Genes and pathways monotonically dysregulated during progression from normal through leukoplakia to gingivo-buccal oral cancer

Abstract

Oral squamous cell carcinoma of the gingivo-buccal region (OSCC-GB) accounts for the highest cancer morbidity and mortality among men in India. It has been observed that about one-third of individuals with oral leukoplakia, a dysplastic precancerous lesion in the oral cavity, progress to oral cancer. We aimed to identify systematic transcriptomic changes as a normal tissue in the oral cavity progresses to frank OSCC-GB. Seventy-two OSCC-GB patients, from multiple hospitals, were recruited, and transcriptome analysis of tumor and adjacent normal tissue (of all patients) and adjacent leukoplakia tissue (of a subset of 25 unselected patients with concomitant leukoplakia) was performed. We have identified many differences in the transcriptomic profiles between OSCC-GB and squamous cell carcinoma of the head and neck regions. Compared to the normal/precancerous tissue, significant enrichment of ECM−receptor interaction, PI3K-Akt signaling, cytokine−cytokine receptor interaction, focal adhesion, and cell cycle pathways were observed in OSCC-GB. Using gene set enrichment analysis, we identified a profound role of interferon receptor signaling in tumor growth by activating immune evasion mechanisms. The role of tumor-infiltrating immune cells further supported the growth and immunosuppressive mechanism of tumor tissues. Some immune evasion genes—CD274, CD80, and IDO1—were found to be activated even in the precancerous tissue. Taken together, our findings provide a clear insight into the sequential genetic dysregulation associated with progression to oral cancer. This insight provides a window to the development of predictive biomarkers and therapeutic targets for gingivo-buccal oral cancer.

Understanding precancerous lesions of the oral cavity†

“…In the oral cavity, leukoplakia (oral leukoplakia or OLK) is a white thickening of the mucosa, which progresses to overt cancer in 9% of individuals and our understanding of this process has, until recently, been limited [1]. Previous studies have identified immunological dysregulation, increasing mutation burden as well as specific changes to signaling pathways and epidermal growth factor receptor (EGFR) amplification with similarity as well as differences compared with squamous cell carcinoma (SCC), the predominant cancer of the oral cavity [2][3][4].…”

Multifunctional photodynamic/photothermal nano-agents for the treatment of oral leukoplakia

“…As high intracellular ROS levels can induce cell damage and even death, we speculate this may change the relative markers. To date, some biological biomarkers have been reported of potential value in predicting malignant transformation of oral leukoplakia, such as ALDH1, p53, Cyclin D1, PDCD5, and PDPN [ 43 – 45 ]. ALDH1, an isomer of aldehyde dehydrogenase, has been demonstrated to be a tumor stem cell marker for various solid tumors, including OSCC, and can be used as a prognostic marker for head and neck squamous cell carcinoma (HNSCC) survival [ 46 ].…”

Systematic review and meta-analysis of oral squamous cell carcinoma associated oral microbiome

“…The pathways that were upregulated among case samples in analysis 2 that are not confounded by later results included connections to primary immunodeficiency (ko05340) and RNA degradation (ko03018), both of which have been researched in the cancer literature. Primary immunodeficiency has been found significantly enriched among gingivo-buccal oral cancer samples (Das et al, 2021 ). Moreover, Goodall and Wickramasinghe ( 2021 ) summarized mounting evidence on the alteration of RNAs as it contributes to cancer in a recent review.…”