Publications by authors named "Yi-Xin Zeng"

400 Publications

Comparison of new magnetic resonance imaging grading system with conventional endoscopy for the early detection of nasopharyngeal carcinoma.

Cancer 2021 Jul 7. Epub 2021 Jul 7.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland, USA.

Background: Although stratifying individuals with respect to nasopharyngeal carcinoma (NPC) risk with Epstein-Barr virus-based markers is possible, the performance of diagnostic methods for detecting lesions among screen-positive individuals is poorly understood.

Methods: The authors prospectively evaluated 882 participants aged 30 to 70 years who were enrolled between October 2014 and November 2018 in an ongoing, population-based NPC screening program and had an elevated NPC risk. Participants were offered endoscopy and magnetic resonance imaging (MRI), and lesions were identified either by biopsy at a follow-up endoscopy or further contact and linkage to the local cancer registry through December 31, 2019. The diagnostic performance characteristics of endoscopy and MRI for NPC detection were investigated.

Results: Eighteen of 28 identified NPC cases were detected by both methods, 1 was detected by endoscopy alone, and 9 were detected by MRI alone. MRI had significantly higher sensitivity than endoscopy for NPC detection overall (96.4% vs 67.9%; P = .021) and for early-stage NPC (95.2% vs 57.1%; P = .021). The sensitivity of endoscopy was suggestively lower among participants who had previously been screened in comparison with those undergoing an initial screening (50.0% vs 81.2%; P = .11). The authors observed a higher overall referral rate by MRI versus endoscopy (17.3% vs 9.1%; P < .001). Cases missed by endoscopy had early-stage disease and were more commonly observed for tumors originating from the pharyngeal recess.

Conclusions: MRI was more sensitive than endoscopy for NPC detection in the context of population screening but required the referral of a higher proportion of screen-positive individuals. The sensitivity of endoscopy was particularly low for individuals who had previously been screened.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cncr.33552DOI Listing
July 2021

Corrigendum to ‟The telomere/telomerase binding factor PinX1 regulates paclitaxel sensitivity depending on spindle assembly checkpoint in human cervical squamous cell carcinomas" [Canc. Lett. 353 (2014) 104-114].

Cancer Lett 2021 Sep 3;516:61-63. Epub 2021 Jun 3.

State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China. Electronic address:

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.canlet.2021.05.023DOI Listing
September 2021

The Evolving Epidemiology of Nasopharyngeal Carcinoma.

Cancer Epidemiol Biomarkers Prev 2021 Jun 13;30(6):1035-1047. Epub 2021 Apr 13.

Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.

Background: The epidemiology of nasopharyngeal carcinoma (NPC) has long been a source of fascination due to the malignancy's striking geographic distribution, the involvement of the oncogenic Epstein-Barr virus (EBV), the unique association with intake of Chinese-style salt-preserved fish, and etiologic heterogeneity by histologic subtype.

Methods: This review summarizes the current epidemiologic literature on NPC, highlighting recent results from our population-based case-control study in southern China.

Results: Findings from our case-control study provide new insight into the epidemiology of NPC, including a diminished role of Chinese-style salt-preserved fish, a profound impact of EBV genetic sequence variation, modest positive associations with passive smoking and household air pollution, and possible effects of oral health and the oral microbiome. Recent findings from other studies include a protective association with infectious mononucleosis, suggesting a causal role of early EBV infection; familial risk conferred by shared genetic variation in the host antibody-mediated immune response to EBV infection; and an unclear association with occupational exposure to formaldehyde.

Conclusions: To shed further light on the interplay of environmental, genetic, and viral causes of NPC, large pooled studies must accumulate sufficient cases with detailed exposure data.

Impact: New epidemiologic findings have reshaped the causal model for NPC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1055-9965.EPI-20-1702DOI Listing
June 2021

Occupational exposures and risk of nasopharyngeal carcinoma in a high-risk area: A population-based case-control study.

Cancer 2021 Aug 6;127(15):2724-2735. Epub 2021 Apr 6.

Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden.

Background: The potential role of occupational exposures in the development of nasopharyngeal carcinoma (NPC) remains unclear, particularly in high-incidence areas.

Methods: The authors conducted a population-based case-control study, consisting of 2514 incident NPC cases and 2586 randomly selected population controls, in southern China from 2010 to 2014. Occupational history and other covariates were self-reported using a questionnaire. Multivariate logistic regression was used to estimate odds ratios (ORs) with 95% confidence intervals (CIs) for the risk of NPC associated with occupational exposures. Restricted cubic splines were used to evaluate potentially nonlinear duration-response relations.

Results: Individuals who had exposure to occupational dusts (OR, 1.45; 95% CI, 1.26-1.68), chemical vapors (OR, 1.37; 95% CI, 1.17-1.61), exhausts/smokes (OR, 1.42; 95% CI, 1.25-1.60), or acids/alkalis (OR, 1.56; 95% CI, 1.30-1.89) in the workplace had an increased NPC risk compared with those who were unexposed. Risk estimates for all 4 categories of occupational exposures appeared to linearly increase with increasing duration. Within these categories, occupational exposure to 14 subtypes of agents conferred significantly higher risks of NPC, with ORs ranging from 1.30 to 2.29, including dust from metals, textiles, cement, or coal; vapor from formaldehyde, organic solvents, or dyes; exhaust or smoke from diesel, firewood, asphalt/tar, vehicles, or welding; and sulfuric acid, hydrochloric acid, nitric acid, and concentrated alkali/ammonia.

Conclusions: Occupational exposures to dusts, chemical vapors, exhausts/smokes, or acids/alkalis are associated with an excess risk of NPC. If the current results are causal, then the amelioration of workplace conditions might alleviate the burden of NPC in endemic areas.

Lay Summary: The role of occupational exposures in the development of nasopharyngeal carcinoma (NPC) remains unclear, particularly in high-incidence areas. The authors conducted a population-based study with 2514 incident NPC cases and 2586 population controls in southern China and observed that occupational exposures were associated with an increased risk of NPC. Duration-response trends were observed with increasing duration of exposure. These findings provide new evidence supporting an etiologic role of occupational exposures for NPC in a high-incidence region.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cncr.33536DOI Listing
August 2021

Immunization with a Self-Assembled Nanoparticle Vaccine Elicits Potent Neutralizing Antibody Responses against EBV Infection.

