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.

Gallbladder cancer incidence shows characteristic geographic patterns. Here the authors perform a genomic analysis of gallbladder cancers in patients from countries with high incidence (South Korea, India and Chile) and identify ELF3 and other significantly mutated genes not previously associated with gallbladder cancer.

Details

Title
Integrated genomic analysis reveals mutated ELF3 as a potential gallbladder cancer vaccine candidate
Author
Pandey Akhilesh 1   VIAFID ORCID Logo  ; Stawiski, Eric W 2 ; Durinck Steffen 3 ; Gowda Harsha 4 ; Goldstein, Leonard D 3 ; Barbhuiya, Mustafa A 5 ; Schröder, Markus S 6 ; Sreenivasamurthy, Sreelakshmi K 7   VIAFID ORCID Logo  ; Sun-Whe, Kim 8 ; Phalke Sameer 9 ; Suryamohan Kushal 10 ; Lee, Kayla 10 ; Chakraborty Papia 10 ; Kode Vasumathi 10 ; Shi Xiaoshan 10 ; Chatterjee Aditi 7   VIAFID ORCID Logo  ; Datta Keshava 7 ; Khan, Aafaque A 7 ; Subbannayya Tejaswini 7 ; Wang, Jing 10 ; Chaudhuri Subhra 11 ; Gupta, Sanjiv 12 ; Shrivastav, Braj Raj 13 ; Jaiswal, Bijay S 11 ; Poojary, Satish S 14 ; Bhunia Shushruta 14 ; Garcia, Patricia 15 ; Bizama Carolina 15 ; Rosa, Lorena 16 ; Kwon Wooil 17 ; Kim Hongbeom 17   VIAFID ORCID Logo  ; Han, Youngmin 17   VIAFID ORCID Logo  ; Yadav Thakur Deen 18 ; Ramprasad, Vedam L 19 ; Chaudhuri Amitabha 10 ; Modrusan Zora 11 ; Roa, Juan Carlos 15 ; Tiwari, Pramod Kumar 14 ; Jin-Young, Jang 20   VIAFID ORCID Logo  ; Seshagiri Somasekar 21   VIAFID ORCID Logo 

1  Institute of Bioinformatics, Bangalore, India (GRID:grid.452497.9) (ISNI:0000 0004 0500 9768); Manipal Academy of Higher Education (MAHE), Manipal, India (GRID:grid.411639.8) (ISNI:0000 0001 0571 5193); Center for Individualized Medicine and Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, USA (GRID:grid.66875.3a) (ISNI:0000 0004 0459 167X) 
2  Bioinformatics and Computational Biology Department, Genentech Inc, South San Francisco, USA (GRID:grid.418158.1) (ISNI:0000 0004 0534 4718); Genentech Inc., Molecular Biology Department, South San Francisco, USA (GRID:grid.418158.1) (ISNI:0000 0004 0534 4718); Research and Development Department, MedGenome Inc, Foster City, USA (GRID:grid.34474.30) (ISNI:0000 0004 0370 7685) 
3  Bioinformatics and Computational Biology Department, Genentech Inc, South San Francisco, USA (GRID:grid.418158.1) (ISNI:0000 0004 0534 4718); Genentech Inc., Molecular Biology Department, South San Francisco, USA (GRID:grid.418158.1) (ISNI:0000 0004 0534 4718) 
4  Institute of Bioinformatics, Bangalore, India (GRID:grid.452497.9) (ISNI:0000 0004 0500 9768); QIMR Berghofer Medical Research Institute, Brisbane, Australia (GRID:grid.1049.c) (ISNI:0000 0001 2294 1395) 
5  Institute of Bioinformatics, Bangalore, India (GRID:grid.452497.9) (ISNI:0000 0004 0500 9768); Pennsylvania State University College of Medicine, Department of Pathology and Laboratory Medicine, Hershey, USA (GRID:grid.29857.31) (ISNI:0000 0001 2097 4281) 
6  Genentech Inc., Molecular Biology Department, South San Francisco, USA (GRID:grid.418158.1) (ISNI:0000 0004 0534 4718); SciGenom Labs, Cochin, India (GRID:grid.452841.e) 
7  Institute of Bioinformatics, Bangalore, India (GRID:grid.452497.9) (ISNI:0000 0004 0500 9768) 
8  Division of Hepatobiliary and Pancreatic Surgery, Seoul National University Hospital, Seoul National University College of Medicine, Department of Surgery, Seoul, South Korea (GRID:grid.452497.9) 
9  MedGenome Labs Pvt. Ltd., Research and Development Department, Bangalore, India (GRID:grid.452497.9) 
10  Research and Development Department, MedGenome Inc, Foster City, USA (GRID:grid.34474.30) (ISNI:0000 0004 0370 7685) 
11  Genentech Inc., Molecular Biology Department, South San Francisco, USA (GRID:grid.418158.1) (ISNI:0000 0004 0534 4718) 
12  Cancer Hospital and Research Institute, Department of Pathology, Gwalior, India (GRID:grid.479673.8) 
13  Cancer Hospital and Research Institute, Department of Surgical Oncology, Gwalior, India (GRID:grid.479673.8) 
14  Jiwaji University, Gwalior, India (GRID:grid.411913.f) (ISNI:0000 0000 9081 2096) 
15  Millennium Institute on Immunology and Immunotherapy, School of Medicine, Pontificia Universidad Católica de Chile, Department of Pathology, Santiago, Chile (GRID:grid.7870.8) (ISNI:0000 0001 2157 0406) 
16  Applied Molecular and Cellular Biology PhD Program Universidad De la Frontera, Temuco, Chile (GRID:grid.412163.3) (ISNI:0000 0001 2287 9552) 
17  Division of Hepatobiliary and Pancreatic Surgery, Seoul National University Hospital, Seoul National University College of Medicine, Department of Surgery, Seoul, South Korea (GRID:grid.412163.3) 
18  Postgraduate Institute of Medical Education and Research, Department of Surgery, Chandigarh, India (GRID:grid.415131.3) (ISNI:0000 0004 1767 2903) 
19  MedGenome Labs Pvt. Ltd., Research and Development Department, Bangalore, India (GRID:grid.415131.3) 
20  Division of Hepatobiliary and Pancreatic Surgery, Seoul National University Hospital, Seoul National University College of Medicine, Department of Surgery, Seoul, South Korea (GRID:grid.411913.f) 
21  Genentech Inc., Molecular Biology Department, South San Francisco, USA (GRID:grid.418158.1) (ISNI:0000 0004 0534 4718); SciGenom Research Foundation, 3rd Floor, Narayana Nethralaya Building, Narayana Health City, Bangalore, India (GRID:grid.418158.1) 
Publication year
2020
Publication date
2020
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-020-17880-4
ProQuest document ID
2436698067
Copyright
© The Author(s) 2020. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.