INAEME: Integral Neoantigen Analysis with Entirety of Mutational Events

  1. Vladimir Kovacevic
  2. Ognjen S. Milicevic
  3. Nevena M. Ilic Raicevic
  4. Milica Kojicic
  5. Ana Mijalkovic Lazic
  6. Nikola Skundric
  7. Jack DiGiovanna

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Abstract

Neoantigens are peptides on the surface of cancer cells presented to the immune system. Multiple novel therapeutic approaches involve the administration of neoantigens to trigger immunity-induced tumor regression. Identification of neoantigens includes a personalized approach consisting of detailed analyses of the sequenced tumor tissue and its comparison with wild type to identify somatic mutations. Alternated peptides are translated from nucleotides around somatic mutations and their binding affinity and immunogenicity need to be further evaluated. Still, the entire bioinformatics analysis is very complex, and accurate prediction of the neoantigen candidates represents a true challenge. Here, we present the novel, integral bioinformatic analysis workflow for neoantigen discovery, denoted INAEME (Integral Neoantigen Analysis with Entirety of Mutational Events). The workflow performs integral processing of an individual’s DNA tumor-normal and RNA tumor raw reads to output prioritized neoantigen candidates. Our evaluation analysis includes a wide scope of mutational events so far not considered in the existing solutions, including phasing of variants, influence of both somatic and germline variants, positions of all transcripts, neighboring variants, and frameshifts. The influence of each mutational event on the accuracy of predicted neoantigen candidates is tested across 300 TCGA samples from multiple cancer types. The obtained results have demonstrated the significance of considering the entirety of mutational events to obtain an accurate set of strong neoantigen candidates for cancer immunotherapy targets or vaccines. The adaption of the described methods in the bioinformatics analysis minimizes the existence of false positives which are only later discovered in a laboratory environment using expensive methods such as mass spectrometry or microscopy.

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  1. PREreview

    This Zenodo record is a permanently preserved version of a Structured PREreview. You can view the complete PREreview at https://prereview.org/reviews/11075706.

    Does the introduction explain the objective of the research presented in the preprint? Partly Early in the abstract, the authors talk about neoantigens are and they move on to neoantigen discovery. If they can include what is neoantigen discovery, how it is useful, then the information flow will be much more natural. I do see a much detailed and beautiful explanation of the background in the introduction. However, after describing some of the other tools that exist out there, the authors do not mention in detail what they attempted and how in the introduction.
    Are the methods well-suited for this research? Somewhat appropriate The precision and recall curves seem noisy. The knee portions of the curves do not have sufficient data.
    Are the conclusions supported by the data? Highly supported
    Are the data presentations, including visualizations, well-suited to represent the data? Somewhat appropriate and clear I applaud the authors' work in trying to get the truth datasaet through the TESLA challenge. A confusion matrix to present the results would probably be more appropriate here.
    How clearly do the authors discuss, explain, and interpret their findings and potential next steps for the research? Somewhat clearly The entire paper has been written well with clear and concise explanation. However, it would be useful to see what the authors think the weakness in their tool is and what the next steps would be.
    Is the preprint likely to advance academic knowledge? Highly likely
    Would it benefit from language editing? No There are a few typos and in couple of places consecutive commas in between words. However, it does not hinder the understanding of the paper.
    Would you recommend this preprint to others? Yes, it's of high quality
    Is it ready for attention from an editor, publisher or broader audience? Yes, after minor changes 1. Just a few grammatical minor errors. 2. A confusion matrix when challenged against truth dataset. 3. A small blurb on what is missing in the algorithm currently and what the next steps would be.

    Competing interests

    The author declares that they have no competing interests.

  2. Version published to 10.1101/2023.09.28.559901v2 on bioRxiv
  3. Version published to 10.1101/2023.09.28.559901v1 on bioRxiv