Nano Lett 2021 03 8;21(6):2476-2486. Epub 2021 Mar 8.

State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Department of Experimental Research, Sun Yat-sen University Cancer Center, Sun Yat-sen University, Guangzhou 510060, P. R. China.

Epstein-Barr virus (EBV) infection is a global health concern infecting over 90% of the population. However, there is no currently available vaccine. EBV primarily infects B cells, where the major glycoprotein 350 (gp350) is the main target of neutralizing antibodies. Given the advancement of nanoparticle vaccines, we describe rationally designed vaccine modalities presenting 60 copies of gp350 on self-assembled nanoparticles in a repetitive array. In a mouse model, gp350s on lumazine synthase (LS) and I3-01 adjuvanted with MF59 or aluminum hydroxide (Alhydrogel) elicited over 65- to 133-fold higher neutralizing antibody titers than the corresponding gp350 monomer to EBV. Furthermore, immunization with gp350D-LS and gp350D-I3-01 vaccine induced a Th2-biased response. For the nonhuman primate model, gp350D-LS in MF59 elicited higher titers of total IgG and neutralizing antibodies than the monomeric gp350D. Overall, these results support gp350D-based nanoparticle vaccine design as a promising vaccine candidate for potent protection against EBV infection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.nanolett.0c04687DOI Listing
March 2021

T cell epitope screening of Epstein-Barr virus fusion protein gB.

J Virol 2021 Mar 3. Epub 2021 Mar 3.

State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, P. R. China

Glycoprotein B (gB) is an essential fusion protein for the Epstein-Barr virus (EBV) infection of both B cells and epithelial cells and is thus a promising target antigen for a prophylactic vaccine to prevent or reduce EBV-associated disease. T cell responses play key roles in the control of persistent EBV infection and in the efficacy of a vaccine. However, to date, T cell responses to gB have been characterized for only a limited number of human leukocyte antigen (HLA) alleles. Here, we screened gB T cell epitopes in 23 healthy EBV carriers and ten patients with nasopharyngeal cancer (NPC) using a peptide library spanning the entire gB sequence. We identified twelve novel epitopes in the context of seven new HLA restrictions that are common in Asian populations. Two epitopes, gB and gB, restricted by HLA-B*58:01 and B*38:02, respectively, elicited specific CD8 T cell responses to inhibit EBV-driven B cell transformation. Interestingly, gB-specific CD8 T cells were more frequent in healthy viral carriers with EBV reactivation than in those without EBV reactivation, indicating that EBV reactivation stimulates both humoral (VCA-gp125-IgA) and cellular responses to gB. We further found that most gB epitopes are conserved among different EBV strains. Our study broadens the diversity and HLA restrictions of gB epitopes and suggests that gB is a common target of T cell responses in healthy viral carriers with EBV reactivation. In particular, the precisely mapped and conserved gB epitopes provide valuable information for prophylactic vaccine development.T cells are crucial for the control of persistent EBV infection and the development of EBV-associated diseases. The EBV gB protein is essential for virus entry into B cells and epithelial cells and is thus a target antigen for vaccine development. Understanding T cell responses to gB is important for subunit vaccine design. Herein, we comprehensively characterized T cell responses to full-length gB. Our results expand the available gB epitopes and HLA restrictions, particularly those common in Asian populations. Furthermore, we showed that gB-specific CD8 T cells inhibit B cell transformation and that gB-specific CD8 T cell responses may be associated with intermittent EBV reactivation in asymptomatic viral carriers. These gB epitopes are highly conserved among geographically separated EBV strains. Precisely mapped and conserved T cell epitopes may contribute to immune monitoring and to the development of a gB subunit vaccine.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1128/JVI.00081-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8139657PMC
March 2021

Residence characteristics and risk of nasopharyngeal carcinoma in southern China: A population-based case-control study.

Environ Int 2021 06 27;151:106455. Epub 2021 Feb 27.

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Department of Epidemiology and Health Statistics & Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Fujian Medical University, Fuzhou, China. Electronic address:

Objectives: Given the role of exposures related to residence in the development of nasopharyngeal carcinoma (NPC) has not been well explored, present study aims to investigate the magnitude and pattern of associations for NPC with lifelong residential exposures.

Materials And Methods: We carried out a multi-center, population-based case-control study with 2533 incident NPC cases and 2597 randomly selected population controls in southern China between 2010 and 2014. We performed multivariate logistic regression to estimate odds ratios (ORs) with 95% confidence intervals (CIs) for the risk of NPC associated with residential exposures.

Results: Compared with those living in a building over lifetime, risk of NPC was higher for individuals living in a cottage (OR: 1.56; 95% CI: 1.34-1.81) or in a boat (3.87; 2.07-7.21). NPC risk was also increased in individuals using wood (1.34; 1.03-1.75), coal (1.70; 1.17-2.47), or kerosene (3.58; 1.75-7.36) vs. using gas/electricity as cooking fuel; using well water (1.57; 1.34-1.83), river water (1.80; 1.47-2.21), or spring/pond/stream water (2.03; 1.70-2.41) vs. tap water for source of drinking water; living in houses with smaller-sized vs. larger windows in the bedroom (3.08; 2.46-3.86), hall (1.89; 1.55-2.31) or kitchen (1.67; 1.34-2.08); and increasing exposure to cooking smoke [(1.53; 1.20-1.94) for high exposure)] or burned incense [(1.59; 1.31-1.95) for daily use)]. Weighted Cox regression analysis corroborated these results.

Conclusion: Poorer residential conditions and household air pollution are associated with an increased risk of NPC. Large-scale studies in other populations or longitudinal studies are warranted to further corroborate these findings.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.envint.2021.106455DOI Listing
June 2021

N(6)-methyladenosine-binding protein YTHDF1 suppresses EBV replication and promotes EBV RNA decay.

EMBO Rep 2021 04 19;22(4):e50128. Epub 2021 Feb 19.

State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China.

