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

Akhilesh Pandey; Eric W Stawiski; Steffen Durinck; Harsha Gowda; Leonard D Goldstein; Mustafa A Barbhuiya; Markus S Schröder; Sreelakshmi K Sreenivasamurthy; Sun-Whe Kim; Sameer Phalke; Kushal Suryamohan; Kayla Lee; Papia Chakraborty; Vasumathi Kode; Xiaoshan Shi; Aditi Chatterjee; Keshava Datta; Aafaque A Khan; Tejaswini Subbannayya; Jing Wang; Subhra Chaudhuri; Sanjiv Gupta; Braj Raj Shrivastav; Bijay S Jaiswal; Satish S Poojary; Shushruta Bhunia; Patricia Garcia; Carolina Bizama; Lorena Rosa; Wooil Kwon; Hongbeom Kim; Youngmin Han; Thakur Deen Yadav; Vedam L Ramprasad; Amitabha Chaudhuri; Zora Modrusan; Juan Carlos Roa; Pramod Kumar Tiwari; Jin-Young Jang; Somasekar Seshagiri

doi:10.1038/s41467-020-17880-4

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.

Authors

Akhilesh Pandey^#^{1

2

3}, Eric W Stawiski^#^{4

5

6}, Steffen Durinck^#^{7

8}, Harsha Gowda^#^{9

10}, Leonard D Goldstein^{7

8}, Mustafa A Barbhuiya^{9

11}, Markus S Schröder^{8

12}, Sreelakshmi K Sreenivasamurthy⁹, Sun-Whe Kim¹³, Sameer Phalke¹⁴, Kushal Suryamohan¹⁵, Kayla Lee¹⁵, Papia Chakraborty¹⁵, Vasumathi Kode¹⁵, Xiaoshan Shi¹⁵, Aditi Chatterjee⁹, Keshava Datta⁹, Aafaque A Khan⁹, Tejaswini Subbannayya⁹, Jing Wang¹⁵, Subhra Chaudhuri⁸, Sanjiv Gupta¹⁶, Braj Raj Shrivastav¹⁷, Bijay S Jaiswal⁸, Satish S Poojary¹⁸, Shushruta Bhunia¹⁸, Patricia Garcia¹⁹, Carolina Bizama¹⁹, Lorena Rosa²⁰, Wooil Kwon¹³, Hongbeom Kim¹³, Youngmin Han¹³, Thakur Deen Yadav²¹, Vedam L Ramprasad¹⁴, Amitabha Chaudhuri¹⁵, Zora Modrusan⁸, Juan Carlos Roa¹⁹, Pramod Kumar Tiwari¹⁸, Jin-Young Jang²², Somasekar Seshagiri^{23

24}

Affiliations

¹ Institute of Bioinformatics, Bangalore, Karnataka, 560066, India. [email protected].
² Manipal Academy of Higher Education (MAHE), Manipal, Karnataka, 576104, India. [email protected].
³ Center for Individualized Medicine and Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, 55905, USA. [email protected].
⁴ Bioinformatics and Computational Biology Department, Genentech Inc, South San Francisco, CA, 94080, USA. [email protected].
⁵ Molecular Biology Department, Genentech Inc., South San Francisco, CA, 94080, USA. [email protected].
⁶ Research and Development Department, MedGenome Inc, Foster City, CA, 94404, USA. [email protected].
⁷ Bioinformatics and Computational Biology Department, Genentech Inc, South San Francisco, CA, 94080, USA.
⁸ Molecular Biology Department, Genentech Inc., South San Francisco, CA, 94080, USA.
⁹ Institute of Bioinformatics, Bangalore, Karnataka, 560066, India.
¹⁰ QIMR Berghofer Medical Research Institute, Brisbane, QLD, 4006, Australia.
¹¹ Department of Pathology and Laboratory Medicine, Pennsylvania State University College of Medicine, Hershey, PA, 17033, USA.
¹² SciGenom Labs, Cochin, Kerala, 682037, India.
¹³ Department of Surgery, Division of Hepatobiliary and Pancreatic Surgery, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, 08826, South Korea.
¹⁴ Research and Development Department, MedGenome Labs Pvt. Ltd., Bangalore, Karnataka, 560099, India.
¹⁵ Research and Development Department, MedGenome Inc, Foster City, CA, 94404, USA.
¹⁶ Department of Pathology, Cancer Hospital and Research Institute, Gwalior, Madhya Pradesh, 474009, India.
¹⁷ Department of Surgical Oncology, Cancer Hospital and Research Institute, Gwalior, Madhya Pradesh, 474009, India.
¹⁸ Jiwaji University, Gwalior, Madhya Pradesh, 474011, India.
¹⁹ Department of Pathology, Millennium Institute on Immunology and Immunotherapy, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.
²⁰ Applied Molecular and Cellular Biology PhD Program Universidad De la Frontera, Temuco, Chile.
²¹ Department of Surgery, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012, India.
²² Department of Surgery, Division of Hepatobiliary and Pancreatic Surgery, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, 08826, South Korea. [email protected].
²³ Molecular Biology Department, Genentech Inc., South San Francisco, CA, 94080, USA. [email protected].
²⁴ SciGenom Research Foundation, 3rd Floor, Narayana Nethralaya Building, Narayana Health City, #258/A, Bommasandra, Hosur Road, Bangalore, Karnataka, 560099, India. [email protected].

^# Contributed equally.

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
Indien
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

Abstract

Publication types

MeSH terms

Substances

Grants and funding