•GARD is associated with locoregional control in NPC and may serve as a potential framework to personalize radiotherapy dose.•Radiosensitive tumors for which GARD-optimized doses were estimated at ...less than the current standard (<66 Gy) (64.1 %).•Moderately radiosensitive tumors for which GARD-optmized doses were similar to current standard (66–74 Gy) (21.7 %).•Radioresistant tumors that GARD proposes may require dose escalation above the current standard (>74 Gy) (14.1 %).
Locally advanced nasopharyngeal cancer (NPC) patients undergoing radiotherapy are at risk of treatment failure, particularly locoregional recurrence. To optimize the individual radiation dose, we hypothesize that the genomic adjusted radiation dose (GARD) can be used to correlate with locoregional control.
A total of 92 patients with American Joint Committee on Cancer / International Union Against Cancer stage III to stage IVB recruited in a randomized phase III trial were assessed (NPC-0501) (NCT00379262). Patients were treated with concurrent chemo-radiotherapy plus (neo) adjuvant chemotherapy. The primary endpoint is locoregional failure free rate (LRFFR).
Despite the homogenous physical radiation dose prescribed (Median: 70 Gy, range 66–76 Gy), there was a wide range of GARD values (median: 50.7, range 31.1–67.8) in this cohort. In multivariable analysis, a GARD threshold (GARDT) of 45 was independently associated with LRFFR (p = 0.008). By evaluating the physical dose required to achieve the GARDT (RxRSI), three distinct clinical subgroups were identified: (1) radiosensitive tumors that RxRSI at dose < 66 Gy (N = 59, 64.1 %) (b) moderately radiosensitive tumors that RxRSI dose within the current standard of care range (66–74 Gy) (N = 20, 21.7 %), (c) radioresistant tumors that need a significant dose escalation above the current standard of care (>74 Gy) (N = 13, 14.1 %).
GARD is independently associated with locoregional control in radiotherapy-treated NPC patients from a Phase 3 clinical trial. GARD may be a potential framework to personalize radiotherapy dose for NPC patients.
Sulforaphane (SFN), a natural compound present in cruciferous vegetable, has been shown to possess anti-cancer activities. Cancer stem cell (CSC) in bulk tumor is generally considered as treatment ...resistant cell and involved in cancer recurrence. The effects of SFN on nasopharyngeal carcinoma (NPC) CSCs have not yet been explored.
The present study aims to examine the anti-tumor activities of SFN on NPC cells with CSC-like properties and the underlying mechanisms.
NPC cells growing in monolayer culture, CSCs-enriched NPC tumor spheres, and also the NPC nude mice xenograft were used to study the anti-tumor activities of SFN on NPC. The population of cells expressing CSC-associated markers was evaluated using flow cytometry and aldehyde dehydrogenase (ALDH) activity assay. The effect of DNA methyltransferase 1 (DNMT1) on the growth of NPC cells was analyzed by using small interfering RNA (siRNA)-mediated silencing method.
SFN was found to inhibit the formation of CSC-enriched NPC tumor spheres and reduce the population of cells with CSC-associated properties (SRY (Sex determining Region Y)-box 2 (SOX2) and ALDH). In the functional study, SFN was found to restore the expression of Wnt inhibitory factor 1 (WIF1) and the effect was accompanied with the downregulation of DNMT1. The functional activities of WIF1 and DNMT1 were confirmed using exogenously added recombinant WIF1 and siRNA knockdown of DNMT1. Moreover, SFN was found to inhibit the in vivo growth of C666-1 cells and enhance the anti-tumor effects of cisplatin.
Taken together, we demonstrated that SFN could suppress the growth of NPC cells via the DNMT1/WIF1 axis.
