Abstract
Highly keratinized oral squamous cell carcinoma (OSCC) exhibits an improved response to treatment and prognosis compared with weakly keratinized OSCC. Therefore, we aimed to develop gene transcript signature and to identify novel full-length isoforms, fusion transcript and non-coding RNA to differentiate well-differentiated (WD) with Moderately Differentiated (MD)/Poorly Differentiated (PD)/WD-lymphadenopathy OSCC through, HTA, Isoform sequencing, and NanoString. Additionally, specific copy number gain and loss were also identify in WD keratinized OSCC through Oncoscan array and validated through Real-time PCR in histopathologically characterized FFPE-WD keratinized OSCC. Three-hundred-thirty-eight (338) differentially expressed full-length (FL) transcript isoforms (317 upregulated and 21 down-regulated in OSCC) were identified through Isoform Sequencing using the PacBio platform. Thirty-four (34) highly upregulated differentially expressed transcripts from IsoSeq data were also correlated with HTA2.0 and validated in 42 OSCC samples. We were able to identify 18 differentially expressed transcripts, 12 fusion transcripts, and two long noncoding RNAs. These transcripts were involved in increased cell proliferation, dysregulated metabolic reprogramming, oxidative stress, and immune system markers with enhanced immune rearrangements, suggesting a cancerous nature. However, an increase in proteasomal activity and hemidesmosome proteins suggested an improved prognosis and tumor cell stability in keratinized OSCC and helped to characterize WD with MD/PD/WD with lymphadenopathy OSCC. Additionally, novel isoforms of IL37, NAA10, UCHL3, SPAG7, and RAB24 were identified while in silico functionally validated SPAG7 represented the premalignant phenotype of keratinized (K4) OSCC. Most importantly we found copy number gain and overexpression of EGFR suggest that TKIs may also be used as therapeutics in WD-OSCCs.
Highlights
The oral cavity includes the lips, the inner lining of the lips and cheeks, the teeth, the gums, the front two-thirds of the tongue, the floor of the mouth below the tongue, and the bony roof of the mouth
Patients with both a high degree of keratinization and human papillomavirus (HPV)-positive oral cancers have an improved response to treatment and an improved prognosis compared with patients with a low degree of keratinization and HPV-negative oral squamous cell carcinoma (OSCC) [4]
The study was carried out in 30 Oral Squamous Cell Carcinoma (OSCC) patients based on the degree of keratinization
Summary
The oral cavity includes the lips, the inner lining of the lips and cheeks (buccal mucosa), the teeth, the gums, the front two-thirds of the tongue, the floor of the mouth below the tongue, and the bony roof of the mouth (hard palate). Keratinizing lesions may occur in any of the cell types in the oral cavity and may be initiated due to defects in keratinization, including reactive, preneoplastic and neoplastic lesions. OSCC patients are regarded as harboring tumors with various degree of keratinization (K0 to K4), which plays an important role in the prognosis of OSCC. There are very few studies reported the degree of keratinization is the prognostic and risk factors for OSCC [3]. Patients with both a high degree of keratinization and human papillomavirus (HPV)-positive oral cancers have an improved response to treatment and an improved prognosis compared with patients with a low degree of keratinization and HPV-negative OSCCs [4]. The proliferation index (Ki-67), vascularization (CD34), p53 and bcl-2 expression and HPV are used to evaluate the prognosis of OSCC [5]
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