miR-31 is consistently inactivated in EBV-associated nasopharyngeal carcinoma and contributes to its tumorigenesis

BACKGROUND: As a distinctive type of head and neck cancers, nasopharyngeal carcinoma (NPC) is genesis from the clonal Epstein-Barr virus (EBV)-infected nasopharyngeal epithelial cells accumulated with multiple genetic lesions. Among the recurrent genetic alterations defined, loss of 9p21.3 is the most frequent early event in the tumorigenesis of EBV-associated NPC. In addition to the reported CDKN2A/p16, herein, we elucidated the role of a miRNA, miR-31 within this 9p21.3 region as NPC-associated tumor suppressor. METHODS: The expression and promoter methylation of miR-31 were assessed in a panel of NPC tumor lines and primary tumors. Its in vitro and in vivo tumor suppression function was investigated through the ectopic expression of miR-31 in NPC cells. We also determined the miR-31 targeted genes and its involvement in the growth in NPC. RESULTS: Downregulation of miR-31 expression was detected in almost all NPC cell line, patient-derived xenografts (PDXs) and primary tumors. Both homozygous deletion and promoter hypermethylation were shown to be major mechanisms for miR-31 silencing in this cancer. Strikingly, loss of miR-31 was also obviously observed in the dysplastic lesions of nasopharynx. Restoration of miR-31 in C666-1 cells inhibited the cell proliferation, colony-forming and migratory capacities. Dramatic reduction of in vitro anchorage-independent growth and in vivo tumorigenic potential were demonstrated in the stable clones expressing miR-31. Furthermore, we proved that miR-31 suppressed the NPC cell growth via targeting FIH1 and MCM2. CONCLUSIONS: The findings provide strong evidence to support miR-31 as a new NPC-associated tumor suppressor on 9p21.3 region. The inactivation of miR-31 may contribute to the early development of NPC.published_or_final_versio

Therapeutic targeting of CBP/β-catenin signaling reduces cancer stem-like population and synergistically suppresses growth of EBV-positive nasopharyngeal carcinoma cells with cisplatin

Nasopharyngeal carcinoma (NPC) is an EBV-associated epithelial malignancy prevalent in southern China. Presence of treatment-resistant cancer stem cells (CSC) may associate with tumor relapse and metastasis in NPC. ICG-001 is a specific CBP/β-catenin antagonist that can block CBP/β-catenin-mediated transcription of stem cell associated genes and enhance p300/β-catenin-mediated transcription, thereby reducing the CSC-like population via forced differentiation. In this study, we aimed to evaluate the effect of ICG-001 on the CSC-like population, and the combination effect of ICG-001 with cisplatin in the C666-1 EBV-positive NPC cells. Results showed that ICG-001 inhibited C666-1 cell growth and reduced expression of CSC-associated proteins with altered expression of epithelial-mesenchymal transition (EMT) markers. ICG-001 also inhibited C666-1 tumor sphere formation, accompanied with reduced SOX2 hi /CD44 hi CSC-like population. ICG-001 was also found to restore the expression of a tumor suppressive microRNA-145 (miR-145). Ectopic expression of miR-145 effectively repressed SOX2 protein expression and inhibited tumor sphere formation. Combination of ICG-001 with cisplatin synergistically suppressed in vitro growth of C666-1 cells and significantly suppressed growth of NPC xenografts. These results suggested that therapeutically targeting of the CBP/β-catenin signaling pathway with ICG-001 can effectively reduce the CSC-like population and combination with cisplatin can effectively suppress the growth of NPC.link_to_OA_fulltex

Breast cancer in Hong Kong, Southern China: The population-based, ten-year analysis of epidemiological characteristics, stage-specific, cancer-specific, & disease-free survival in breast cancer patients: 1997–2006

