Large-scale genetic association studies have identified multiple susceptibility loci for nasopharyngeal carcinoma (NPC), but the underlying biological mechanisms remain to be explored. To gain ...insights into the genetic etiology of NPC, we conducted a follow-up study encompassing 6,907 cases and 10,472 controls and identified two additional NPC susceptibility loci, 9q22.33 (rs1867277; OR = 0.74, 95% CI = 0.68–0.81, p = 3.08 × 10−11) and 17q12 (rs226241; OR = 1.42, 95% CI = 1.26–1.60, p = 1.62 × 10−8). The two additional loci, together with two previously reported genome-wide significant loci, 5p15.33 and 9p21.3, were investigated by high-throughput sequencing for chromatin accessibility, histone modification, and promoter capture Hi-C (PCHi-C) profiling. Using luciferase reporter assays and CRISPR interference (CRISPRi) to validate the functional profiling, we identified PHF2 at locus 9q22.33 as a susceptibility gene. PHF2 encodes a histone demethylase and acts as a tumor suppressor. The risk alleles of the functional SNPs reduced the expression of the target gene PHF2 by inhibiting the enhancer activity of its long-range (4.3 Mb) cis-regulatory element, which promoted proliferation of NPC cells. In addition, we identified CDKN2B-AS1 as a susceptibility gene at locus 9p21.3, and the NPC risk allele of the functional SNP rs2069418 promoted the expression of CDKN2B-AS1 by increasing its enhancer activity. The overexpression of CDKN2B-AS1 facilitated proliferation of NPC cells. In summary, we identified functional SNPs and NPC susceptibility genes, which provides additional explanations for the genetic association signals and helps to uncover the underlying genetic etiology of NPC development.
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We performed a large-scale genetic association study of nasopharyngeal carcinoma (NPC) followed by high-throughput profiling of cis-regulatory elements and experimental validation. We identified two NPC susceptibility genes, PHF2 at locus 9q22.33 and CDKN2B-AS1 at locus 9p21.3, which helps to uncover the genetic etiology of NPC development.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract
Background
Oral Epstein-Barr virus (EBV) status reflects host EBV activity and potentially links to EBV-associated diseases, however, factors influencing oral EBV loads or reactivation, such ...as environmental exposures or host factors, are not fully understood.
Methods
A 2-stage, multicenter, cross-sectional study of 6558 subjects from 21 administrative cities of southern China and 3 populations from representative geographical areas in China (referred to as the south, north, and northeastern populations) was performed. The relationships between demographical factors and environmental exposures to EBV loads were analyzed by logistic regression models.
Results
Current smoking, with a dose-response effect, was found to be strongly associated with higher oral EBV loads in the pooled data, with an odds ratio of 1.58 (95% confidence interval, 1.39–1.79), as well as in each of the separate populations. The odds ratio increased to 3.06 when current smokers in southern China were compared to never smokers in northern China. Additionally, higher oral EBV loads tended to be detected in older participants, male participants, and participants in southern China.
Conclusions
This study provided evidence linking the effect of host-environmental factors, particularly smoking, to oral EBV activity. It could strengthen our understanding of the possible causal roles of EBV-related diseases, which may help to prevent or mitigate EBV-associated diseases.
Our multicenter cross-sectional study in China provided evidence linking the effect of host-environmental factors to oral Epstein-Barr virus (EBV) activity. Higher oral EBV loads tended to be detected in smokers, older participants, male participants, and participants in southern China.
The human leukocyte antigen (HLA) is a highly polymorphic region, and HLA diversity may play a role in presenting tumour-associated peptides and inducing immune responses. However, the effect of HLA ...diversity on cancers has not been fully assessed. We aimed to explore the role of HLA diversity on cancer development.
A pan-cancer analysis was performed to evaluate the effect of HLA diversity, measured by HLA heterozygosity and HLA evolutionary divergence (HED), on the susceptibility of 25 cancers in the UK Biobank.
We observed that the diversity of HLA class II locus was associated with a lower risk of lung cancer (ORhetero = 0.94, 95% CI = 0.90–0.97, P = 1.29 × 10−4) and head and neck cancer (ORhetero = 0.91, 95% CI = 0.86–0.96, P = 1.56 × 10−3). Besides, a lower risk of non-Hodgkin lymphoma was associated with an increased diversity of HLA class I (ORhetero = 0.92, 95% CI = 0.87–0.98, P = 8.38 × 10−3) and class II locus (ORhetero = 0.89, 95% CI = 0.86–0.92, P = 1.65 × 10−10). A lower risk of Hodgkin lymphoma was associated with the HLA class I diversity (ORhetero = 0.85, 95% CI = 0.75–0.96, P = 0.011). The protective effect of HLA diversity was mainly observed in pathological subtypes with higher tumour mutation burden, such as lung squamous cell carcinoma (P = 9.39 × 10−3) and diffuse large B cell lymphoma (Pclass I = 4.12 × 10−4; Pclass Ⅱ = 4.71 × 10−5), as well as the smoking subgroups of lung cancer (P = 7.45 × 10−5) and head and neck cancer (P = 4.55 × 10−3).
We provided a systematic insight into the effect of HLA diversity on cancers, which might help to understand the etiological role of HLA on cancer development.