N -methyladenosine (m A) modification of mRNA mediates diverse cellular and viral functions. Infection with Epstein-Barr virus (EBV) is causally associated with nasopharyngeal carcinoma (NPC), 10% of gastric carcinoma, and various B-cell lymphomas, in which the viral latent and lytic phases both play vital roles. Here, we show that EBV transcripts exhibit differential m A modification in human NPC biopsies, patient-derived xenograft tissues, and cells at different EBV infection stages. m A-modified EBV transcripts are recognized and destabilized by the YTHDF1 protein, which leads to the m A-dependent suppression of EBV infection and replication. Mechanistically, YTHDF1 hastens viral RNA decapping and mediates RNA decay by recruiting RNA degradation complexes, including ZAP, DDX17, and DCP2, thereby post-transcriptionally downregulating the expression of EBV genes. Taken together, our results reveal the critical roles of m A modifications and their reader YTHDF1 in EBV replication. These findings contribute novel targets for the treatment of EBV-associated cancers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.15252/embr.202050128DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8025027PMC
April 2021

Rab22a-NeoF1 fusion protein promotes osteosarcoma lung metastasis through its secretion into exosomes.

Signal Transduct Target Ther 2021 Feb 11;6(1):59. Epub 2021 Feb 11.

State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.

It remains unknown for decades how some of the therapeutic fusion proteins positive in a small percentage of cancer cells account for patient outcome. Here, we report that osteosarcoma Rab22a-NeoF1 fusion protein, together with its binding partner PYK2, is sorted into exosomes by HSP90 via its KFERQ-like motif (RVLFLN). The exosomal Rab22a-NeoF1 fusion protein facilitates the pulmonary pre-metastatic niche formation by recruiting bone marrow-derived macrophages. The exosomal PYK2 activates RhoA in its negative recipient osteosarcoma cells and induces signal transducer and activator of transcription 3 activation in its recipient macrophages to increase M2 phenotype. Consequently, lung metastases of its recipient osteosarcoma cells are promoted by this exosomal Rab22a-NeoF1 fusion protein, and this event can be targeted by disrupting its interaction with PYK2 using a designed internalizing RGD peptide.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41392-020-00414-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7876000PMC
February 2021

Tumour heterogeneity and intercellular networks of nasopharyngeal carcinoma at single cell resolution.

Nat Commun 2021 02 2;12(1):741. Epub 2021 Feb 2.

Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangzhou, 510060, People's Republic of China.

The heterogeneous nature of tumour microenvironment (TME) underlying diverse treatment responses remains unclear in nasopharyngeal carcinoma (NPC). Here, we profile 176,447 cells from 10 NPC tumour-blood pairs, using single-cell transcriptome coupled with T cell receptor sequencing. Our analyses reveal 53 cell subtypes, including tumour-infiltrating CD8 T, regulatory T (Treg), and dendritic cells (DCs), as well as malignant cells with different Epstein-Barr virus infection status. Trajectory analyses reveal exhausted CD8 T and immune-suppressive TNFRSF4 Treg cells in tumours might derive from peripheral CX3CR1CD8 T and naïve Treg cells, respectively. Moreover, we identify immune-regulatory and tolerogenic LAMP3 DCs. Noteworthily, we observe intensive inter-cell interactions among LAMP3 DCs, Treg, exhausted CD8 T, and malignant cells, suggesting potential cross-talks to foster an immune-suppressive niche for the TME. Collectively, our study uncovers the heterogeneity and interacting molecules of the TME in NPC at single-cell resolution, which provide insights into the mechanisms underlying NPC progression and the development of precise therapies for NPC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-021-21043-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7854640PMC
February 2021

Rapid Development of SARS-CoV-2 Spike Protein Receptor-Binding Domain Self-Assembled Nanoparticle Vaccine Candidates.

ACS Nano 2021 02 19;15(2):2738-2752. Epub 2021 Jan 19.

State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Department of Experimental Research, Sun Yat-sen University Cancer Center, Sun Yat-sen University, Guangzhou 510060, P. R. China.

The coronavirus disease pandemic of 2019 (COVID-19) caused by the novel SARS-CoV-2 coronavirus resulted in economic losses and threatened human health worldwide. The pandemic highlights an urgent need for a stable, easily produced, and effective vaccine. SARS-CoV-2 uses the spike protein receptor-binding domain (RBD) to bind its cognate receptor, angiotensin-converting enzyme 2 (ACE2), and initiate membrane fusion. Thus, the RBD is an ideal target for vaccine development. In this study, we designed three different RBD-conjugated nanoparticle vaccine candidates, namely, RBD-Ferritin (24-mer), RBD-mi3 (60-mer), and RBD-I53-50 (120-mer), via covalent conjugation using the SpyTag-SpyCatcher system. When mice were immunized with the RBD-conjugated nanoparticles (NPs) in conjunction with the AddaVax or Sigma Adjuvant System, the resulting antisera exhibited 8- to 120-fold greater neutralizing activity against both a pseudovirus and the authentic virus than those of mice immunized with monomeric RBD. Most importantly, sera from mice immunized with RBD-conjugated NPs more efficiently blocked the binding of RBD to ACE2 , further corroborating the promising immunization effect. Additionally, the vaccine has distinct advantages in terms of a relatively simple scale-up and flexible assembly. These results illustrate that the SARS-CoV-2 RBD-conjugated nanoparticles developed in this study are a competitive vaccine candidate and that the carrier nanoparticles could be adopted as a universal platform for a future vaccine development.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acsnano.0c08379DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7839421PMC
February 2021

Intake of Alcohol and Tea and Risk of Nasopharyngeal Carcinoma: A Population-Based Case-Control Study in Southern China.

Cancer Epidemiol Biomarkers Prev 2021 Mar 10;30(3):545-553. Epub 2020 Dec 10.

Department of Cancer Prevention Center, Sun Yat-sen University Cancer Center, Guangzhou, China.

Background: The potential effect of alcohol or tea intake on the risk of nasopharyngeal carcinoma (NPC) remains controversial.

Methods: In a population-based case-control study in southern China, we assessed alcohol or tea intake from 2,441 histopathologically confirmed NPC cases and 2,546 controls. We calculated mean daily ethanol (g/day) and tea intake (mL/day). Fully adjusted ORs with 95% confidence intervals (CI) were estimated using logistic regression; potential dose-response trends were evaluated using restricted cubic spline analysis.

