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Nat Genet. 2019 Jan;51(1):175-179. doi: 10.1038/s41588-018-0283-9. Epub 2018 Dec 3.

Accounting for proximal variants improves neoantigen prediction.

Author information

1
McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO, USA.
2
Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, USA.
3
Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA.
4
Department of Surgery, Washington University School of Medicine, St. Louis, MO, USA.
5
Department of Surgery/Otolaryngology, Brigham and Women's Hospital and Dana-Farber Cancer Institute, Boston, MA, USA.
6
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA.
7
Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA.
8
Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, OH, USA. elaine.mardis@nationwidechildrens.org.
9
McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO, USA. mgriffit@wustl.edu.
10
Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, USA. mgriffit@wustl.edu.
11
Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA. mgriffit@wustl.edu.
12
Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA. mgriffit@wustl.edu.

Abstract

Recent efforts to design personalized cancer immunotherapies use predicted neoantigens, but most neoantigen prediction strategies do not consider proximal (nearby) variants that alter the peptide sequence and may influence neoantigen binding. We evaluated somatic variants from 430 tumors to understand how proximal somatic and germline alterations change the neoantigenic peptide sequence and also affect neoantigen binding predictions. On average, 241 missense somatic variants were analyzed per sample. Of these somatic variants, 5% had one or more in-phase missense proximal variants. Without incorporating proximal variant correction for major histocompatibility complex class I neoantigen peptides, the overall false discovery rate (incorrect neoantigens predicted) and the false negative rate (strong-binding neoantigens missed) across peptides of lengths 8-11 were estimated as 0.069 (6.9%) and 0.026 (2.6%), respectively.

PMID:
30510237
PMCID:
PMC6309579
[Available on 2019-06-03]
DOI:
10.1038/s41588-018-0283-9

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