Poster Session 3: Epidemiology, Risk, and Prevention: Epidemiology - Population Studies: no. P3-07-32This journal suppl. entitled: Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium; December 9-13, 2014; San Antonio, TXBACKGROUND: Breast cancer is the most common cancer and second leading cause of cancer death among women, after lung cancer in Asia. The age-standardized incidence rates of breast cancer in Hong Kong is 61.0 per 100,000 women, after Singapore and Taiwan. With such increase, it would be important to better understand breast cancer to guide health care professionals and health policy makers to plan clinical management. However, to date such information is still under-reported, this study provide a comprehensive ten-year analyses of breast cancer in Hong Kong. METHODS: A retrospective study on population database over 10-year obtained from Hong Kong Cancer Registry was performed. A total of 20,290 female breast cancers’ medical records, diagnosed between January 1, 1997 and December 31, 2006, were reviewed. Descriptive statistics were employed to describe the epidemiological, clinical, and diagnostic data. The prognostic information for diagnostic and pathological data of relative survival (RS) was estimated using the maximum likelihood approach with program Strel in STATA; while the overall survival (OS), cancer-specific survival (CSS) & disease-free survival (DFS) were estimated by the Kaplan-Meier method with SPSS. Chi-squared test and Student's t-test were employed to compare variables in the two 5-year-periods of 1997-2001 and 2002-2006, with plotted RS curves for diagnostic and pathological data between these two 5-year-periods. RESULTS: 18,110 invasive breast cancer medical records in 1997-2006 were eligible for analysis, after 2,180 cases were excluding due to incomplete data. The ages at diagnosis ranged from 16 to 105; and median age was 51 years old. There was a drop from 14.1% in 1997-2001 to only 10.6% in 2002-2006 for those were diagnosed with breast cancer at age 39 years & younger. 26.2%, 55.2%, 13.0%, & 5.6% in 1997-2001, versus 30.1%, 46.4%, 16.9%, & 6.6% in 2002-2006 had tumor staging of stages I, II, III, and IV cancers at diagnosis, respectively. In ten-year period, the 5-year OS, RS, CSS, & DFS for the whole cohort were 80.6%, 85.6%, 87.1%, & 90.5%, respectively. The 5-year tumor stage-specific RS were 97.8%, 90.4%, 70.4%, & 21.4% for stages I, II, III, & IV, respectively. Between the two time periods, all the stage-specific RS improved by about 1%, 4%, 6% & 2% for stages I, II, III, & IV, respectively. There were 2,670 (14.7%) triple negative cases in 1997-2006, the ER-positive, PR-positive, & HER2-positive cancers increased from 66.1%, 52.6%, & 25.5% in 1997-2001 to 72.0%, 57.1%, & 29.4% in 2002-2006, respectively. DISCUSSION: Comprehensive analyses of breast cancer with population database from the Hong Kong Cancer Registry were performed to provide detailed information of a baseline study cohort in Southern China for comparative studies with other Asian regions.link_to_OA_fulltex

Management of nasopharyngeal carcinoma

Nasopharyngeal carcinoma is a distinctly radiosensitive and chemosensitive tumor. Best quality radiotherapy is demanded to build up the complex concave high-dose zone for this critical location. Intensity-modulated radiotherapy (IMRT) is advocated; image guidance to ensure setup precision and adaptive re-planning if major deviations from intended dose distribution occur during the treatment course are useful improvements if resources allow. Stringent dose constraint to organs at risk should be attempted to minimize late toxicities. Addition of cisplatin-based concurrent-adjuvant chemotherapy is recommended for patients with stages III–IVB and high-risk stage IIB diseases. Contemporary series using IMRT together with extensive use of chemotherapy reported very encouraging long-term results with locoregional control in excess of 85 % at 5 years; the key remaining problems are advanced T4 disease and distant failure. Further improvement of efficacy by more potent systemic therapy and changing chemotherapy sequence to induction-concurrent is being explored. The plasma level of Epstein–Barr Viral Deoxyribonucleic Acid is a well-established tool for non-keratinizing carcinoma for prognostication and monitoring disease progress. Integrated fluorodeoxyglucose positron emission tomography and computed tomography is useful for excluding distant metastases and posttreatment persistent/recurrent disease. Early detection of failure is critical; and aggressive treatment should be attempted as long survival could be achieved for patients with limited failure. Different salvage methods and reported results are summarized

Clinicopathological features and outcome of late relapses of natural killer cell lymphomas 10-29 years after initial remission

Natural killer (NK)-cell lymphomas are aggressive and relapses occur early. Late relapses are exceptional. Ten relapses 17.5 (11-29) years after first complete remission (CR1) were analyzed. Initial diseases were stage-I (nasal, n = 8; tonsil, n = 1; ileum, n = 1), treated with radiotherapy (n = 6), combined radiotherapy/chemotherapy (n = 3), and chemotherapy (n = 1). Relapse occurred at the same (nasal, n = 6; tonsil, n = 1), adjacent (initial: nasal, relapse: palate; n = 1) or distant (n = 2) sites. Five patients died soon afterwards. Four patients remitted with chemotherapy, two remaining in CR2 (3, 14 years). This series documented the rare late relapses in NK-cell lymphomas, which may still respond to salvage therapy. © 2010 Wiley-Liss, Inc.link_to_subscribed_fulltex

A prospective study on volumetric and dosimetric changes during intensity-modulated radiotherapy for nasopharyngeal carcinoma patients

