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.
Highlights
Gallbladder cancer (GBC) is an aggressive gastrointestinal malignancy with no approved targeted therapy
To search for additional genes that may be involved in pathway activation, we considered significantly mutated GBC genes or known cancerassociated genes recurrently mutated in our data set and tested for overrepresentation among NRF2+ patients
We found somatic mutations in cholecystitis that were indicative of a premalignant stage
Summary
Gallbladder cancer (GBC) is an aggressive gastrointestinal malignancy with no approved targeted therapy. 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. GBC is a highly fatal malignancy with median survival of
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