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The effects of the COVID-19 pandemic continue to constrain health-care staff and resources worldwide, despite the availability of effective vaccines. Aerosol-generating procedures such as endoscopy, ...a common investigation tool for nasopharyngeal carcinoma, are recognised as a likely cause of SARS-CoV-2 spread in hospitals. Plasma Epstein-Barr virus (EBV) DNA is considered the most accurate biomarker for the routine management of nasopharyngeal carcinoma. A consensus statement on whether plasma EBV DNA can minimise the need for or replace aerosol-generating procedures, imaging methods, and face-to-face consultations in managing nasopharyngeal carcinoma is urgently needed amid the current pandemic and potentially for future highly contagious airborne diseases or natural disasters. We completed a modified Delphi consensus process of three rounds with 33 international experts in otorhinolaryngology or head and neck surgery, radiation oncology, medical oncology, and clinical oncology with vast experience in managing nasopharyngeal carcinoma, representing 51 international professional societies and national clinical trial groups. These consensus recommendations aim to enhance consistency in clinical practice, reduce ambiguity in delivering care, and offer advice for clinicians worldwide who work in endemic and non-endemic regions of nasopharyngeal carcinoma, in the context of COVID-19 and other airborne pandemics, and in future unexpected settings of severe resource constraints and insufficiency of personal protective equipment.
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.
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Background: Survival of NPC patients has improved in past decades. Yet, survivors continue to face elevated risks of life-threatening late effects. Their impact on late mortality ...remains poorly quantified. Methods: 1353 five-year NPC survivors diagnosed between 1997 and 2013 at Queen Mary Hospital were reviewed. Their demographics and treatment data were taken from electronic medical records. Survival probability, standardized mortality ratios (SMRs) and absolute excessive risk were calculated for overall and cause-specific deaths. Results: At median follow-up time of 12.4 years, 412 (30.5%) five-year survivors had died at the time of analysis. 66.2% of deaths attributed to non-recurrence death. Estimated 10-, 15-, and 20-year survival probability were 81.4%, 67.6%, and 57.3% respectively. Compared to Hong Kong general population, absolute excessive risk of death from any causes was 17 deaths per 1000 person-years; overall SMR was 3.52 (95% CI: 3.19 to 3.87, p<0.001). Increases in cause-specific mortality were seen for death due to pulmonary (SMR: 6.75; 95% CI: 5.67 to 7.98) and secondary malignancy (SMR: 1.41; 95% CI: 1.06 to 1.83). Conclusions: Five-year NPC survivors still face excessive mortality long after diagnosis, and majority of death was from non-recurrence death. Further analyses are needed to determine predictive factors of excessive mortality. Table: see text
Nidogen-2 (NID2) is a key component of the basement membrane that stabilizes the extracellular matrix (ECM) network. The aim of the study is to analyze the functional roles of NID2 in the ...pathogenesis of nasopharyngeal carcinoma (NPC) and esophageal squamous cell carcinoma (ESCC). We performed genome-wide methylation profiling of NPC and ESCC and validated our findings using the methylation-sensitive high-resolution melting (MS-HRM) assay. Results showed that promoter methylation of NID2 was significantly higher in NPC and ESCC samples than in their adjacent non-cancer counterparts. Consistently, down-regulation of NID2 was observed in the clinical samples and cell lines of both NPC and ESCC. Re-expression of NID2 suppresses clonogenic survival and migration abilities of transduced NPC and ESCC cells. We showed that NID2 significantly inhibits liver metastasis. Mechanistic studies of signaling pathways also confirm that NID2 suppresses the EGFR/Akt and integrin/FAK/PLCγ metastasis-related pathways. This study provides novel insights into the crucial tumor metastasis suppression roles of NID2 in cancers.
