PURPOSE: The field cancerization concept indicates the presence of pre-cancerous changes in clinically normal tissue surrounding the tumor. In squamous cell carcinoma of the oral tongue (SCCOT) which is infrequently linked to human papillomavirus infection, we have previously reported that clinically normal tongue contralateral to tumor (NTCT) is molecularly abnormal. Here, combining our transcriptomic and genomic data, we aimed to investigate the contribution of molecular changes in NTCT to cancer development. METHODS: Microarray gene expression data of 14 healthy controls, 23 NTCT and 29 SCCOT samples were investigated to characterize transcriptional profiles in NTCT. Whole exome sequencing and RNA-sequencing data of paired NTCT and tumor samples from 15 SCCOT patients were used to study correlation between copy number variation and differential gene expression. RESULTS: Using supervised multivariate partial least squares discriminant analysis, a total of 61 mRNAs that distinguish NTCT from healthy tongue were selected. Functional enrichment analysis of the 22 upregulated genes showed increased "positive regulation of nitrogen compound metabolic process" in NTCT. All 12 genes involved in this process have roles in apoptosis (anti- and/or pro-apoptotic). Compared to healthy controls, Zinc Finger Protein 395 (ZNF395), a pro-apoptotic tumor suppressor located on chromosome 8p, was the only gene showing increased mRNA level in NTCT whereas decreased in SCCOT. Given the frequent loss of chromosome 8p in SCCOT, the impact of ZNF395 copy number variation on gene expression was further examined, revealing a positive correlation between copy number and mRNA level (correlation coefficient = 0.572, p < 0.001). CONCLUSION: NTCT is susceptible to malignant transformation, where tissue homeostasis is maintained at least partly through regulation of apoptosis. Loss of the pro-apoptotic gene ZNF395 could thus initiate cancer development.

• Keywords
• ZNF395, Apoptosis, Etiologic field effect, Field cancerization, SCCOT,
• MeSH
• Apoptosis * genetics   MeSH
• Squamous Cell Carcinoma of Head and Neck * genetics   pathology   MeSH
• Adult MeSH
• Homeostasis genetics   MeSH
• Middle Aged MeSH
• Humans MeSH
• Tongue Neoplasms * genetics   pathology   MeSH
• Gene Expression Regulation, Neoplastic MeSH
• Aged MeSH
• Carcinoma, Squamous Cell genetics   pathology   MeSH
• Transcriptome MeSH
• Up-Regulation * MeSH
• DNA Copy Number Variations MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

Transfer-RNA-derived fragments (tRFs) are a class of small non-coding RNAs that are functionally different from their parental transfer RNAs (tRNAs). tRFs can regulate gene expression by several mechanisms, and are involved in a variety of pathological processes. Here, we aimed at understanding the composition and abundance of tRFs in squamous cell carcinoma of the head and neck (SCCHN), and evaluated the potential of tRFs as prognostic markers in this cancer type. We obtained tRF expression data from The Cancer Genome Atlas (TCGA) HNSC cohort (523 patients) using MINTbase v2.0, and correlated to available TCGA clinical data. RNA-binding proteins were predicted according to the calculated Position Weight Matrix (PWM) score from the RNA-Binding Protein DataBase (RBPDB). A total of 10,158 tRFs were retrieved and a high diversity in expression levels was seen. Fifteen tRFs were found to be significantly associated with overall survival (Kaplan-Meier survival analysis, log rank test p-value < 0.01). The top prognostic marker, tRF-20-S998LO9D (p < 0.001), was further measured in tumor and tumor-free samples from 16 patients with squamous cell carcinoma of the oral tongue and 12 healthy controls, and was significantly upregulated in tumor compared to matched tumor-free tongue (p < 0.001). Results suggest that tRFs are useful prognostic markers in SCCHN.

• Keywords
• SCCHN, prognostic marker, tRNA-derived fragment,
• MeSH
• Databases, Factual MeSH
• Squamous Cell Carcinoma of Head and Neck genetics   mortality   MeSH
• Kaplan-Meier Estimate MeSH
• Humans MeSH
• Biomarkers, Tumor genetics   MeSH
• Head and Neck Neoplasms genetics   mortality   MeSH
• Prognosis MeSH
• RNA-Binding Proteins genetics   MeSH
• RNA, Transfer genetics   MeSH
• Case-Control Studies MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Biomarkers, Tumor MeSH
• RNA-Binding Proteins MeSH
• RNA, Transfer MeSH

Oral cancers are surrounded by epithelium that histologically might seem normal, but genetically has aberrations. In patients with squamous cell carcinoma of the oral tongue (SCCOT), it is therefore important to study not only the tumor but also the clinically tumor-free contralateral tongue tissue that remains in the patient after treatment to map changes of prognostic and/or diagnostic value. The transporter associated with antigen processing (TAP) dimer is a key factor in the process of activating cytotoxic T cells. By downregulating the expression of TAP, tumor cells can escape cytotoxic T cell recognition. Biopsies from tumor and clinically tumor-free contralateral tongue tissue in 21 patients with SCCOT were analyzed together with tongue biopsies from 14 healthy individuals, which served as the control group. Dividing patients into TAP1-high and TAP1-low groups according to the median TAP1 level in tumor-free samples showed that patients with lower TAP1 mRNA levels in tumor-free samples had better overall (p = 0.003) and disease-free survival (p = 0.002). The results showing that TAP1 levels in tumor-free tongue tissue contralateral to the SCCOT correlate with survival is an important contribution to early diagnosis and follow up of SCCOT.

• Keywords
• MHC I, SCCOT, TAP1, field cancerization,
• MeSH
• Survival Analysis MeSH
• Biopsy MeSH
• Early Detection of Cancer MeSH
• Adult MeSH
• Down-Regulation * MeSH
• Tongue chemistry   pathology   MeSH
• Middle Aged MeSH
• Humans MeSH
• Biomarkers, Tumor genetics   MeSH
• Tongue Neoplasms genetics   mortality   pathology   MeSH
• ATP Binding Cassette Transporter, Subfamily B, Member 2 genetics   MeSH
• Prognosis MeSH
• Gene Expression Regulation, Neoplastic MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Carcinoma, Squamous Cell genetics   mortality   pathology   MeSH
• Case-Control Studies MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Biomarkers, Tumor MeSH
• ATP Binding Cassette Transporter, Subfamily B, Member 2 MeSH
• TAP1 protein, human MeSH Browser