STUDY OF DYSREGULATED GENES DURING SQUAMOUS CELL CARCINOMA FOR IDENDIFICATION OF POTENTIAL BIOMARKERS AND THERAPEUTICS

Abstract

The aim of this study was to investigate dysregulated genes during Squamous Cell Carcinoma (SCC) and identify potential biomarkers and therapeutics for the disease. Three specific objectives were pursued: (1) to identify key genes and pathways involved in the progression of Cutaneous SCC from AK, (2) to investigate the impact of somatic non-synonymous mutations on BTK protein and their potential influence on FDA-approved therapies for SCC, and (3) to find chemical perturbations associated with identified biomarkers for the correction of SCC. The first objective focused on identifying key genes and pathways involved in the progression of cutaneous SCC from AK. To accomplish this, the study applied an eXplainable Artificial Intelligence (XAI) approach to the XGBoost classification model. XAI techniques, such as SHAP barplot and SHAP summary plots, were utilized to establish interpretability by linking the model outputs to relevant genes. By analyzing the model’s predictions, significant genes associated with SCC progression were identified. This approach not only provided insights into the genes involved in the disease but also demonstrated the potential of XAI methods in identifying biomarkers [1]. The second objective aimed to investigate the impact of somatic non-synonymous mutations on Bruton’s tyrosine kinase (BTK) protein and their potential influence on FDA-approved therapies for SCC. A literature survey was conducted to identify FDA-approved drugs for skin cancer, leading to the discovery of Ibrutinib, a BTK inhibitor. Although there has been limited research on the role of BTK protein in SCC, the study chose to focus on it to address the existing research gap. Molecular dynamics (MD) simulations were performed to analyze the effects of individual amino acid mutations on the stability of the BTK protein. The findings indicated that these mutations may contribute to the prognosis of SCC by rendering the protein unstable. Additionally, the interaction between the BTK protein and its mutants with Ibrutinib was Page | xiii examined, revealing that the mutants exhibited comparable binding to Ibrutinib as the wild type protein. This observation highlighted the potential efficacy of Ibrutinib-based therapy in targeting these mutations for SCC treatment [2]. The third objective aimed to find chemical perturbations associated with the identified biomarkers for the correction of SCC. To achieve this, gene expression profiles of individuals diagnosed with SCC, healthy individuals, and those with AK were rigorously compared. Several dysregulated genes that exhibited significant differential expression were identified. These dysregulated genes were found to be involved in crucial biological processes closely associated with SCC progression, such as cellular disassembly, regulation of protein catabolism, and extracellular matrix disassembly. Additionally, important biological pathways, including WNT signaling and regulation of the actin cytoskeleton, were found to play a role in SCC progression. To further augment the research outcomes, the Drug Gene Budger tool was utilized to investigate potential therapeutic interventions. Analysis using this tool revealed the notable effectiveness of certain drugs, such as Doxorubicin, Dasatinib, and Tretinoin, in rectifying the abnormal expression patterns of the identified dysregulated genes associated with SCC. This study contributes to the identification of potential biomarkers and therapeutics for SCC through a comprehensive approach. The utilization of XAI techniques facilitated the identification of significant genes associated with SCC progression. The investigation of somatic non-synonymous mutations in the BTK protein provided insights into its stability and potential therapeutic targeting with Ibrutinib. The exploration of chemical perturbations associated with dysregulated genes shed light on potential treatment options for SCC. Collectively, these findings have implications for precision medicine and innovative drug discovery strategies in the field of SCC.