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Blood DOI:10.1182/blood-2014-04-567933

Systematic identification of personal tumor-specific neoantigens in chronic lymphocytic leukemia.

Publication TypeJournal Article
Year of Publication2014
AuthorsRajasagi, M, Shukla, SA, Fritsch, EF, Keskin, DB, DeLuca, D, Carmona, E, Zhang, W, Sougnez, C, Cibulskis, K, Sidney, J, Stevenson, K, Ritz, J, Neuberg, D, Brusic, V, Gabriel, S, Lander, ES, Getz, G, Hacohen, N, Wu, CJ
JournalBlood
Volume124
Issue3
Pages453-62
Date Published2014 Jul 17
ISSN1528-0020
KeywordsAntigens, Neoplasm, Cancer Vaccines, Epitopes, T-Lymphocyte, Exome, Female, HLA Antigens, Humans, Immunologic Memory, Leukemia, Lymphocytic, Chronic, B-Cell, Male, Mutation, Precision Medicine, Protein Binding, T-Lymphocytes, Cytotoxic
Abstract

Genome sequencing has revealed a large number of shared and personal somatic mutations across human cancers. In principle, any genetic alteration affecting a protein-coding region has the potential to generate mutated peptides that are presented by surface HLA class I proteins that might be recognized by cytotoxic T cells. To test this possibility, we implemented a streamlined approach for the prediction and validation of such neoantigens derived from individual tumors and presented by patient-specific HLA alleles. We applied our computational pipeline to 91 chronic lymphocytic leukemias (CLLs) that underwent whole-exome sequencing (WES). We predicted ∼22 mutated HLA-binding peptides per leukemia (derived from ∼16 missense mutations) and experimentally confirmed HLA binding for ∼55% of such peptides. Two CLL patients that achieved long-term remission following allogeneic hematopoietic stem cell transplantation were monitored for CD8(+) T-cell responses against predicted or confirmed HLA-binding peptides. Long-lived cytotoxic T-cell responses were detected against peptides generated from personal tumor mutations in ALMS1, C6ORF89, and FNDC3B presented on tumor cells. Finally, we applied our computational pipeline to WES data (N = 2488 samples) across 13 different cancer types and estimated dozens to thousands of predicted neoantigens per individual tumor, suggesting that neoantigens are frequent in most tumors.

URLhttp://bloodjournal.hematologylibrary.org/cgi/pmidlookup?view=long&pmid=24891321
DOI10.1182/blood-2014-04-567933
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/24891321?dopt=Abstract

Alternate JournalBlood
PubMed ID24891321
PubMed Central IDPMC4102716
Grant List1R01CA155010-02 / CA / NCI NIH HHS / United States
U54 HG003067 / HG / NHGRI NIH HHS / United States
R01 HL103532 / HL / NHLBI NIH HHS / United States
U54HG003067 / HG / NHGRI NIH HHS / United States
P30 CA014051 / CA / NCI NIH HHS / United States
R01 CA183560 / CA / NCI NIH HHS / United States
R01 CA155010 / CA / NCI NIH HHS / United States
5R01HL103532-03 / HL / NHLBI NIH HHS / United States
R01 CA183559 / CA / NCI NIH HHS / United States