Results: Compared with nondrinkers, no significantly increased NPC risk in men was observed among current alcohol drinkers overall (OR, 1.08; 95% CI, 0.93-1.25), nor among current heavy drinkers (OR for ≥90 g/day ethanol vs. none, 1.32; 95% CI, 0.95-1.84) or former alcohol drinkers. Current tea drinking was associated with a decreased NPC risk (OR, 0.73; 95% CI, 0.64-0.84). Compared with never drinkers, those with the low first three quintiles of mean daily current intake of tea were at significantly lower NPC risk (OR, 0.53, 0.68, and 0.65, respectively), but not significant for the next two quintiles. Current daily tea intake had a significant nonlinear dose-response relation with NPC risk.

Conclusions: Our study suggests no significant association between alcohol and NPC risk. Tea drinking may moderately reduce NPC risk, but the lack of a monotonic dose-response association complicates causal inference.

Impact: Tea drinking might be a healthy habit for preventing NPC. More studies on biological mechanisms that may link tea with NPC risk are needed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1055-9965.EPI-20-1244DOI Listing
March 2021

Single cell sequencing reveals cell populations that predict primary resistance to imatinib in chronic myeloid leukemia.

Aging (Albany NY) 2020 11 23;12(24):25337-25355. Epub 2020 Nov 23.

State Key Lab of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.

The treatment of chronic myeloid leukemia (CML), a disease caused by t(9;22)(q34;q11) reciprocal translocation, has advanced largely through the use of targeted tyrosine kinase inhibitors (TKIs). To identify molecular differences that might distinguish TKI responders from non-responders, we performed single cell RNA sequencing on cells (n = 41,723 cells) obtained from the peripheral blood of four CML patients at different stages of treatment to generate single cell expression profiles. Analysis of our single cell expression profiles in conjunction with those previously obtained from the bone marrow of additional CML patients and healthy donors (total = 69,263 cells) demonstrated that imatinib treatment significantly altered leukocyte population compositions in both responders and non-responders, and affected the expression profiles of multiple cell populations, including non-neoplastic cell types. Notably, in imatinib poor-responders, patient-specific pre-treatment unique stem/progenitor cells became enriched in peripheral blood compared to the responders. These results indicate that resistance to TKIs might be intrinsic in some CML patients rather than acquired, and that non-neoplastic immune cell types may also play vital roles in dispersing the responsiveness of patients to TKIs. Furthermore, these results demonstrated the potential utility of peripheral blood as a diagnostic tool in the TKI sensitivity of CML patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.18632/aging.104136DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7803567PMC
November 2020

Structure of Epstein-Barr virus tegument protein complex BBRF2-BSRF1 reveals its potential role in viral envelopment.

Nat Commun 2020 10 26;11(1):5405. Epub 2020 Oct 26.

State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 510060, Guangzhou, China.

Epstein-Barr virus (EBV) is a γ-herpesvirus associated with the occurrence of several human malignancies. BBRF2 and BSRF1 are two EBV tegument proteins that have been suggested to form a hetero-complex and mediate viral envelopment, but the molecular basis of their interaction and the functional mechanism of this complex remains unknown. Here, we present crystal structures of BBRF2 alone and in complex with BSRF1. BBRF2 has a compact globular architecture featuring a central β-sheet that is surrounded by 10 helices, it represents a novel fold distinct from other known protein structures. The central portion of BSRF1 folds into two tightly associated antiparallel α-helices, forming a composite four-helix bundle with two α-helices from BBRF2 via a massive hydrophobic network. In vitro, a BSRF1-derived peptide binds to BBRF2 and reduces the number of viral genome copies in EBV-positive cells. Exogenous BBRF2 and BSRF1 co-localize at the Golgi apparatus. Furthermore, BBRF2 binds capsid and capsid-associated proteins, whereas BSRF1 associates with glycoproteins. These findings indicate that the BBRF2-BSRF1 complex tethers EBV nucleocapsids to the glycoprotein-enriched Golgi membrane, facilitating secondary envelopment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-020-19259-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7588443PMC
October 2020

Genome-Wide Meta-Analysis Identifies Three Novel Susceptibility Loci and Reveals Ethnic Heterogeneity of Genetic Susceptibility for IgA Nephropathy.

J Am Soc Nephrol 2020 12 10;31(12):2949-2963. Epub 2020 Sep 10.

Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China

Background: Eighteen known susceptibility loci for IgAN account for only a small proportion of IgAN risk.

Methods: Genome-wide meta-analysis was performed in 2628 patients and 11,563 controls of Chinese ancestry, and a replication analysis was conducted in 6879 patients and 9019 controls of Chinese descent and 1039 patients and 1289 controls of European ancestry. The data were used to assess the association of susceptibility loci with clinical phenotypes for IgAN, and to investigate genetic heterogeneity of IgAN susceptibility between the two populations. Imputation-based analysis of the MHC/HLA region extended the scrutiny.

Results: Identification of three novel loci (rs6427389 on 1q23.1 [=8.18×10, OR=1.132], rs6942325 on 6p25.3 [=1.62×10, OR=1.165], and rs2240335 on 1p36.13 [=5.10×10, OR=1.114]), implicates , , and as susceptibility genes for IgAN. Rs2240335 is associated with the expression level of , and rs6427389 is in high linkage disequilibrium with rs11264799, which showed a strong expression quantitative trail loci effect on . Of the 24 confirmed risk SNPs, six showed significant heterogeneity of genetic effects and showed clear evidence of allelic heterogeneity between the populations. Imputation-based analysis of the MHC region revealed significant associations at three HLA polymorphisms (HLA allele DPB1*02, AA_DRB1_140_32657458_T, and AA_DQA1_34_32717152) and two SNPs (rs9275464 and rs2295119).

