The Cancer Exome Generated by Alternative mRNA Splicing Dilutes Predicted HLA Class I Epitope Density

Thomas Stranzl, Mette Voldby Larsen, Ole Lund, Morten Nielsen, Søren Brunak

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    Abstract

    Several studies have shown that cancers actively regulate alternative splicing. Altered splicing mechanisms in cancer lead to cancer-specific transcripts different from the pool of transcripts occurring only in healthy tissue. At the same time, altered presentation of HLA class I epitopes is frequently observed in various types of cancer. Down-regulation of genes related to HLA class I antigen processing has been observed in several cancer types, leading to fewer HLA class I antigens on the cell surface. Here, we use a peptidome wide analysis of predicted alternative splice forms, based on a publicly available database, to show that peptides over-represented in cancer splice variants comprise significantly fewer predicted HLA class I epitopes compared to peptides from normal transcripts. Peptides over-represented in cancer transcripts are in the case of the three most common HLA class I supertype representatives consistently found to contain fewer predicted epitopes compared to normal tissue. We observed a significant difference in amino acid composition between protein sequences associated with normal versus cancer tissue, as transcripts found in cancer are enriched with hydrophilic amino acids. This variation contributes to the observed significant lower likelihood of cancer-specific peptides to be predicted epitopes compared to peptides found in normal tissue.
    Original languageEnglish
    JournalP L o S One
    Volume7
    Issue number9
    Pages (from-to)e38670
    Number of pages8
    ISSN1932-6203
    Publication statusPublished - 2012

    Bibliographical note

    This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for
    any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

    This work was supported by a grant from the Danish Research Council for Technology and Production Sciences (Project ‘‘Disease Gene Finding,
    Somatic Mutations, and Vaccine Design’’; principal funding recipient, Søren Brunak) and was supported by the National Institutes of Health (contract
    HHSN26620040006C). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

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