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

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.

SUBMITTER: Pandey A

PROVIDER: S-EPMC7445288 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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

Pandey Akhilesh A Stawiski Eric W EW Durinck Steffen S Gowda Harsha H Goldstein Leonard D LD Barbhuiya Mustafa A MA Schröder Markus S MS Sreenivasamurthy Sreelakshmi K SK Kim Sun-Whe SW Phalke Sameer S Suryamohan Kushal K Lee Kayla K Chakraborty Papia P Kode Vasumathi V Shi Xiaoshan X Chatterjee Aditi A Datta Keshava K Khan Aafaque A AA Subbannayya Tejaswini T Wang Jing J Chaudhuri Subhra S Gupta Sanjiv S Shrivastav Braj Raj BR Jaiswal Bijay S BS Poojary Satish S SS Bhunia Shushruta S Garcia Patricia P Bizama Carolina C Rosa Lorena L Kwon Wooil W Kim Hongbeom H Han Youngmin Y Yadav Thakur Deen TD Ramprasad Vedam L VL Chaudhuri Amitabha A Modrusan Zora Z Roa Juan Carlos JC Tiwari Pramod Kumar PK Jang Jin-Young JY Seshagiri Somasekar S

Nature communications 20200824 1

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 ...[more]

PMID: 32839463

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Project description:Breast cancer (BC) is the leading malignancy in women worldwide, yet relatively little is known about the genes and signaling pathways involved in BC tumorigenesis and progression. The present study aimed to elucidate potential key candidate genes and pathways in BC. Five gene expression profile data sets (GSE22035, GSE3744, GSE5764, GSE21422 and GSE26910) were downloaded from the Gene Expression Omnibus (GEO) database, which included data from 113 tumorous and 38 adjacent non?tumorous tissue samples. Differentially expressed genes (DEGs) were identified using t?tests in the limma R package. These DEGs were subsequently investigated by pathway enrichment analysis and a protein?protein interaction (PPI) network was constructed. The most significant module from the PPI network was selected for pathway enrichment analysis. In total, 227 DEGs were identified, of which 82 were upregulated and 145 were downregulated. Pathway enrichment analysis results revealed that the upregulated DEGs were mainly enriched in 'cell division', the 'proteinaceous extracellular matrix (ECM)', 'ECM structural constituents' and 'ECM?receptor interaction', whereas downregulated genes were mainly enriched in 'response to drugs', 'extracellular space', 'transcriptional activator activity' and the 'peroxisome proliferator?activated receptor signaling pathway'. The PPI network contained 174 nodes and 1,257 edges. DNA topoisomerase 2?a, baculoviral inhibitor of apoptosis repeat?containing protein 5, cyclin?dependent kinase 1, G2/mitotic?specific cyclin?B1 and kinetochore protein NDC80 homolog were identified as the top 5 hub genes. Furthermore, the genes in the most significant module were predominantly involved in 'mitotic nuclear division', 'mid?body', 'protein binding' and 'cell cycle'. In conclusion, the DEGs, relative pathways and hub genes identified in the present study may aid in understanding of the molecular mechanisms underlying BC progression and provide potential molecular targets and biomarkers for BC.

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

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

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