Conclusions: A meta-analysis of GWAS data revealed three novel genetic risk loci for IgAN, and three HLA polymorphisms and two SNPs within the MHC region, and demonstrated the genetic heterogeneity of seven loci out of 24 confirmed risk SNPs.  These variants may explain susceptibility differences between Chinese and European populations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1681/ASN.2019080799DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7790208PMC
December 2020

Autocrine INSL5 promotes tumor progression and glycolysis via activation of STAT5 signaling.

EMBO Mol Med 2020 09 12;12(9):e12050. Epub 2020 Jul 12.

State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.

Metabolic reprogramming plays important roles in development and progression of nasopharyngeal carcinoma (NPC), but the underlying mechanism has not been completely defined. In this work, we found INSL5 was elevated in NPC tumor tissue and the plasma of NPC patients. Plasma INSL5 could serve as a novel diagnostic marker for NPC, especially for serum VCA-IgA-negative patients. Moreover, higher plasma INSL5 level was associated with poor disease outcome. Functionally, INSL5 overexpression increased, whereas knockdown of its receptor GPCR142 or inhibition of INSL5 reduced cell proliferation, colony formation, and cell invasion in vitro and tumorigenicity in vivo. Mechanistically, INSL5 enhanced phosphorylation and nuclear translocation of STAT5 and promoted glycolytic gene expression, leading to induced glycolysis in cancer cells. Pharmaceutical inhibition of glycolysis by 2-DG or blockade of INSL5 by a neutralizing antibody reversed INSL5-induced proliferation and invasion, indicating that INSL5 can be a potential therapeutic target in NPC. In conclusion, INSL5 enhances NPC progression by regulating cancer cell metabolic reprogramming and is a potential diagnostic and prognostic marker as well as a therapeutic target for NPC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.15252/emmm.202012050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7507000PMC
September 2020

Author Correction: Chromosomal translocation-derived aberrant Rab22a drives metastasis of osteosarcoma.

Nat Cell Biol 2020 Jul;22(7):907

State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41556-020-0541-9DOI Listing
July 2020

A novel vaccine candidate based on chimeric virus-like particle displaying multiple conserved epitope peptides induced neutralizing antibodies against EBV infection.

Theranostics 2020 27;10(13):5704-5718. Epub 2020 Apr 27.

State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Department of Experimental Research, Sun Yat-sen University Cancer Center, Sun Yat-sen University, Guangzhou, Guangdong, PR China.

: Epstein-Barr virus (EBV) is the causative pathogen for infectious mononucleosis and many kinds of malignancies including several lymphomas such as Hodgkin's lymphoma, Burkitt's lymphoma and NK/T cell lymphoma as well as carcinomas such as nasopharyngeal carcinoma (NPC) and EBV-associated gastric carcinoma (EBV-GC). However, to date no available prophylactic vaccine was launched to the market for clinical use. : To develop a novel vaccine candidate to prevent EBV infection and diseases, we designed chimeric virus-like particles (VLPs) based on the hepatitis B core antigen (HBc149). Various VLPs were engineered to present combinations of three peptides derived from the receptor binding domain of EBV gp350. All the chimeric virus-like particles were injected into Balb/C mice for immunogenicity evaluation. Neutralizing titer of mice sera were detected using an cell model. : All chimeric HBc149 proteins self-assembled into VLPs with gp350 epitopes displayed on the surface of spherical particles. Interestingly, the different orders of the three epitopes in the chimeric proteins induced different immune responses in mice. Two constructs (149-3A and 149-3B) induced high serum titer against the receptor-binding domain of gp350. Most importantly, these two VLPs elicited neutralizing antibodies in immunized mice, which efficiently blocked EBV infection in cell culture. Competition analysis showed that sera from these mice contained antibodies to a major neutralizing epitope recognized by the strong neutralizing mAb 72A1. : Our data demonstrate that HBc149 chimeric VLPs provide a valuable platform to present EBV gp350 antigens and offer a robust basis for the development of peptide-based candidate vaccines against EBV.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7150/thno.42494DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7255000PMC
August 2021

Chromosomal translocation-derived aberrant Rab22a drives metastasis of osteosarcoma.

Nat Cell Biol 2020 07 1;22(7):868-881. Epub 2020 Jun 1.

State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.

Osteosarcoma is a type of aggressive malignant bone tumour that frequently metastasizes to lungs, resulting in poor prognosis. However, the molecular mechanisms of lung metastasis of osteosarcoma remain poorly understood. Here we identify exon-intron fusion genes in osteosarcoma cell lines and tissues. These fusion genes are derived from chromosomal translocations that juxtapose the coding region for amino acids 1-38 of Rab22a (Rab22a) with multiple inverted introns and untranslated regions of chromosome 20. The resulting translation products, designated Rab22a-NeoFs, acquire the ability to drive lung metastasis of osteosarcoma. The Rab22a moiety governs the function of Rab22a-NeoFs by binding to SmgGDS-607, a GTP-GDP exchange factor of RhoA. This association facilitates the release of GTP-bound RhoA from SmgGDS-607, which induces increased activity of RhoA and promotes metastasis. Disrupting the interaction between Rab22a-NeoF1 and SmgGDS-607 with a synthetic peptide prevents lung metastasis in an orthotopic model of osteosarcoma. Our findings may provide a promising strategy for a subset of osteosarcoma patients with lung metastases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41556-020-0522-zDOI Listing
July 2020

Germline Polymorphisms and Length of Survival of Nasopharyngeal Carcinoma: An Exome-Wide Association Study in Multiple Cohorts.

Adv Sci (Weinh) 2020 May 20;7(10):1903727. Epub 2020 Mar 20.

Sun Yat-sen University Cancer Center State Key Laboratory of Oncology in South China Collaborative Innovation Center for Cancer Medicine Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy Guangzhou 510060 P. R. China.

