Abstract
Gallbladder cancer (GBC) is an aggressive gastrointestinal malignancy with no approved targeted therapy. Here, we analyze exomes (n = 160), transcriptomes (n = 115), and low pass whole genomes (n = 146) from 167 gallbladder cancers (GBCs) from patients in Korea, India and Chile. In addition, we also sequence samples from 39 GBC high-risk patients and detect evidence of early cancer-related genomic lesions. Among the several significantly mutated genes not previously linked to GBC are ETS domain genes ELF3 and EHF, CTNNB1, APC, NSD1, KAT8, STK11 and NFE2L2. A majority of ELF3 alterations are frame-shift mutations that result in several cancer-specific neoantigens that activate T-cells indicating that they are cancer vaccine candidates. In addition, we identify recurrent alterations in KEAP1/NFE2L2 and WNT pathway in GBC. Taken together, these define multiple targetable therapeutic interventions opportunities for GBC treatment and management.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Cancer Vaccines / genetics
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Cancer Vaccines / immunology
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Chile
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DNA-Binding Proteins / genetics*
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DNA-Binding Proteins / immunology
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DNA-Binding Proteins / metabolism
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Frameshift Mutation*
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Gallbladder Neoplasms / diagnosis
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Gallbladder Neoplasms / genetics*
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Gallbladder Neoplasms / metabolism
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Gene Expression Profiling / methods
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Gene Expression Regulation, Neoplastic
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Genetic Predisposition to Disease / genetics*
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Genomics / methods
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Humans
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India
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Kelch-Like ECH-Associated Protein 1 / genetics
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Kelch-Like ECH-Associated Protein 1 / metabolism
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NF-E2-Related Factor 2 / genetics
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NF-E2-Related Factor 2 / metabolism
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Proto-Oncogene Proteins c-ets / genetics*
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Proto-Oncogene Proteins c-ets / immunology
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Proto-Oncogene Proteins c-ets / metabolism
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Republic of Korea
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Transcription Factors / genetics*
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Transcription Factors / immunology
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Transcription Factors / metabolism
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Wnt Signaling Pathway / genetics
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beta Catenin / genetics
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beta Catenin / metabolism
Substances
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Cancer Vaccines
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DNA-Binding Proteins
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ELF3 protein, human
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KEAP1 protein, human
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Kelch-Like ECH-Associated Protein 1
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NF-E2-Related Factor 2
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Proto-Oncogene Proteins c-ets
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Transcription Factors
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beta Catenin