Background and purpose: Significant tumor shrinkage and weight loss may occur during Intensity-modulated radiotherapy (IMRT) for nasopharyngeal carcinoma (NPC). This study aims to evaluate the dosimetric effect of volumetric changes on target volumes and organs at risk (OARs) during IMRT, using reassessment of computed tomography (CT) and magnetic resonance imaging (MRI). Material and methods: Nineteen loco-regionally advanced NPC patients treated with IMRT were recruited prospectively. Repeat planning CT and MRI were acquired at 30 and 50 Gy intervals. Recontouring of target volumes and OARs was based on the fused CT-MRI images. Hybrid plans with recontouring were generated. The assessment of volumetric and dosimetric changes was performed by comparing the hybrid plans with the original plan. Results: There was volume reduction of target volumes and parotid glands over the course of IMRT. Relative to the original plan, the hybrid plans demonstrated significantly higher dose to most of target volumes with greater dose inhomogeneity, higher maximum doses to the spinal cord and brainstem, and higher median doses to the parotid glands. Conclusions: Replanning with repeat CT and MRI scans at 30 Gy is essential to keep a satisfactory dose to the target volumes and avoid overdosing the OARs. © 2012 Elsevier Ireland Ltd. All rights reserved.link_to_subscribed_fulltex

A prospective study on volumetric and dosimetric changes during intensity-modulated radiotherapy for nasopharyngeal carcinoma patients

Background and purpose: Significant tumor shrinkage and weight loss may occur during Intensity-modulated radiotherapy (IMRT) for nasopharyngeal carcinoma (NPC). This study aims to evaluate the dosimetric effect of volumetric changes on target volumes and organs at risk (OARs) during IMRT, using reassessment of computed tomography (CT) and magnetic resonance imaging (MRI). Material and methods: Nineteen loco-regionally advanced NPC patients treated with IMRT were recruited prospectively. Repeat planning CT and MRI were acquired at 30 and 50 Gy intervals. Recontouring of target volumes and OARs was based on the fused CT-MRI images. Hybrid plans with recontouring were generated. The assessment of volumetric and dosimetric changes was performed by comparing the hybrid plans with the original plan. Results: There was volume reduction of target volumes and parotid glands over the course of IMRT. Relative to the original plan, the hybrid plans demonstrated significantly higher dose to most of target volumes with greater dose inhomogeneity, higher maximum doses to the spinal cord and brainstem, and higher median doses to the parotid glands. Conclusions: Replanning with repeat CT and MRI scans at 30 Gy is essential to keep a satisfactory dose to the target volumes and avoid overdosing the OARs. © 2012 Elsevier Ireland Ltd. All rights reserved.link_to_subscribed_fulltex

Case-control association studies of DNA damage repair genes associated with genetic susceptibility of nasopharyngeal carcinoma

Conference Theme: Mechanisms That Cause DNA Damage and Related DiseasesNasopharyngeal carcinoma (NPC) has a distinctive racial and geographical distribution and is especially prevalent in Southern Chinese. Its genetic etiology and the mechanisms responsible for inherited genetic susceptibility are complex and unclear. We hypothesized that heritable risk for NPC is attributable to cumulative effects of multiple common low-risk variants, especially those of the DNA damage repair (DDR) genes. To score the harmful effects of multiple common variants together conferring subtle effects for cancer risk, a multigenic pathway-based approach was used to systematically examine associations between NPC genetic susceptibility with SNPs in genes in DNA repair pathways and other cancer-linked loci. This case - control association study covers 161 genes/loci with a focus on DDR pathway-based analyses in 2,349 Hong Kong individuals. Three SNPs (rs401681, rs6774494, rs3757318) corresponding to TERT/CLPTM1L, MDS1-EVI1, and CCDC170 conferred modest protective effects individually for NPC risk by the logistic regression analysis after multiple testing adjustment. Stratification of NPC according to familial status identified rs2380165 in BLM association with family history-positive (FH+) NPC patients. FH+ NPC patients carrying higher numbers of unfavorable genotypes in different DDR pathways, including homologous recombination (HR), Fanconi Anemia (FA)-HR, FA-BLM, non-homologous end-joining (NHEJ), double-strand break repair (DSBR) - (HR+NHEJ), exhibited elevated NPC risk, while similar pathway-based analysis was not observed in sporadic NPC patients. The combined effects of TERT-CLPTM1L and DSB repairs for NPC risk were examined, since shortened telomeres are recognized as DSBs and DNA repair and recombination machineries are crucial for maintaining normal telomere function. Both FH+ and sporadic patients exhibited progressively significantly elevated NPC risk; a similar but less pronounced risk elevation was observed in sporadic NPC patients with regards to the cumulative effects in the DSBR pathways and TERT-CLPTM1L. The data suggested increasing NPC risk associated with TERT-CLPTM1L and DSBR signaling pathways correlate with NPC genetic susceptibility. This suggested a potential translational relevance for patient stratification and therapeutics