Germline polymorphisms are linked with differential survival outcomes in cancers but are not well studied in nasopharyngeal carcinoma (NPC). Here, a two-phase association study is conducted to discover germline polymorphisms that are associated with the prognosis of NPC. The discovery phase includes two consecutive hospital cohorts of patients with NPC from Southern China. Exome-wide genotypes at 246 173 single nucleotide polymorphisms (SNPs) are determined, followed by survival analysis for each SNP under Cox proportional hazard regression model. Candidate SNP is replicated in another two independent cohorts from Southern China and Singapore. Meta-analysis of all samples ( = 5553) confirms that the presence of rs1131636-T, located in the 3'-UTR of , confers an inferior overall survival (HR = 1.33, 95% CI = 1.20-1.47, = 6.31 × 10). Bioinformatics and biological assays show that rs1131636 has regulatory effects on upstream . Functional studies further demonstrate that RPA1 promotes the growth, invasion, migration, and radioresistance of NPC cells. Additionally, miR-1253 is identified as a suppressor for RPA1 expression, likely through regulation of its binding affinity to rs1131636 locus. Collectively, these findings provide a promising biomarker aiding in stratifying patients with poor survival, as well as a potential drug target for NPC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/advs.201903727DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7237860PMC
May 2020

Targeting the CK1α/CBX4 axis for metastasis in osteosarcoma.

Nat Commun 2020 02 28;11(1):1141. Epub 2020 Feb 28.

State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.

Osteosarcoma, an aggressive malignant cancer, has a high lung metastasis rate and lacks therapeutic target. Here, we reported that chromobox homolog 4 (CBX4) was overexpressed in osteosarcoma cell lines and tissues. CBX4 promoted metastasis by transcriptionally up-regulating Runx2 via the recruitment of GCN5 to the Runx2 promoter. The phosphorylation of CBX4 at T437 by casein kinase 1α (CK1α) facilitated its ubiquitination at both K178 and K280 and subsequent degradation by CHIP, and this phosphorylation of CBX4 could be reduced by TNFα. Consistently, CK1α suppressed cell migration and invasion through inhibition of CBX4. There was a reverse correlation between CK1α and CBX4 in osteosarcoma tissues, and CK1α was a valuable marker to predict clinical outcomes in osteosarcoma patients with metastasis. Pyrvinium pamoate (PP) as a selective activator of CK1α could inhibit osteosarcoma metastasis via the CK1α/CBX4 axis. Our findings indicate that targeting the CK1α/CBX4 axis may benefit osteosarcoma patients with metastasis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-020-14870-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7048933PMC
February 2020

Genetic risk of extranodal natural killer T-cell lymphoma: a genome-wide association study in multiple populations.

Lancet Oncol 2020 02 23;21(2):306-316. Epub 2019 Dec 23.

Department of Epidemiology and Biostatistics, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, School of Public Health, Nanjing Medical University, Nanjing, China.

Background: Extranodal natural killer T-cell lymphoma (NKTCL; nasal type) is an aggressive malignancy with a particularly high prevalence in Asian and Latin American populations. Epstein-Barr virus infection has a role in the pathogenesis of NKTCL, and HLA-DPB1 variants are risk factors for the disease. We aimed to identify additional novel genetic variants affecting risk of NKTCL.

Methods: We did a genome-wide association study of NKTCL in multiple populations from east Asia. We recruited a discovery cohort of 700 cases with NKTCL and 7752 controls without NKTCL of Han Chinese ancestry from 19 centres in southern, central, and northern regions of China, and four independent replication samples including 717 cases and 12 650 controls. Three of these independent samples (451 cases and 5301 controls) were from eight centres in the same regions of southern, central, and northern China, and the fourth (266 cases and 7349 controls) was from 11 centres in Hong Kong, Taiwan, Singapore, and South Korea. All cases had primary NKTCL that was confirmed histopathologically, and matching with controls was based on geographical region and self-reported ancestry. Logistic regression analysis was done independently by geographical regions, followed by fixed-effect meta-analyses, to identify susceptibility loci. Bioinformatic approaches, including expression quantitative trait loci, binding motif and transcriptome analyses, and biological experiments were done to fine-map and explore the functional relevance of genome-wide association loci to the development of NKTCL.

Findings: Genetic data were gathered between Jan 1, 2008, and Jan 23, 2019. Meta-analysis of all samples (a total of 1417 cases and 20 402 controls) identified two novel loci significantly associated with NKTCL: IL18RAP on 2q12.1 (rs13015714; p=2·83 × 10; odds ratio 1·39 [95% CI 1·28-1·50]) and HLA-DRB1 on 6p21.3 (rs9271588; 9·35 × 10 1·53 [1·41-1·65]). Fine-mapping and experimental analyses showed that rs1420106 at the promoter of IL18RAP was highly correlated with rs13015714, and the rs1420106-A risk variant had an upregulatory effect on IL18RAP expression. Cell growth assays in two NKTCL cell lines (YT and SNK-6 cells) showed that knockdown of IL18RAP inhibited cell proliferation by cell cycle arrest in NKTCL cells. Haplotype association analysis showed that haplotype 47F-67I was associated with reduced risk of NKTCL, whereas 47Y-67L was associated with increased risk of NKTCL. These two positions are component parts of the peptide-binding pocket 7 (P7) of the HLA-DR heterodimer, suggesting that these alterations might account for the association at HLA-DRB1, independent of the previously reported HLA-DPB1 variants.

Interpretation: Our findings provide new insights into the development of NKTCL by showing the importance of inflammation and immune regulation through the IL18-IL18RAP axis and antigen presentation involving HLA-DRB1, which might help to identify potential therapeutic targets. Taken in combination with additional genetic and other risk factors, our results could potentially be used to stratify people at high risk of NKTCL for targeted prevention.

Funding: Guangdong Innovative and Entrepreneurial Research Team Program, National Natural Science Foundation of China, National Program for Support of Top-Notch Young Professionals, Chang Jiang Scholars Program, Singapore Ministry of Health's National Medical Research Council, Tanoto Foundation, National Research Foundation Singapore, Chang Gung Memorial Hospital, Recruitment Program for Young Professionals of China, First Affiliated Hospital and Army Medical University, US National Institutes of Health, and US National Cancer Institute.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S1470-2045(19)30799-5DOI Listing
February 2020

Identification of Novel Loci and New Risk Variant in Known Loci for Colorectal Cancer Risk in East Asians.

Cancer Epidemiol Biomarkers Prev 2020 02 11;29(2):477-486. Epub 2019 Dec 11.

Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan.

Background: Risk variants identified so far for colorectal cancer explain only a small proportion of familial risk of this cancer, particularly in Asians.

