Transcriptome sequencing of human breast cancer reveals aberrant intronic transcription in amplicons and dysregulation of alternative splicing with major therapeutic implications

Abstract

Abstract. Advances in genomic and transcriptome sequencing are revealing the massive scale of previously unrecognised alterations occurring during neoplastic transformation. Breast cancers are genetically and phenotypically heterogeneous. Each of the three major subtypes [ERBB2 amplified, estrogen receptor (ESR)-positive and triple-negative] poses diagnostic and therapeutic challenges. Here we show, using highresolution next-generation transcriptome sequencing, that in all three breast cancer subtypes, but not matched controls, there was significant overexpression of transcripts from intronic and untranslated regions in addition to exons from specific genes, particularly amplified oncogenes and hormone receptors. For key genes ERBB2 and ESR1, we demonstrate that overexpression is linked to the production of highly modified and truncated splice variants in tumours, but not controls, correlated with tumour subtype. Translation of these tumour-specific splice variants generates truncated proteins with altered subcellular locations and functions, modifying the phenotype, affecting tumour biology, and targeted antitumour therapies. In contrast, tumour suppressors TP53, BRCA1/2 and NF1 did not show intronic overexpression or truncated splice variants in cancers. These findings emphasize the detection of intronic as well as exonic changes in the transcriptional landscapes of cancers have profound therapeutic implications.

Androgen and estrogen sensitivity of bird song: a comparative view on gene regulatory levels

“…Splice variants of the AR and ESR1 are frequently found in prostata (Wadosky and Koochekpour 2016 ; Karantanos et al 2015 ) and breast cancer (Hu et al 2014 ; Forootan et al 2016 ), but are as well found in the brain of mammals including humans (Hu et al 2014 ; Ishunina et al 2013 ; Kundu et al 2015 ). AR splice variants have not been analyzed in birds.…”

Analysis of RANK-c interaction partners identifies TRAF3 as a critical regulator of breast cancer aggressiveness

“…Alternative splicing generates multiple gene transcripts and consequently relevant protein isoforms, expanding biological complexity and protein functionality [35] . Several splicing events in breast cancer modulate disease biology and progression [ 36 , 37 ]. We have previously identified RANK-c as an alternatively spliced transcript of the TNFRSF11A gene with a role in NF-κB regulation and breast cancer aggressiveness [20] .…”

A Single-Subject Method to Detect Pathways Enriched With Alternatively Spliced Genes

“…Most RNA-Seq analytics ignore alternative splicing patterns despite recent evidence that alternative splicing is implicated in nearly a third of common diseases. In cancer, a tumor often displays dysregulation of the cellular machinery that controls alternative splicing (Yoshida et al, 2011; Kaida et al, 2012; Ladomery, 2013; Forootan et al, 2016). Yet, the clinical interpretation of alternative splicing patterns lies largely unexplored.…”