SpliceHetero: An information theoretic approach for measuring spliceomic intratumor heterogeneity from bulk tumor RNA-seq

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...

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Bibliographic Details
Published in:PloS one 2019-10, Vol.14 (10), p.e0223520-e0223520
Main Authors: Kim, Minsu, Lee, Sangseon, Lim, Sangsoo, Kim, Sun
Format: Article
Language:English
Subjects:
Algorithms
Bioinformatics
Biology and Life Sciences
Biomarkers, Tumor
Breast cancer
Cancer
Computational Biology - methods
Computer science
Copy number
Deoxyribonucleic acid
Diagnostic software
Diagnostic systems
DNA
DNA Copy Number Variations
DNA methylation
Evolution
Gene expression
Gene sequencing
Genetic diversity
Genetic Heterogeneity
Genomes
Heterogeneity
High-Throughput Nucleotide Sequencing
Humans
Information theory
Interdisciplinary aspects
Levels
Linear programming
Medicine and Health Sciences
Mutation
Neoplasms - genetics
Neoplasms - metabolism
Probability distribution
Reproducibility of Results
Research and analysis methods
Ribonucleic acid
RNA
RNA Splicing
Sequence Analysis, RNA
Spliceosomes
Splicing
Studies
Tumors
Xenografts
Xenotransplantation
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Summary: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. 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.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0223520