Methods: We performed a genome-wide association study (GWAS) of colorectal cancer in East Asians, including 23,572 colorectal cancer cases and 48,700 controls. To identify novel risk loci, we selected 60 promising risk variants for replication using data from 58,131 colorectal cancer cases and 67,347 controls of European descent. To identify additional risk variants in known colorectal cancer loci, we performed conditional analyses in East Asians.

Results: An indel variant, rs67052019 at 1p13.3, was found to be associated with colorectal cancer risk at × 10 in Asians ( per allele deletion = 1.13, 95% confidence interval = 1.08-1.18). This association was replicated in European descendants using a variant (rs2938616) in complete linkage disequilibrium with rs67052019 ( = 7.7 × 10). Of the remaining 59 variants, 12 showed an association at < 0.05 in the European-ancestry study, including rs11108175 and rs9634162 at < 5 × 10 and two variants with an association near the genome-wide significance level (rs60911071, = 5.8 × 10; rs62558833, = 7.5 × 10) in the combined analyses of Asian- and European-ancestry data. In addition, using data from East Asians, we identified 13 new risk variants at 11 loci reported from previous GWAS.

Conclusions: In this large GWAS, we identified three novel risk loci and two highly suggestive loci for colorectal cancer risk and provided evidence for potential roles of multiple genes and pathways in the etiology of colorectal cancer. In addition, we showed that additional risk variants exist in many colorectal cancer risk loci identified previously.

Impact: Our study provides novel data to improve the understanding of the genetic basis for colorectal cancer risk.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1055-9965.EPI-19-0755DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7571256PMC
February 2020

Genome-Wide CRISPR-Cas9 Screen Reveals Selective Vulnerability of -Mutant Cancers to WEE1 Inhibition.

Cancer Res 2020 02 24;80(3):510-523. Epub 2019 Sep 24.

State Key Lab of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

The tumor suppressor gene is frequently mutated in a variety of tumors including gliomas and liver cancers, which are highly unresponsive to current therapies. Here, we performed a genome-wide synthetic lethal screen, using CRISPR-Cas9 genome editing, to identify potential therapeutic targets specific for -mutated cancers. In isogenic hepatocellular carcinoma (HCC) cell lines engineered for ATRX loss, we identified 58 genes, including the checkpoint kinase , uniquely required for the cell growth of ATRX null cells. Treatment with the WEE1 inhibitor AZD1775 robustly inhibited the growth of several ATRX-deficient HCC cell lines , as well as xenografts . The increased sensitivity to the WEE1 inhibitor was caused by accumulated DNA damage-induced apoptosis. AZD1775 also selectively inhibited the proliferation of patient-derived primary cell lines from gliomas with naturally occurring mutations, indicating that the synthetic lethal relationship between and could be exploited in a broader spectrum of human tumors. As WEE1 inhibitors have been investigated in several phase II clinical trials, our discovery provides the basis for an easily clinically testable therapeutic strategy specific for cancers deficient in . SIGNIFICANCE: -mutant cancer cells depend on WEE1, which provides a basis for therapeutically targeting WEE1 in -deficient cancers..
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/0008-5472.CAN-18-3374DOI Listing
February 2020

Chinese nonmedicinal herbal diet and risk of nasopharyngeal carcinoma: A population-based case-control study.

Cancer 2019 12 22;125(24):4462-4470. Epub 2019 Sep 22.

Department of Cancer Prevention Center, Sun Yat-Sen University Cancer Center, Guangzhou, China.

Background: An association between a nonmedicinal herbal diet and nasopharyngeal carcinoma (NPC) has often been hypothesized but never thoroughly investigated.

Methods: This study enrolled a total of 2469 patients with incident NPC and 2559 population controls from parts of Guangdong and Guangxi Provinces in southern China between 2010 and 2014. Questionnaire information was collected on the intake of traditional herbal tea and herbal soup as well as the specific herbal plants used in soups and other potentially confounding lifestyle factors. Multivariate logistic regression models were used to estimate odds ratios (ORs) with 95% confidence intervals (CIs) for the NPC risk in association with herbal tea and soup intake.

Results: Ever consumption of herbal tea was not associated with NPC risk (OR, 1.03; 95% CI, 0.91-1.17). An inverse association was observed for NPC among ever drinkers of herbal soup (OR, 0.78; 95% CI, 0.67-0.90) but without any monotonic trend with an increasing frequency or duration of herbal soup consumption. Inverse associations with NPC risk were detected with 9 herbal plants used in herbal soup, including Ziziphus jujuba, Fructus lycii, Codonopsis pilosula, Astragalus membranaceus, Semen coicis, Smilax glabra, Phaseolus calcaratus, Morinda officinalis, and Atractylodes macrocephala (OR range, 0.31-0.79).

Conclusions: Consuming herbal soups including specific plants, but not herbal tea, was inversely associated with NPC. If replicated, these results might provide potential for NPC prevention in endemic areas.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cncr.32458DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6891117PMC
December 2019

Clonal Mutations Activate the NF-κB Pathway to Promote Recurrence of Nasopharyngeal Carcinoma.

Cancer Res 2019 Dec 4;79(23):5930-5943. Epub 2019 Sep 4.

Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, P.R. China.

The genetic events occurring in recurrent nasopharyngeal carcinoma (rNPC) are poorly understood. Here, we performed whole-genome and whole-exome sequencing in 55 patients with rNPC and 44 primarily diagnosed NPC (pNPC), with 7 patients having paired rNPC and pNPC samples. Previously published pNPC exome data were integrated for analysis. rNPC and pNPC tissues had similar mutational burdens, however, the number of clonal mutations was increased in rNPC samples. TP53 and three NF-κB pathway components (, and ) were significantly mutated in both pNPC and rNPC. Notably, mutations in , and were all clonal in rNPC, however, 55.6% to 57.9% of them were clonal in pNPC. In general, the number of clonal mutations in NF-κB pathway-associated genes was significantly higher in rNPC than in pNPC. The NF-κB mutational clonality was selected and/or enriched during NPC recurrence. The amount of NF-κB translocated to the nucleus in samples with clonal NF-κB mutants was significantly higher than that in samples with subclonal NF-κB mutants. Moreover, the nuclear abundance of NF-κB protein was significantly greater in pNPC samples with locoregional relapse than in those without relapse. Furthermore, high nuclear NF-κB levels were an independent negative prognostic marker for locoregional relapse-free survival in pNPC. Finally, inhibition of NF-κB enhanced both radiosensitivity and chemosensitivity and . In conclusion, NF-κB pathway activation by clonal mutations plays an important role in promoting the recurrence of NPC. Moreover, nuclear accumulation of NF-κB is a prominent biomarker for predicting locoregional relapse-free survival. SIGNIFICANCE: This study uncovers genetic events that promote the progression and recurrence of nasopharyngeal carcinoma and has potential prognostic and therapeutic implications..
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/0008-5472.CAN-18-3845DOI Listing
December 2019

Associations between environmental factors and serological Epstein-Barr virus antibodies in patients with nasopharyngeal carcinoma in South China.

