1. Integrated genomic analysis reveals mutated ELF3 as a potential gallbladder cancer vaccine candidate.
- Author
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Pandey A, Stawiski EW, Durinck S, Gowda H, Goldstein LD, Barbhuiya MA, Schröder MS, Sreenivasamurthy SK, Kim SW, Phalke S, Suryamohan K, Lee K, Chakraborty P, Kode V, Shi X, Chatterjee A, Datta K, Khan AA, Subbannayya T, Wang J, Chaudhuri S, Gupta S, Shrivastav BR, Jaiswal BS, Poojary SS, Bhunia S, Garcia P, Bizama C, Rosa L, Kwon W, Kim H, Han Y, Yadav TD, Ramprasad VL, Chaudhuri A, Modrusan Z, Roa JC, Tiwari PK, Jang JY, and Seshagiri S
- Subjects
- Cancer Vaccines genetics, Cancer Vaccines immunology, Chile, DNA-Binding Proteins immunology, DNA-Binding Proteins metabolism, Gallbladder Neoplasms diagnosis, Gallbladder Neoplasms metabolism, Gene Expression Profiling methods, Gene Expression Regulation, Neoplastic, Genomics methods, Humans, India, Kelch-Like ECH-Associated Protein 1 genetics, Kelch-Like ECH-Associated Protein 1 metabolism, NF-E2-Related Factor 2 genetics, NF-E2-Related Factor 2 metabolism, Proto-Oncogene Proteins c-ets immunology, Proto-Oncogene Proteins c-ets metabolism, Republic of Korea, Transcription Factors immunology, Transcription Factors metabolism, Wnt Signaling Pathway genetics, beta Catenin genetics, beta Catenin metabolism, DNA-Binding Proteins genetics, Frameshift Mutation, Gallbladder Neoplasms genetics, Genetic Predisposition to Disease genetics, Proto-Oncogene Proteins c-ets genetics, Transcription Factors genetics
- 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.
- Published
- 2020
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