Telomere shortening occurs as an early event in tumorigenesis. The TERT‐CLPTM1L locus associates with nasopharyngeal carcinoma (NPC) risk. It remains unknown if leukocyte telomere length (LTL) ...associates with NPC risk and survival. The relative LTL (rLTL) was measured by quantitative‐PCR in 2,996 individuals comprised of 1,284 NPC cases and 1712 matched controls. The odds ratio (OR) and 95% confidence intervals (CI) were calculated by logistic regression. The hazard ratio (HR) and 95% CI were calculated by Cox regression for survival analysis with rLTL and other clinical parameters in 1,243 NPC with a minimum follow‐up period of 25 months. NPC patients had significantly shorter telomere length than controls. Shorter rLTL significantly associated with increased NPC risk, when the individuals were dichotomized into long and short telomeres based on median‐split rLTL in the control group (OR = 2.317; 95% CI = 1.989–2.700, p = 4.10 × 10 −27 ). We observed a significant dose–response association ( p trend = 3.26 × 10 −34 ) between rLTL and NPC risk with OR being 3.555 (95% CI = 2.853–4.429) for the individuals in the first quartile (shortest) compared with normal individuals in the fourth quartile (longest). A multivariate Cox regression analysis adjusted by age demonstrated an independent effect of rLTL on NPC survival for late‐stage NPC patients, when the individuals were categorized into suboptimal rLTL versus the medium rLTL based on a threshold set from normal (HR = 1.471, 95% CI = 1.056–2.048, p = 0.022). Shorter blood telomeres may be markers for higher susceptibility for NPC risk. Suboptimal rLTL may be a poor prognostic factor for advanced NPC patients, as it associates independently with poor survival.
What's new? Telomere length can contribute to age‐related diseases, including cancer. These authors measured telomere length in leukocytes to look for a relationship with nasopharyngeal carcinoma (NPC). Shorter telomeres, they found, associated with increased risk of NPC. Somewhat surprisingly, people with suboptimal telomere length, either shorter or longer than average, appeared to have increased risk of late‐stage disease and poorer survival. Measuring blood telomere length could provide a simple, non‐invasive prognostic test for NPC.
Background: Epstein-Barr virus (EBV) latent infection is associated with genome-wide epigenomic changes in several malignancies, but its role in epigenetic dysregulation remains unclear in ...nasopharyngeal carcinoma (NPC). Methods: To investigate EBV-associated epigenetic dysregulation, we performed a multi-omics study by integrating whole-genome bisulfite sequencing (WGBS), assay for transposase-accessible chromatin using sequencing (ATAC-Seq), whole-exome sequencing (WES), and single-cell RNA sequencing (scRNA-Seq) data. Findings: In addition to the known global DNA hypermethylated subtype, we discovered a novel subtype with global hypomethylation in EBV + NPC. The consistent EBV-specific differentially methylated regions (EBV-DMRs) in the human genome were identified from both subtypes and associated with loss of CTCF binding (P < 2.2e-16). Importantly, CTCF is a master chromatin regulator and CTCF protein was reduced in 45% of NPC cases, especially in those with advanced NPC (Stage IV vs. others: 62% vs. 38%, P = 0.034). This result links EBV with chromatin changes. The ATAC-Seq data suggest regulatory epigenome reprogramming through chromatin accessibility changes in EBV + NPC with altered CTCF binding and the switch of transcription factor binding from differentiation-associated KLF/SP family to the innate and adaptive immunity-related NF-ĸB and IRF families. Detailed chromatin accessibility analysis identified a potential EBV target gene CD74, which mediated EBV-specific cell-cell communications in the tumor microenvironment (TME) and was strongly correlated with T cell exhaustion (r2 = 0.55). Interpretation: Our study reveals the unexpected epigenetic heterogeneity, providing insights into NPC pathogenesis and highlighting the involvement of host factors in virus-associated epigenetic changes. EBV infection is associated with epigenome reprogramming and may promote immune evasion. Funding: This study was funded by the Hong Kong Research Grants Council grant (AoE/M-06/08) to MLL, General Research Fund (17103218 and 17102619) and seed funding for basic research (201611159158) to WD, and General Research Fund (17119618) to HC.
Abstract
Background: Nasopharyngeal carcinoma (NPC) has the highest incidence in Guangdong province and Hong Kong in Southern China. Early detection of NPC is necessary to improve patient survival. ...Although aberrant methylation at promoter region of the tumour suppressors were often reported in NPC, genome-wide methylation changes have not been comprehensively investigated.
Aim: We aimed to examine the methylation profile of NPC patient tumours using a high-throughput approach to discover candidate biomarkers for early detection of NPC.
