A comprehensive analysis of mRNA expression profiles of Esophageal Squamous Cell Carcinoma reveals downregulation of Desmoglein 1 and crucial genomic targets

Article type: Research Article

Authors: Alotaibi, Amal^{a; 1} | Gadekar, Veerendra P.^{b; 1} | Gundla, Pranav Swaroop^b | Mandarthi, Sumana^b | Ravi, Subramanyeshwari^b | Mallya, Dhyeya^b | Tungekar, Asna^b | Lavanya, B.V.^b | Bhagavath, Ashok Kumar^c | Cordero, MaryAnne Wong^a | Pitkaniemi, Janne^{d; e} | Seetharam, Raviraja N.^f | Bepari, Asmatanzeem^{a; *} | Hebbar, Prashantha^{b; f; g; *}

Affiliations: [a] Basic Science Department, College of Medicine, Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia | [b] Mbiomics LLC, Lewes DE, USA | [c] Department of Cellular and Molecular Biology, University of Texas Health Science Center, Tyler, Texas, TX, USA | [d] Finnish Cancer Registry, Helsinki, Finland | [e] Department of Public Health, Faculty of Medicine, University of Helsinki, Helsinki, Finland | [f] Manipal Center for Biotherapeutics Research, Manipal Academy of Higher Education, Manipal, India | [g] Meta Biosciences Pvt Ltd., Manipal – GOK Bioincubator, Advanced Research Center, Manipal, India

Correspondence: [*] Corresponding authors: Asmatanzeem Bepari, Basic Science Department, College of Medicine, Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia. E-mail: ambepari@pnu.edu.sa. Prashantha Hebbar, Mbiomics LLC, 16192 Coastal Highway, Lewes DE 19958, USA. Tel.: +1 917259664454; E-mail: hebbar.prashantha @gmail.com.

Note: [1] These two authors contributed equally.

Abstract: AIM: Esophageal Squamous Cell Carcinoma (ESCC) is a histological subtype of esophageal cancer that begins in the squamous cells in the esophagus. In only 19% of the ESCC-diagnosed patients, a five-year survival rate has been seen. This necessitates the identification of high-confidence biomarkers for early diagnosis, prognosis, and potential therapeutic targets for the mitigation of ESCC. METHOD: We performed a meta-analysis of 10 mRNA datasets and identified consistently perturbed genes across the studies. Then, integrated with ESCC ATLAS to segregate ‘core’ genes to identify consequences of primary gene perturbation events leading to gene-gene interactions and dysregulated molecular signaling pathways. Further, by integrating with toxicogenomics data, inferences were drawn for gene interaction with environmental exposures, trace elements, chemical carcinogens, and drug chemicals. We also deduce the clinical outcomes of candidate genes based on survival analysis using the ESCC related dataset in The Cancer Genome Atlas. RESULT: We identified 237 known and 18 novel perturbed candidate genes. Desmoglein 1 (DSG1) is one such gene that we found significantly downregulated (Fold Change =-1.89, p-value = 8.2e-06) in ESCC across six different datasets. Further, we identified 31 ‘core’ genes (that either harbor genetic variants or are regulated by epigenetic modifications) and found regulating key biological pathways via adjoining genes in gene-gene interaction networks. Functional enrichment analysis showed dysregulated biological processes and pathways including “Extracellular matrix”, “Collagen trimmer” and “HPV infection” are significantly overrepresented in our candidate genes. Based on the toxicogenomic inferences from Comparative Toxicogenomics Database we report the key genes that interacted with risk factors such as tobacco smoking, zinc, nitroso benzylmethylamine, and drug chemicals such as cisplatin, Fluorouracil, and Mitomycin in relation to ESCC. We also point to the STC2 gene that shows a high risk for mortality in ESCC patients. CONCLUSION: We identified novel perturbed genes in relation to ESCC and explored their interaction network. DSG1 is one such gene, its association with microbiota and a clinical presentation seen commonly with ESCC hints that it is a good candidate for early diagnostic marker. Besides, in this study we highlight candidate genes and their molecular connections to risk factors, biological pathways, drug chemicals, and the survival probability of ESCC patients.

Keywords: Esophagus cancer, ESCC, desmogleins, toxicogenomics, krüppel-like factor, stanniocalcin

DOI: 10.3233/CBM-230145

Journal: Cancer Biomarkers, vol. 38, no. 4, pp. 465-487, 2023