Oncogenic induction of cellular high CpG methylation by Epstein-Barr virus in malignant epithelial cells / 癌症

Epstein-Barr virus (EBV) is a well-known human herpesvirus associated with virtually all nasopharyngeal carcinoma (NPC) and approximately 10% of gastric cancer (GC) worldwide. Increasing evidence shows that acquired genetic and epigenetic alterations lead to the initiation and progression of NPC and GC. However, even deep whole exome sequencing studies showed a relatively low frequency of gene mutations in NPC and EBV-associated GC (EBVaGC), suggesting a predominant role of epigenetic abnormities, especially promoter CpG methylation, in the pathogenesis of NPC and EBVaGC. High frequencies of promoter methylation of tumor suppressor genes (TSGs) have been frequently reported in NPC and EBVaGC, with several EBV-induced methylated TSGs identified. Further characterization of the epigenomes (genome-wide CpG methylation profile--methylome) of NPC and EBVaGC shows that these EBV-associated tumors display a unique high CpG methylation epigenotype with more extensive gene methylation accumulation, indicating that EBV acts as a direct epigenetic driver for these cancers. Mechanistically, oncogenic modulation of cellular CpG methylation machinery, such as DNA methyltransferases (DNMTs), by EBV-encoded viral proteins accounts for the EBV-induced high CpG methylation epigenotype in NPC and EBVaGC. Thus, uncovering the EBV-associated unique epigenotype of NPC and EBVaGC would provide new insight into the molecular pathogenesis of these unique EBV-associated tumors and further help to develop pharmacologic strategies targeting cellular methylation machinery in these malignancies.

Validation of Self-administrated Questionnaire for Psychiatric Disorders in Patients with Functional Dyspepsia

INTRODUCTION: Psychiatric comorbidity is common in patients with functional dyspepsia (FD) but a good screening tool for psychiatric disorders in gastrointestinal clinical practice is lacking. Aims: 1) Evaluate the performance and optimal cut-off of 12-item General Health Questionnaire (GHQ-12) as a screening tool for psychiatric disorders in FD patients; 2) Compare health-related quality of life (HRQoL) in FD patients with and without psychiatric comorbidities. METHODS: Consecutive patients fulfilling Rome III criteria for FD without medical co-morbidities and gastroesophageal reflux disease were recruited in a gastroenterology clinic. The followings were conducted at 4 weeks after index oesophagogastroduodenoscopy: self-administrated questionnaires on socio-demographics, dyspeptic symptom severity (4-point Likert scale), GHQ-12, and 36-item short-form health survey (SF-36). Psychiatric disorders were diagnosed with Structured Clinical Interview for DSM-IV Axis I Disorders (SCID) by a trained psychiatrist, which served as reference standard. RESULTS: 55 patients underwent psychiatrist-conducted interview and questionnaire assessment. 27 (49.1%) had current psychiatric disorders as determined by SCID (anxiety disorders: 38.2%, depressive disorders: 16.4%). Receiver operating characteristic curve analysis of GHQ-12 revealed an area under curve of 0.825 (95%CI: 0.698-0.914). Cut-off of GHQ-12 at > or =3 gave a sensitivity of 63.0% (95%CI = 42.4-80.6%) and specificity of 92.9% (95%CI = 76.5%-98.9%). Subjects with co-existing psychiatric disorders scored significantly lower in multiple domains of SF-36 (mental component summary, general health, vitality and mental health). By multivariate linear regression analysis, current psychiatric morbidities (Beta = -0.396, p = 0.002) and family history of psychiatric illness (Beta = -0.299, p = 0.015) were independent risk factors for poorer mental component summary in SF-36, while dyspepsia severity was the only independent risk factor for poorer physical component summary (Beta = -0.332, p = 0.027). CONCLUSIONS: Concomitant psychiatric disorders adversely affect HRQoL in FD patients. The use of GHQ-12 as a reliable screening tool for psychiatric disorders allows early intervention and may improve clinical outcomes of these patients.