Integrated genomic analysis reveals mutated ELF3 as a potential gallbladder cancer vaccine candidate

Nat Commun. 2020 Aug 24;11(1):4225. doi: 10.1038/s41467-020-17880-4.

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

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cancer Vaccines / genetics
  • Cancer Vaccines / immunology
  • Chile
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / immunology
  • DNA-Binding Proteins / metabolism
  • Frameshift Mutation*
  • Gallbladder Neoplasms / diagnosis
  • Gallbladder Neoplasms / genetics*
  • Gallbladder Neoplasms / metabolism
  • Gene Expression Profiling / methods
  • Gene Expression Regulation, Neoplastic
  • Genetic Predisposition to Disease / genetics*
  • 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 / genetics*
  • Proto-Oncogene Proteins c-ets / immunology
  • Proto-Oncogene Proteins c-ets / metabolism
  • Republic of Korea
  • Transcription Factors / genetics*
  • Transcription Factors / immunology
  • Transcription Factors / metabolism
  • Wnt Signaling Pathway / genetics
  • beta Catenin / genetics
  • beta Catenin / metabolism

Substances

  • Cancer Vaccines
  • DNA-Binding Proteins
  • ELF3 protein, human
  • KEAP1 protein, human
  • Kelch-Like ECH-Associated Protein 1
  • NF-E2-Related Factor 2
  • Proto-Oncogene Proteins c-ets
  • Transcription Factors
  • beta Catenin