MYB alternative promoter activity is increased in adenoid cystic carcinoma metastases and is associated with a specific gene expression signature.

OBJECTIVE: Adenoid cystic carcinoma (ACC) is a head and neck cancer with a poor long-term prognosis that shows frequent local recurrences and distant metastases. The tumors are characterized by MYB oncogene activation and are notoriously unresponsive to systemic therapies. The biological underpinnings behind therapy resistance of disseminated ACC are largely unknown. Here, we have studied the molecular and clinical significance of MYB alternative promoter (TSS2) usage in ACC metastases. MATERIALS AND METHODS: MYB TSS2 activity was investigated in primary tumors and metastases from 26 ACC patients using RNA-sequencing and quantitative real-time PCR analysis. Differences in global gene expression between MYB TSS2 high and low cases were studied, and pathway analyses were performed. RESULTS: MYB TSS2 activity was significantly higher in ACC metastases than in primary tumors (median activity 15.1 vs 3.0, P = 0.0003). MYB TSS2 high ACC metastases showed a specific gene expression signature, including increased expression of multi-drug resistance genes and canonical MYB target genes, and suppression of the p53 and NOTCH pathways. CONCLUSIONS: Collectively, our findings indicate that elevated MYB TSS2 activity is associated with metastases, potential drug resistance, and augmented MYB-driven gene expression in ACC. Our study advocates the need for new therapies that specifically target MYB and drug resistance mechanisms in disseminated ACC.

Recurrent copy number alterations involving EGFR, CDKN2A, and CCND1 in oral premalignant lesions.

BACKGROUND: A major challenge in the management of patients with oral leukoplakia is the difficulty to identify patients at high risk of developing oral squamous cell carcinoma. Our knowledge about genomic alterations in oral leukoplakia, and in particular those that progress to oral squamous cell carcinoma, is scarce and there are no useful biomarkers that can predict the risk of malignant transformation. METHODS: Using a novel, custom-made tissue microarray including 28 high-risk oral leukoplakias and the corresponding oral squamous cell carcinomas from 14 cases that progressed to cancer, we assayed copy number alterations involving the oral squamous cell carcinoma driver genes CDKN2A, CCND1, EGFR, and MYC by fluorescence in situ hybridization. The copy number alterationss were correlated with clinicopathological data from all patients. RESULTS: Copy number alterations were identified in 14/24 oral leukoplakias, analyzable for one or more of the oral squamous cell carcinoma driver genes. EGFR was the most frequently altered gene in oral leukoplakias with amplification/gain in 43.5% followed by loss of CDKN2A (26.1%), gains of CCND1 (26.1%), and MYC (8.3%). Losses of CDKN2A were more common in oral leukoplakias progressing to oral squamous cell carcinoma compared to those that did not. Copy number alterations were more common in oral squamous cell carcinomas than in oral leukoplakias. CONCLUSIONS: Our findings demonstrate that copy number alterations involving the oral squamous cell carcinoma drivers CDKN2A, EGFR, and CCND1 occur in oral leukoplakias and suggest a possible role for these genes in the development and/or progression of subsets of oral leukoplakias.

Regular clinical follow-up of oral potentially malignant disorders results in improved survival for patients who develop oral cancer.

OBJECTIVES: To evaluate whether clinical follow-up programs of oral potentially malignant disorders (OPMD) result in earlier detection and improved survival rates if malignant transformation occurs, as compared to OPMD patients without follow-up and other patients with oral squamous cell carcinoma (OSCC). MATERIALS AND METHODS: Three OSCC groups were retrospectively studied for disease stage at diagnosis and survival rates (N = 739): Group A, patients with OSCC with regular follow-up of preceding OPMD (N = 94); Group B, patients with OSCC with preceding OPMD but no follow-up (N = 68); Group C, patients with OSCC without previously known OPMD diagnosis (N = 577). RESULTS: The patients with OPMD with follow-up (Group A) was diagnosed at a significantly earlier stage and have significantly higher survival rates compared to Group B (p < 0.001 and p = 0.022, respectively) and Group C (p < 0.001 and p < 0.001, respectively). There was no significant difference between Group B and Group C in terms of survival rate (p = 0.143) or stage at diagnosis (p = 0.475). Patients with OPMD and follow-up (Group A) had a 5-year net survival rate of 90.0% (95%CI 80.3-100.8%), as compared to 68.3% percent (95% CI 54.5-85.7) for Group B and 56.1% (95% CI 51.4-61.3) for Group C. CONCLUSION: The results of this study indicate that regular follow-up of patients with OPMD results in earlier detection of OSCC (if malignant transformation occurs) and improved survival.

Expression of high mobility group A proteins in oral leukoplakia.

BACKGROUND: Oral leukoplakia (LPL) is considered a potentially malignant disorder in the oral cavity and the gastric tract. High mobility group A (HMGA) proteins are important in the transformation of normal cells into cancer cells, but there is a lack of knowledge on their importance in oral cancer development. The aim of the current project was to investigate HMGA expression in LPLs with different levels of dysplasia. MATERIALS AND METHODS: Biopsies were histologically processed to visualize the expression of HMGA1 and HMGA2 using immunohistochemistry. RESULTS: An increase of HMGA1-positive cells correlating to the degree of dysplasia was registered in the epithelium and in the connective tissue. HMGA2 expression was seen in the epithelium and in the connective tissue but with no obvious correlation to the level of dysplasia. CONCLUSION: This is, to our knowledge, the first study showing the expression of HMGA proteins in healthy and non-healthy oral mucosa.

Loss of 5-hydroxymethylcytosine and TET2 in oral squamous cell carcinoma.

AIM: Epigenetic modifications, such as DNA methylation, are considered important in the regulation of target genes in cancer development. 5-Hydroxymethylcytosine (5hmC) was recently discovered to be related to the process of malignant transformation. The influence of DNA methylation in oral squamous cell carcinomas (OSCC) is not fully-understood. Therefore, the aim of the present study was to investigate the DNA methylation pattern in OSCC compared to healthy oral epithelium. MATERIALS AND METHODS: Oral mucosal samples from patients with OSCC (n=15) and healthy mucosa (n=12) were analyzed using immunohistochemistry with antibodies against 5hmC, 5mC and ten-eleven-translocation-2 (TET2). RESULTS: A significant decrease in 5hmC and TET2 expression was found in OSCC compared to healthy oral epithelium. In contrast, there was a significant increase in 5mC expression in OSCC compared to healthy epithelium. CONCLUSION: Our results indicate that loss of 5hmC is an epigenetic event of OSCC.