Copy Number Variation That Influences the Ionizing Radiation Sensitivity of Oral Squamous Cell Carcinoma.

Genome instability in cancer cells causes not only point mutations but also structural variations of the genome, including copy number variations (CNVs). It has recently been proposed that CNVs arise in cancer to adapt to a given microenvironment to survive. However, how CNV influences cellular resistance against ionizing radiation remains unknown. PRMT5 (protein arginine methyltransferase 5) and APE1 (apurinic/apyrimidinic endonuclease 1), which enhance repair of DNA double-strand breaks and oxidative DNA damage, are closely localized in the chromosome 14 of the human genome. In this study, the genomics data for the PRMT5 and APE1 genes, including their expression, CNVs, and clinical outcomes, were analyzed using TCGA's data set for oral squamous cell carcinoma patients. The two genes were found to share almost identical CNV values among cancer tissues from oral squamous cell carcinoma (OSCC) patients. Levels of expression of PRMT5 and APE1 in OSCC tissues are highly correlated in cancer but not in normal tissues, suggesting that regulation of PRMT5 and APE1 were overridden by the extent of CNV in the PRMT5-APE1 genome region. High expression levels of PRMT5 and APE1 were both associated with poor survival outcomes after radiation therapy. Simultaneous down-regulation of PRMT5 and APE1 synergistically hampered DNA double-strand break repair and sensitized OSCC cell lines to X-ray irradiation in vitro and in vivo. These results suggest that the extent of CNV in a particular genome region significantly influence the radiation resistance of cancer cells. Profiling CNV in the PRMT5-APE1 genome region may help us to understand the mechanism of the acquired radioresistance of tumor cells, and raises the possibility that simultaneous inhibition of PRMT5 and APE1 may increase the efficacy of radiation therapy.

Human Papillomavirus-Associated Oral Cavity Squamous Cell Carcinoma: An Entity with Distinct Morphologic and Clinical Features.

BACKGROUND: HPV-associated oral cavity squamous cell carcinoma (SCC) is not well-characterized in the literature, and also has a clinical significance that is poorly understood. METHODS: We gathered a cohort of oral cavity (OC) SCC with nonkeratinizing morphology, either in the invasive or in situ carcinoma (or both), tested for p16 by immunohistochemistry and high risk HPV E6/E7 mRNA by RTPCR (reference standard for transcriptionally-active high risk HPV) and gathered detailed morphologic and clinicopathologic data. RESULTS: Thirteen patients from two institutions were proven to be HPV-associated by combined p16 and high risk HPV mRNA positivity. All 13 patients (100%) were males, all were heavy smokers (average 57 pack/year), and most were active drinkers (9/11 or 81.8%). All 13 (100%) involved the tongue and/or floor of mouth. All had nonkeratinizing features, but maturing squamous differentiation varied widely (0-90%; mean 37.3%). Nonkeratinizing areas had high N:C ratios and larger nests, frequently with pushing borders, and minimal (or no) stromal desmoplasia. The carcinoma in situ, when present, was Bowenoid/nonkeratinizing with cells with high N:C ratios, full thickness loss of maturation, and abundant apoptosis and mitosis. HPV was type 16 in 11 patients (84.6%) and type 33 in two (15.4%). Nine patients had treatment data available. These underwent primary surgical resection with tumors ranging from 1.6 to 5.2 cm. Most had bone invasion (6/9-66.7% were T4a tumors), and most (6/9-66.7%) had extensive SCC in situ with all 6 of these patients having final margins positive for in situ carcinoma. CONCLUSIONS: HPV-associated OCSCC is an uncommon entity that shows certain distinct clinical and pathologic features. Recognition of these features may help pathologic diagnosis and could potentially help guide clinical management.

Genomic landscape of Epstein-Barr virus-positive extranodal marginal zone lymphomas of mucosa-associated lymphoid tissue.

Epstein-Barr virus (EBV)-positive extranodal marginal zone lymphomas of mucosa-associated lymphoid tissue (MALT lymphomas) were initially described in solid organ transplant recipients, and, more recently, in other immunodeficiency settings. The overall prevalence of EBV-positive MALT lymphomas has not been established, and little is known with respect to their genomic characteristics. Eight EBV-positive MALT lymphomas were identified, including 1 case found after screening a series of 88 consecutive MALT lymphomas with EBER in situ hybridization (1%). The genomic landscape was assessed in 7 of the 8 cases with a targeted high throughput sequencing panel and array comparative genomic hybridization. Results were compared to published data for MALT lymphomas. Of the 8 cases, 6 occurred post-transplant, 1 in the setting of primary immunodeficiency, and 1 case was age-related. Single pathogenic/likely pathogenic mutations were identified in 4 of 7 cases, including mutations in IRF8, BRAF, TNFAIP3, and SMARCA4. Other than TNFAIP3, these genes are mutated in <3% of EBV-negative MALT lymphomas. Copy number abnormalities were identified in 6 of 7 cases with a median of 6 gains and 2 losses per case, including 4 cases with gains in regions encompassing several IRF family or interacting genes (IRF2BP2, IRF2, and IRF4). There was no evidence of trisomies of chromosomes 3 or 18. In summary, EBV-positive MALT lymphomas are rare and, like other MALT lymphomas, are usually genetically non-complex. Conversely, while EBV-negative MALT lymphomas typically show mutational abnormalities in the NF-κB pathway, other than the 1 TNFAIP3-mutated case, no other NF-κB pathway mutations were identified in the EBV-positive cases. EBV-positive MALT lymphomas often have either mutations or copy number abnormalities in IRF family or interacting genes, suggesting that this pathway may play a role in these lymphomas.