Cancer Med 2019 08 26;8(10):4852-4866. Epub 2019 Jun 26.

School of Public Health, Sun Yat-sen University, Guangzhou, China.

Epstein-Barr virus (EBV) reactivation, reflected by aberrantly increased levels of various serological antibodies, has been suggested to be an early indicator of nasopharyngeal carcinoma (NPC) onset and progression. We have previously suggested that certain lifestyle and dietary factors were associated with elevated serological levels of the antibody against various EBV antigens namely VCA, Zta, EBNA1, and oral EBV DNA loads among healthy population. It remains unclear whether these potential environmental factors would also influence EBV serological antibodies in NPC patients. We conducted an epidemiological study to evaluate the associations between such environmental factors and EBV antibody levels among 1701 NPC patients in South China. Pretreatment serums were collected and examined for VCA-IgA and EA-IgA by immunoenzymatic assays and antienzyme rate (AER) of EBV DNase-specific neutralizing antibody. We found that consumption of Canton-style herbal tea was significantly correlated with increased serological antibody levels of VCA-IgA and EA-IgA, with adjusted ORs of 1.35 (95% CI: 1.03-1.76) and 1.32 (95% CI: 1.01-1.73), respectively, in the weekly intake frequency stratum, while not related to AER of EBV DNase-specific neutralizing antibody. Smoking was found to be not only an apparent risk factor for higher antibody levels of AER in stage III-IV patients (OR = 1.60, 95% CI: 1.11-2.30), but also associated closely with NPC stage at diagnosis (OR = 2.17, 95% CI: 1.47-3.22), with dose-response effects. In conclusion, we found consumption of Canton-style herbal tea and cigarette smoking were in positive associations with elevated EBV antibodies in NPC patients, which may be of public health significance for the primary prevention of EBV-associated diseases especially NPC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cam4.2348DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6712476PMC
August 2019

Genome sequencing analysis identifies Epstein-Barr virus subtypes associated with high risk of nasopharyngeal carcinoma.

Nat Genet 2019 07 17;51(7):1131-1136. Epub 2019 Jun 17.

State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China.

Epstein-Barr virus (EBV) infection is ubiquitous worldwide and is associated with multiple cancers, including nasopharyngeal carcinoma (NPC). The importance of EBV viral genomic variation in NPC development and its striking epidemic in southern China has been poorly explored. Through large-scale genome sequencing of 270 EBV isolates and two-stage association study of EBV isolates from China, we identify two non-synonymous EBV variants within BALF2 that are strongly associated with the risk of NPC (odds ratio (OR) = 8.69, P = 9.69 × 10 for SNP 162476_C; OR = 6.14, P = 2.40 × 10 for SNP 163364_T). The cumulative effects of these variants contribute to 83% of the overall risk of NPC in southern China. Phylogenetic analysis of the risk variants reveals a unique origin in Asia, followed by clonal expansion in NPC-endemic regions. Our results provide novel insights into the NPC endemic in southern China and also enable the identification of high-risk individuals for NPC prevention.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41588-019-0436-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6610787PMC
July 2019

Past and Recent Salted Fish and Preserved Food Intakes Are Weakly Associated with Nasopharyngeal Carcinoma Risk in Adults in Southern China.

J Nutr 2019 09;149(9):1596-1605

Department of Medical Epidemiology and Biostatistics and.

Background: Chinese-style salted fish intake in early life is considered an established risk factor for nasopharyngeal carcinoma (NPC). However, results for adult intakes of salted fish and preserved foods are inconsistent.

Objective: The aim of this study was to ascertain the relations of Chinese-style hard and soft salted fish and preserved food intakes with NPC risk.

Methods: We conducted a population-based case-control study in southern China with 2554 NPC cases identified through a rapid case ascertainment system and 2648 healthy controls, frequency-matched on age, sex, and area. Subjects (aged 20-74 y) were interviewed via a food-frequency questionnaire, including information on portion size. Data were also collected on alcohol consumption and potential confounders. Food intake was grouped into 3-5 energy-adjusted intake levels during adulthood (10 y prior) and adolescence (16-18 y). For childhood (at age 10 y), intake frequency of selected food items was collected. Multivariate-adjusted ORs with 95% CIs were estimated via logistic regression.

Results: We found no association between NPC and intake of hard Chinese-style salted fish during adulthood, and an increased risk at the highest level of intake during adolescence (OR: 1.19; 95% CI: 1.03, 1.39). In contrast, we found a decreased risk for the middle intake level of soft salted fish during adulthood (OR: 0.68; 95% CI: 0.57, 0.81) and adolescence (OR: 0.71; 95% CI: 0.59, 0.85). Preserved foods showed contrasting risk profiles, e.g., the highest adult intake level of salted egg (OR: 1.51; 95% CI: 1.22, 1.87) and fermented black beans (OR: 0.67; 95% CI: 0.56, 0.80). Associations with NPC were weaker than previously reported, e.g., for weekly childhood intake of salted fish (OR: 1.56; 95% CI: 1.24, 1.97).

Conclusions: Hard and soft salted fish have different risk profiles. Salted fish and other preserved foods were at most weak risk factors for NPC in all periods and may play a smaller role in NPC occurrence than previously thought.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/jn/nxz095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6736189PMC
September 2019
-->