Abstract
This study probes the distribution of putatively cancer-specific junctions across a broad set of publicly available non-cancer human RNA sequencing (RNA-seq) datasets. We compared cancer and non-cancer RNA-seq data from The Cancer Genome Atlas (TCGA), the Genotype-Tissue Expression (GTEx) Project and the Sequence Read Archive. We found that (i) averaging across cancer types, 80.6% of exon–exon junctions thought to be cancer-specific based on comparison with tissue-matched samples (σ = 13.0%) are in fact present in other adult non-cancer tissues throughout the body; (ii) 30.8% of junctions not present in any GTEx or TCGA normal tissues are shared by multiple samples within at least one cancer type cohort, and 87.4% of these distinguish between different cancer types; and (iii) many of these junctions not found in GTEx or TCGA normal tissues (15.4% on average, σ = 2.4%) are also found in embryological and other developmentally associated cells. These findings refine the meaning of RNA splicing event novelty, particularly with respect to the human neoepitope repertoire. Ultimately, cancer-specific exon–exon junctions may have a substantial causal relationship with the biology of disease.
Highlights
IntroductionAberrant RNA splicing is increasingly recognized as a feature of malignancy (Climente-González et al, 2017; Sebestyén et al, 2015; Srebrow and Kornblihtt, 2006; Sveen et al, 2016; Xiong et al, 2015), with potential prognostic significance across many cancer types including non-small cell lung cancer, ovarian cancer, breast cancer, colorectal cancer, uveal melanoma, and glioblastoma (Bjørklund et al, 2017; Li et al, 2017; Marcelino Meliso et al, 2017; Robertson et al, 2018; Zhu et al, 2018; Zong et al, 2018)
Cancers harbor many novel shared exon-exon junctions not present in adult non-cancer tissues or cells While cancer-specific exon-exon junctions identified using tissue-matched normal samples have the potential to give rise to neoantigens (Kahles et al, 2018), we reasoned that they could be expressed in other normal tissues due to variability in patterns of transcription and alternative splicing among different tissues (Saha et al, 2017)
We found that on average, across cancer types, 80.6% of junctions thought to be cancer-specific based on comparison only with tissuematched samples are present in other adult non-cancer tissues and cell types throughout the body
Summary
Aberrant RNA splicing is increasingly recognized as a feature of malignancy (Climente-González et al, 2017; Sebestyén et al, 2015; Srebrow and Kornblihtt, 2006; Sveen et al, 2016; Xiong et al, 2015), with potential prognostic significance across many cancer types including non-small cell lung cancer, ovarian cancer, breast cancer, colorectal cancer, uveal melanoma, and glioblastoma (Bjørklund et al, 2017; Li et al, 2017; Marcelino Meliso et al, 2017; Robertson et al, 2018; Zhu et al, 2018; Zong et al, 2018). Due to its potential for generating novel peptide sequences, aberrant RNA splicing is interesting as a potential source of neoantigens for cancer immunotherapy targeting. Retained intronic sequences can give rise to numerous potential antigens among patients with melanoma, they are not a significant predictor of cancer immunotherapy response (Smart et al, 2018), and a patient-specific neoantigen arising from a gene fusion has been shown to lead to complete response from immune checkpoint blockade (Yang et al, 2019). Prediction of cancer-specific antigens depends explicitly on their sequence novelty, and requires a comparison with non-cancer cells
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
