal breast tissue. Methods In this study, we have conducted a pan-cancer analysis of IR with emphasis on BrCa and its subtypes. We explored mechanisms that could cause aberrant and pathological IR and clarified why normal breast tissue has unusually high IR. Results Strikingly, we found that aberrantly decreasing IR in BrCa can be largely attributed to normal breast tissue having the highest occurrence of IR events compared to other healthy tissues. Our analyses suggest that low numbers of IR events in breast tumours are associated with poor prognosis, particularly in the luminal B subtype. Interestingly, we found that IR frequencies negatively correlate with cell proliferation in BrCa cells, i.e. rapidly dividing tumour cells have the lowest number of IR events. Aberrant RNA-binding protein expression and changes in tissue composition are among the causes of aberrantly decreasing IR in BrCa. Conclusions Our results suggest that IR should be considered for therapeutic manipulation in BrCa patients with aberrantly low IR levels and that further work is needed to understand the cause and impact of high IR in other tumour types.

RNA-seq–based miRNA signature as an independent predictor of relapse in pediatric B-cell acute lymphoblastic leukemia

“…Many malignancies are characterized by increased IR; however, we found (unexpectedly) that the MLC had lower levels of IR than the non-MLC and normal B-cell precursors. Decreased IR has been reported in SF3B1 -mutated myelodysplastic syndrome 51 and breast cancer 52 , and an inverse relationship between IR and cell proliferation has been observed during B-cell development. 53 Reduced IR in the MLC is presumably due to altered expression of spliceosome components through dysregulated miRNAs or to increased MYC activity.…”

Association of Genetic Markers with the Risk of Early-Onset Breast Cancer in Kazakh Women

“…Although, intronic sequences are poorly understood, there is evidence demonstrating mechanisms of intronic variants cause diseases and cancer. Variations in the canonical splice sequences, deep intronic variants, and intron retention variants may cause abnormal splicing [31,32]. They may account for 15-60% of human diseases [33].…”