Methods: We systematically analyzed methylome data in the primary tumours and matched normal adjacent tissues from 25 NPC patients collected by Area of Excellence (AoE) NPC Tissue Bank using the Illumina HumanMethylation450 BeadChip platform. Comparatively, methylome data of solid tumours including prostate cancer, invasive breast cancer, pancreatic cancer, kidney cancer, thyroid cancer, liver cancer, rectal cancer, colon cancer, head and neck cancer, lung adenocarcinoma and lung squamous cell carcinoma collected by The Cancer Genome Atlas (TCGA) were examined. A quantitative method, bisulfite pyrosequencing, was applied to evaluate the aberrant methylation in an independent NPC patient cohort.
Results: In NPC, the hypermethylation pattern was more dominant than hypomethylation, where over 90% of the differentially methylated loci were hypermethylated within or close to CpG islands in tumours. The comparative methylome analysis reveals aberrant methylation at chromosome 6p frequently occurred in NPC (FDR = 1.33×10-9), but was rare in other types of solid tumours. Evident enrichment of the repressive mark H3K27me3 was found at this region, indicating both DNA methylation and histone modification function together, leading to epigenetic deregulation. Bisulfite pyrosequencing results further confirmed the aberrant methylation at 6p in an additional patient cohort, and 76.9% of the early-stage NPC patients can be detected by aberrant methylation on 6p. Furthermore, aberrant methylation at this region was observed in NPC recurrent tumours and matched metastatic lymph nodes, indicating the potential use of genes in this region for prognosis.
Conclusion: Our study highlights the importance of epigenetic deregulation in NPC. A novel genomic region on 6p with aberrant methylation was identified. This region contains several important genes that have great potential to be used as biomarkers for NPC early detection. The global genome-wide unbiased approach is useful to discover potential biomarkers for early diagnosis and prognosis in cancers.
Acknowledgements: NPC AoE funding was provided by the Hong Kong Research Grants Council (AoE/M-06/08) to MLL and HKU Small Project Funding to WD.
Citation Format: Wei Dai, Arthur Kwok Leung Cheung, Josephine Mun Yee Ko, Hong Zheng, Yue Cheng, Roger Kai Cheong Ngan, Wai Tong Ng, Anne Wing Mui Lee, Chun Chung Yau, Victor Ho Fu Lee, Maria Li Lung. Aberrant methylation at chromosome 6p as novel biomarkers for diagnosis and prognosis of nasopharyngeal carcinoma. abstract. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4773. doi:10.1158/1538-7445.AM2015-4773
NF-kappaB is a well-characterized transcription factor, widely known as a key player in tumor-derived inflammation and cancer development. Herein, we present the functional and molecular relevance of ...the canonical NF-kappaB p65 subunit in nasopharyngeal carcinoma (NPC). Loss- and gain-of-function approaches were utilized to reveal the functional characteristics of p65 in propagating tumor growth, tumor-associated angiogenesis, and epithelial-to-mesenchymal transition in NPC cells. Extracellular inflammatory stimuli are critical factors that trigger the NF-kappaB p65 signaling; hence, we investigated the components of the tumor microenvironment that might potentially influence the p65 signaling pathway. This led to the identification of an extracellular matrix (ECM) protein that was previously reported as a candidate tumor suppressor in NPC. Our studies on the Latent Transforming Growth Factor-beta Binding Protein 2 (LTBP2) protein provides substantial evidence that it can modulate the p65 transcriptional activity. Re-expression of LTBP2 elicits tumor suppressive effects that parallel the inactivation of p65 in NPC cells. LTBP2 was able to reduce phosphorylation of p65 at Serine 536, inhibit nuclear localization of active phosphorylated p65, and impair the p65 DNA-binding ability. This results in a consequential down-regulation of p65-related gene expression. Therefore, the data suggest that the overall up-regulation of p65 expression and the loss of this candidate ECM tumor suppressor are milestone events contributing to NPC development.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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![NF-[kappa]B p65 Subunit Is ...](http://api.summon.serialssolutions.com/2.0.0/image/issn/XR4PS5YY4K/1932-6203/small "NF-[kappa]B p65 Subunit Is Modulated by Latent Transforming Growth Factor-[beta] Binding Protein 2 in Nasopharyngeal Carcinoma HONE1 and HK1 Cells")