Post-translational regulation of stemness under DNA damage response contributes to the gingivobuccal oral squamous cell carcinoma relapse and progression

Abstract

Tobacco consumption (smoking and specifically smokeless form) in India contributes to a high prevalence of gingivobuccal oral squamous cell carcinoma (OSCC-GB). OSCC-GB exhibits high rates of locoregional relapse and therapeutic resistance, often attributed to the involvement of cancer stem cells (CSCs). The goal of this study is to leverage the generalizability of the machine learning prediction model for ‘Tumor Status’ for a comparative somatic mutation analysis between ‘With Tumor’ (recurred/relapsed/progressed) and ‘Tumor Free’ (disease-free/complete remission) OSCC-GB patients. Our results showed that support vector machines (SVM) classified the ‘Tumor Status’ classes at a mean accuracy of 89% based on clinical features. Furthermore, RNA-seq based somatic mutation analysis using the classified groups revealed molecular mechanisms underlying tumor progression and remission within OSCC-GB subgroups. The identified mutational signature (C>T mutations) related to DNA damage indicates the influence of tobacco-related carcinogens in OSCC-GB subgroups. The analysis of distinct somatic variants, functional impact predictions, protein-protein interactions, and survival analysis highlights the involvement of DNA damage response (DDR)-related genes in ‘With Tumor’, with particular focus on the significant role of the Mitogen-activated protein kinase associated protein 1 (MAPKAP1) gene, a key player in the mTORC2 signaling pathway. The study indicates that loss-of-function in the identified MAPKAP1 somatic variant may promote stemness and elevated risk of relapse and disease progression in OSCC-GB under conditions of DDR in ‘With Tumor’ OSCC-GB, potentially contributing to increased mortality rates among Indian OSCC-GB patients.