Radiation-induced oral mucositis hamster model using a linear accelerator enhances clinical relevance of preclinical studies for treatment strategy investigation.

Translational animal models for oral mucositis (OM) are necessary to simulate and assess the bioclinical effects and response in humans. These models should simulate high levels of radiation exposure that leads to oxidative stress and inflammatory-initiated tissue changes. Hamster models have been extensively studied to observe pathological effects of radiation exposure and help in the development of effective treatments. To successfully evaluate the potential for treatment regimens with consistency and relevance, a radiation-induced OM hamster model was developed using a clinical linear accelerator utilized by cancer patients daily. The dose exposure to the isolated, everted cheek pouch of a hamster, as well as the progression of injury, pro-inflammatory marker, histological, and elasticity analyses of the buccal pouch were conducted to verify replicability and reproducibility of the injury model. The findings from this model demonstrated its ability to consistently induce injury and resolution over 28 days using an acute dose of 60 Gy. This model was developed to enhance clinical relevance when evaluating potential efficacious treatments and can now be utilized in efficacy studies to better evaluate developed therapeutics in a preclinical model that is easy to translate to clinical studies..

Medication use and medical history of 155 patients with oral lichenoid lesions: a retrospective study.

Several medications have been reported as possible etiologic factors for oral lichen planus (OLP) and oral lichenoid lesions (OLLs). This study investigated the medication profile and medical history of patients with biopsy-proven OLP or OLLs, also classified by the clinically nonspecific term oral lichenoid mucositis (OLM), in a busy oral medicine clinic. The University of Florida College of Dentistry records from 2009 to 2014 were searched retrospectively for all patients with a biopsy-proven diagnosis of OLP, OLLs, or OLM. Patients were excluded if dysplasia or carcinoma was diagnosed concurrently at the same biopsy site. The demographics, clinical parameters, systemic diseases, histologic diagnosis, and direct immunofluorescence testing results were recorded. Medication category use was recorded based on both commonly used medications and those that have been reportedly linked to lichenoid disease in the literature. A total of 155 patients with an average age of 63.6 years were included. The majority of patients were women (76.8%) and Caucasian (91.8%). Most of the lesions were multifocal and mixed (white-red) in appearance. The most common systemic conditions were hypertension (n = 80; 51.6%) followed by thyroid disease (n = 52; 33.5%) and diabetes (n = 26; 16.8%). Antihypertensives were the most common medication category followed by, in descending order, nonsteroidal anti-inflammatory drugs, cholesterol-lowering medications, psychiatric medications, and thyroid replacement drugs. The records revealed that 87.7% of the patients took at least 1 medication from 1 of the categories studied. Medication use is common in patients with biopsy-proven OLP or OLLs. Although causation cannot be assessed from the results of this study, the clinician should consider the possibility of medication as a complicating factor in patients with OLP or OLLs.

MicroRNA-375 as a biomarker for malignant transformation in oral lesions.

OBJECTIVE: Malignant transformation of oral premalignant lesions is the key process in the progression to oral squamous cell carcinoma (OSCC). Previously, we identified miR-7 and miR-21 as candidate oncogenes and miR-375 and miR-494 as candidate tumor suppressors in OSCC. We aim to evaluate these microRNAs as biomarkers of malignant transformation in oral premalignant lesions. STUDY DESIGN: Formalin-fixed, paraffin-embedded samples from progressive premalignant lesions and paired sequential OSCC tumors at the same site were obtained from same patients (n = 31). Total RNA was extracted and analyzed for microRNA levels using real-time polymerase chain reaction. RESULTS: MiR-375 expression in progressive lesions was clearly lower than in nonprogressive control lesions (average eightfold difference, P = .0004). Furthermore, the expression of miR-375 decreased significantly after the progression from premalignant lesion to OSCC (P < .0001). Receiver operating characteristic curve analysis revealed that miR-375 was able to differentiate between progressive and nonprogressive premalignant lesions (P < .0001). CONCLUSIONS: MiR-375 downregulation in oral premalignant lesions is associated with a higher risk of malignant transformation.