The localization of pre mRNA splicing factor PRPF38B is a novel prognostic biomarker that may predict survival benefit of trastuzumab in patients with breast cancer overexpressing HER2

Abstract

Cancer biomarkers that can define disease status and provide a prognostic insight are essential for the effective management of patients with breast cancer (BC).The prevalence, clinicopathological and prognostic significance of PRPF38B expression in a consecutive series of 1650 patients with primary invasive breast carcinoma were examined using immunohistochemistry. Furthermore, the relationship(s) between clinical outcome and PRPF38B expression was explored in 627 patients with ER-negative (oestrogen receptor) disease, and 322 patients with HER2-overexpressing disease.Membranous expression of PRPF38B was observed in 148/1388 (10.7%) cases and was significantly associated with aggressive clinicopathological features, including high grade, high mitotic index, pleomorphism, invasive ductal carcinoma of no specific type (IDC-NST), ER-negative, HER2-overexpression and p53 mutational status (all p < 0.01). In patients with ER-negative disease receiving chemotherapy, nuclear expression of PRPF38B was significantly associated with a reduced risk of relapse (p = 0.0004), whereas membranous PRPF38B expression was significantly associated with increased risk of relapse (p = 0.004; respectively) at a 5 year follow-up. When patients were stratified according to ER-negative/HER2-positive status, membranous PRPF38B expression was associated with a higher risk of relapse in those patients that did not receive trastuzumab therapy (p = 0.02), whereas in those patients with ER-negative/HER2-positive disease that received trastuzumab adjuvant therapy, membranous PRPF38B expression associated with a lower risk of relapse (p = 0.00018).Nuclear expression of PRPF38B is a good prognostic indicator in both ER-negative patients and ER-negative/HER2-positive BC (breast cancer) patients, whereas membranous localisation of PRPF38B is a poor prognostic biomarker that predicts survival benefit from trastuzumab therapy in patients with ER-negative/HER2-overexpressing BC.

Unsupervised reference-free inference reveals unrecognized regulated transcriptomic complexity in human single cells

“…Splicing factors SRSF10 and RBM39 (each found in 17 tissues) were also highly ranked, having 16 and 28 splice variants, respectively, and are all associated with tumor initiation or growth (Kim et al 2015; Xu et al 2021; Shkreta et al 2021). For PRPF38B , a splicing factor with prognostic biomarker potential in breast cancer (Abdel-Fatah et al 2017), 17 distinct splice junctions were detected (across all of its anchors) in 17 tissues. One of its anchors shows compactors with complex alternative splicing involving skipping of two cassette exons, alternative 5’ splice sites, intron retention, and a novel splice junction, which is the dominant isoform in 4 immune and stromal cells (Figure 4H).…”