Open AccessSpliceHetero: An information theoretic approach for measuring spliceomic intratumor heterogeneity from bulk tumor RNA-seq
Author(s) -
Minsu Kim,
Sangseon Lee,
Sangsoo Lim
Publication year - 2019
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0223520
Subject(s) - transcriptome , tumor heterogeneity , cancer , rna splicing , alternative splicing , computational biology , somatic cell , biology , rna , rna seq , gene , bioinformatics , genetics , gene expression , messenger rna
Motivation Intratumor heterogeneity (ITH) represents the diversity of cell populations that make up cancer tissue. The level of ITH in a tumor is usually measured by a genomic variation profile, such as copy number variation and somatic mutation. However, a recent study has identified ITH at the transcriptome level and suggested that ITH at gene expression levels is useful for predicting prognosis. Measuring ITH levels at the spliceome level is a natural extension. There are serious technical challenges in measuring spliceomic ITH (sITH) from bulk tumor RNA sequencing (RNA-seq) due to the complex splicing patterns. Results We propose an information-theoretic method to measure the sITH of bulk tumors to overcome the above challenges. This method has been extensively tested in experiments using synthetic data, xenograft tumor data, and TCGA pan-cancer data. As a result, we showed that sITH is closely related to cancer progression and clonal heterogeneity, along with clinically significant features such as cancer stage, survival outcome and PAM50 subtype. As far as we know, it is the first study to define ITH at the spliceome level. This method can greatly improve the understanding of cancer spliceome and has great potential as a diagnostic and prognostic tool.