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Mucositis in patients with tonsil squamous cell carcinoma: gene expression profile of oral mucosa before, during, and after radiation therapy

ABSTRACT: Objectives: In patients with tonsil squamous cell cancer (TSCC), radiation-therapy (RT) induce mucositis, which is clinically challenging with limited prophylactic interventions and no predictive tests. In a pilot study set-up, we performed global gene-expression analysis on human oral mucosa tissue and blood cells to identify differential expressed genes involved in mucositis pathogenesis. Materials and Methods: Eight patients with TSCC had consecutive buccal biopsies and blood samples taken before, after 7 days of RT, and 20 days following RT. We monitored clinical mucositis and applied gene-expression analysis to the tissues. Single biopsies and blood tests from 9 healthy individuals served as controls (CON). Results: In response to RT, we did not register changes in the blood cells, but we found upregulation of both apoptosis inducers and inhibitors in the mucosa: EDA2R and MDM2; and POLH, encoding a polymerase that replicates UV-damaged DNA. Six members of the histone cluster family, e.g., HIST1H3B, involved in nucleosome structure, were downregulated. Genes related to proliferation were also altered: MKI67 (downregulated), encoding Ki-67-proliferation; and KRT16 (upregulated), encoding keratin16, characteristic in early differentiated epithelial cells. None of these alterations were associated to mucositis severity. However, before treatment, LY6G6C, which encodes a surface immunoregulatory protein, was upregulated in NM compared to UM, although not significantly. Conclusion: RT caused divergent changes in genes expression related to DNA damage and proliferation, all independently altered of mucositis severity. LY6G6C may be a potential predictive biomarker for UM following RT. Based on these result, we will design a prospective clinical validation trial, including more patients.

ORGANISM(S): Homo sapiens

PROVIDER: GSE103412 | GEO | 2017/12/22

SECONDARY ACCESSION(S): PRJNA401715

REPOSITORIES: GEO

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Project description:Background Toxicity of the oral and gastrointestinal mucosa induced by high-dose melphalan is a clinical challenge with no documented prophylactic interventions or predictive tests. The aim of this study was to describe molecular changes in human oral mucosa and to identify biomarkers correlated with the grade of clinical mucositis. Methods and Findings Ten patients with multiple myeloma (MM) were included. For each patient, we acquired three buccal biopsies, one before, one at 2 days, and one at 20 days after high-dose melphalan administration. We also acquired buccal biopsies from 10 healthy individuals that served as controls. We analyzed the biopsies for global gene expression and performed an immunohistochemical analysis to determine HLA-DRB5 expression. We evaluated associations between clinical mucositis and gene expression profiles. Compared to gene expression levels before and 20 days after therapy, at two days after melphalan treatment, we found gene regulation in the p53 and TNF pathways (MDM2, INPPD5, TIGAR), which favored anti-apoptotic defense, and upregulation of immunoregulatory genes (TREM2, LAMP3) in mucosal dendritic cells. This upregulation was independent of clinical mucositis. HLA-DRB1 and HLA-DRB5 (surface receptors on dendritic cells) were expressed at low levels in all patients with MM, in the subgroup of patients with ulcerative mucositis (UM), and in controls; in contrast, the subgroup with low-grade mucositis (NM) displayed 5–6 fold increases in HLA-DRB1 and HLA-DRB5 expression in the first two biopsies, independent of melphalan treatment. Moreover, different splice variants of HLA-DRB1 were expressed in the UM and NM subgroups. Conclusions Our results revealed that, among patients with MM, immunoregulatory genes and genes involved in defense against apoptosis were affected immediately after melphalan administration, independent of the presence of clinical mucositis. Furthermore, our results suggested that the expression levels of HLA-DRB1 and HLA-DRB5 may serve as potential predictive biomarkers for mucositis severity

Project description:41 volunteers (male non-smokers) were exposed to formaldehyde (FA) vapors for 4 h per day over a period of 5 working days under strictly controlled conditions. For each exposure day, different exposure concentrations were used in a random order ranging from 0 up to 0.7 ppm. At concentrations of 0.3 ppm and 0.4 ppm, four peaks of 0.6 or 0.8 ppm for 15 min each were applied. During exposure, subjects had to perform bicycle exercises (about 80 W) four times for 15 min. Blood samples, exfoliated nasal mucosa cells and nasal biopsies were taken before the first and after the last exposure. Nasal epithelial cells were additionally sampled 1, 2 and 3 weeks after the end of the exposure period. The alkaline comet assay, the sister chromatid exchange (SCE) test and the cytokinesis-block micronucleus test (CBMNT) were performed with blood samples. The micronucleus test (MNT) was also performed with exfoliated nasal mucosa cells. The expression (mRNA level) of the GSH-dependent formaldehyde dehydrogenase (FDH, identical to alcohol dehydrogenase 5; ADH5; EC 1.2.1.46) was measured in blood samples by quantitative real-time RT-PCR with TaqMan probes. DNA microarray analyses using a full-genome human microarray were performed on blood samples and nasal biopsies of selected subgroups with the highest FA exposure at different days. None of the tests performed showed a biologically significant effect related to FA exposure. Under the experimental conditions of this study, inhalation of FA did not lead to genotoxic effects in peripheral blood cells and nasal mucosa and had no effect on the expression of the FDH gene. Inhalation of FA also did not cause biologically relevant alterations in the expression of genes in a microarray analysis with nasal biopsies and peripheral blood cells. Gene expression analysis of nasal biopsies and blood samples before and after inhalation of 0.7ppm formaldehyde (0 h, 24 h, or 72 h before sampling), and of blood cells before and after exposure to 200µM formaldehyde for 4 hours.

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Mucositis in patients with tonsil squamous cell carcinoma: gene expression profile of oral mucosa before, during, and after radiation therapy

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