Characterizing Genetic Transitions of Copy Number Alterations and Allelic Imbalances in Oral Tongue Carcinoma Metastasis.

Primary tumor (PT) heterogeneity can significantly affect the genetic profile of clones at metastatic sites. To understand the mechanisms underlying metastasis, we compared the genetic profile of paired PT and metastatic lymph node (MLN) samples obtained from patients with oral tongue squamous cell carcinoma (OTSCC). Large-scale genetic profiling was performed on paired PT-MLN samples obtained from 10 OTSCC patients using high-density single-nucleotide polymorphism microarrays. We compared the genetic profile of PT and MLN OTSCC samples to identify common and specific copy number alterations and copy-neutral loss-of-heterozygosity (CN-LOH). Unsupervised hierarchical clustering analysis indicated that 8 of the 10 PT-MLN sample pairs formed clusters, indicating that the primary and metastatic tumors were composed of predominantly genetically similar tumor cells. In 6 of the 10 pairs, 8q11.21, 8q12.2-3, and 8q21.3 gains, and 22q11.23 loss were detected in both the PT and MLN. In addition, 16p11.2 CN-LOH was identified in 9 of the 10 pairs. Conversely, 20q11.2 gain was only observed in the MLNs of 5 of the 10 sample pairs, indicating that genes in this chromosomal region may play a significant role in OTSCC lymph node metastasis. To confirm this, we investigated the expression of two candidate 20q11.2 genes in a separate patient cohort. The expression of one of these genes, E2F1, was significantly increased during the process of metastasis. This study indicates that additional genetic changes, such as 20q11.2 gain, which encodes the E2F1 gene, can be acquired through clonal evolution, and may be required for the metastatic process. © 2016 Wiley Periodicals, Inc.

Primary intraosseous squamous cell carcinoma derived from a maxillary cyst: A case report and literature review.

Primary intraosseous squamous cell carcinoma (PIOSCC) is a rare malignant central jaw tumor derived from odontogenic epithelial remnants. PIOSCC predominantly affects the mandible, although both jawbones may be involved. This case report describes a PIOSCC type 2 of the maxilla in a 37-year-old man, treated by partial maxillectomy. Histopathologically, the tumor was diagnosed as PIOSCC derived from an odontogenic cyst. Postoperatively, the patient has been followed up for 53 months, with no recurrence of the disease. We herein describe the clinical details, treatment results and histopathological characteristics of a rare case of PIOSCC derived from a maxillary odontogenic cyst with reference to the relevant literature.

Clinical Study of 597 Oral Squamous Cell Carcinomas in Our Department - Especially about 318 Tongue Carcinoma.

This clinico-statistical study includes 597 cases of oral squamous cell carcinoma treated at the Maxillofacial Surgery Section of Tokyo Medical and Dental University between January 2002 and December 2011. There were 373 male and 224 female patients (male to female ratio, 1.7 : 1), and the median age was 67 years. The tongue (53.3%) was the most commonly affected site. The 5-year disease-specific survival rate was 84.8%. Survival rates by clinical stage were as follows : Stage 1, 92.1% (n=195).; Stage , 86.0% (n = 221) ; Stage III, 77.7% (n=65) ; and Stage IV, 73.8% (n =116). Survival rates by primary site were as follows: tongue, 85.4% (n=318) ; lower gingiva, 82.8% (n =114) upper gingiva, 83.7% (n=59) ; buccal mucosa, 89.1% (n 54) ; oral floor, 81.4% (n=49) ; and hard palate, 100% (n=3). According to clinical growth patterns of Stage I / I tongue cancer cases, the 5-year disease-specific survival rate was significantly higher for patients with the exophytic/superficial type (97.3%, n =173) than for those with the endophytic type (77.5%, n=145). Among Stage I/II tongue cancer cases, the corresponding survival rate was significantly higher for patients who had not previously undergone invasive treatments (n=201), such as tooth extraction, compared to those who had previously done so (n=54) (92.7% and 79.7%, respectively). In addition, the incidence of secondary cervical lymph node metastasis was significantly higher in patients who had previously undergone invasive treatments.

The high-temperature requirement factor A3 (HtrA3) is associated with acquisition of the invasive phenotype in oral squamous cell carcinoma cells.

OBJECTIVES: Previous studies have identified several genes involved in the carcinogenesis of oral cancer; however, the detailed mechanisms underlying this process have not been elucidated. Previously, we established a database of the transcriptional progression profile of oral carcinogenesis and identified 15 candidate genes with continuously increasing or decreasing expression (Sumino et al., 2013). MATERIALS AND METHODS: In the present study, using this database, we attempted to identify genes that may specifically contribute to progression from oral dysplastic lesions to invasive tumours. RESULTS: We identified 4 candidate genes. Using a literature survey, we narrowed down the candidates and focused on the high-temperature requirement factor A3 (HtrA3). Quantitative real-time reverse transcription polymerase chain reaction and immunohistochemical analysis confirmed that HtrA3 expression significantly increased during this process. In addition, high HtrA3 expression was significantly associated with decreased disease-free survival (P=0.045) and overall survival (P=0.003). Multivariate Cox proportional hazards analysis found that high HtrA3 expression significantly correlated with overall survival (P=0.018). CONCLUSION: The findings of this study demonstrated that the HtrA3 is likely to be associated with the acquisition of the invasive phenotype in oral squamous cell carcinoma cells and may be a potential prognostic marker for oral cancer.

Synthesis and biological evaluation of (4H-1,2,4-triazol-4-yl)isoquinoline derivatives as selective glycine transporter 1 inhibitors.

To identify novel glycine transporter 1(GlyT1) inhibitors with greater selectivity relative to GlyT2 and improved aqueous solubility, we synthesized a series of 4H-1,2,4-triazole derivatives with heteroaromatic rings at the 4-position and investigated their structure-activity relationships. Replacement of the 2-fluorophenyl group of lead compound 5 with various aromatic groups led to the identification of 5-(3-biphenyl-4-yl-5-ethyl-4H-1,2,4-triazol-4-yl)isoquinoline (15) with 38-fold selectivity between GlyT1 and GlyT2. 15 also showed improved aqueous solubility and in vivo efficacy on (+)-HA966-induced hyperlocomotion in mice over the lead compound.

Synthesis and biological evaluation of 3-biphenyl-4-yl-4-phenyl-4H-1,2,4-triazoles as novel glycine transporter 1 inhibitors.

We describe the preparation and evaluation of a novel series of glycine transporter 1 (GlyT1) inhibitors derived from a high-throughput screening hit. The SAR studies resulted in the discovery of 3-biphenyl-4-yl-4-(2-fluorophenyl)-5-isopropyl-4H-1,2,4-triazole (6p). A pharmacokinetic study was also conducted and revealed that 6p had excellent oral bioavailability and ameliorated learning impairment in passive avoidance tasks in mice.