This study was supported by grants from the National Natural Science Foundation of China (82273705, 82003520); the Basic and Applied Basic Research Foundation of Guangdong Province, China (2021B1515420007); the Science and Technology Planning Project of Guangzhou, China (201804020094); Sino-Sweden Joint Research Programme (81861138006); the National Natural Science Foundation of China (81973131, 81903395, 81803319, 81802708).
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The dysbiosis of oral microbiota is linked to numerous diseases and is associated with personal lifestyles, such as alcohol drinking. However, there is inadequate data to study the effect of alcohol ...drinking on oral microbiota from the Chinese population. Here, we profiled the oral microbiota of 150 healthy subjects in the Chinese population by 16S rRNA gene sequencing. The results showed that drinkers had significantly higher alpha diversity than non-drinkers. A significant difference in overall microbiota composition was observed between non-drinkers and drinkers. Additionally, using DESeq analysis, we found genus
and
, and species
and
were significantly enriched in drinkers; meanwhile, the genus
,
and
, and species
were significantly depleted in drinkers. PICRUSt analysis showed that significantly different genera were mainly related to metabolism pathways. The oxygen-independent pathways, including galactose, fructose and mannose metabolism pathways, were enriched in drinkers and positively associated with genera enriched in drinkers; while the pyruvate metabolism pathway, an aerobic metabolism pathway, was decreased in drinkers and negatively associated with genera enriched in drinkers. Our results suggested that alcohol drinking may affect health by altering oral microbial composition and potentially affecting microbial functional pathways. These findings may have implications for better understanding the potential role those oral bacteria play in alcohol-related diseases.
As an oncovirus, EBV is associated with multiple cancers, including solid tumors and hematological malignancies. EBV methylation plays an important role in regulating tumor occurrence. However, the ...EBV methylation profiles in EBV-associated tumor tissues are poorly understood.
In this study, EBV methylation capture sequencing was conducted in several different tumor tissue samples, including NPC, EBVaGC, lung LELC and parotid LELC. Besides, EBV capture sequencing and following qMSP were performed on nasopharyngeal brushing samples from NPC and nasal NKTCL patients. Our results showed that the EBV genome among different types of tumors displayed specific methylation patterns. Among the four types of tumors from epithelial origin (NPC, EBVaGC, lung LELC and parotid LELC), the most significant differences were found between EBVaGC and the others. For example, in EBVaGC, all CpG sites within 1,44,189-1,45,136 bp of the EBV genome sequence on gene RPMS1 were hyper-methylated compared to the others. Differently, significant differences of EBV CpG sites, particularly those located on gene BILF2, were observed between NPC and nasal NKTCL patients in nasopharyngeal brushing samples. Further, the methylated level of BILF2 was further detected using qMSP, and a diagnostic model distinguishing NPC and nasal NKTCL was established. The AUC of the model was 0.9801 (95% CI 0.9524-1.0000), with the sensitivity and specificity of 98.81% (95% CI 93.63-99.94%) and 76.92% (95% CI 49.74-91.82%), respectively.
Our study reveals more clues for further understanding the pathogenesis of EBV, and provides a possibility for distinguishing EBV-related tumor by detecting specific EBV CpG sites.
Although advancements in medical technology supporting cancer diagnosis and treatment have improved survival, these technologies still have limitations. Recently, the application of noninvasive ...imaging for cancer diagnosis and therapy has become an indispensable component in clinical practice. However, current imaging contrasts and tracers, which are in widespread clinical use, have their intrinsic limitations and disadvantages. Nanotechnologies, which have improved in vivo detection and enhanced targeting efficiency for cancer, may overcome some of the limitations of cancer diagnosis and therapy. Theranostic nanoparticles have great potential as a therapeutic model, which possesses the ability of their nanoplatforms to load targeted molecule for both imaging and therapeutic functions. The resulting nanosystem will likely be critical with the growth of personalized medicine because of their diagnostic potential, effectiveness as a drug delivery vehicle, and ability to oversee patient response to therapy. In this review, we discuss the achievements of modern nanoparticles with the goal of accurate tumor imaging and effective treatment and discuss the future prospects.
We retrospectively analyzed the correlation between different endometrial preparation protocols and pregnancy outcomes in patients with polycystic ovary syndrome (PCOS) who underwent frozen embryo ...transfer (FET).
A total of 200 PCOS patients who underwent FET were divided into HRT group (n = 65), LE group (n = 65), GnRHa + HRT group (n = 70) according to different endometrial preparation protocols. The endometrial thickness on the day of endometrial transformation, the number of embryos transferred, and the number of high-quality embryos transferred were compared among the three groups. The pregnancy outcomes of FET in the three groups were compared and analyzed, and a further multivariate logistic regression model was used to analyze the factors influencing FET pregnancy outcomes in PCOS patients.
Endometrial thickness on the day of endometrial transformation, clinical pregnancy rate and live birth rate in GnRHa + HRT group were higher than those in the HRT group and LE group. The results of multivariate regression analysis showed that the pregnancy outcome of PCOS patients undergoing FET was significantly associated with the patient's age, endometrial preparation protocols, number of embryos transferred, endometrial thickness, and duration of infertility.
Compared with HRT or LE alone, GnRHa + HRT protocol results in higher levels of endometrial thickness on the day of endometrial transformation, clinical pregnancy rate, and live birth rate. Female age, endometrial preparation protocols, number of embryos transferred, endometrial thickness, and duration of infertility are determined as factors influencing pregnancy outcomes in PCOS patients undergoing FET.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
The specific roles of mutant p53's dominant-negative (DN) or gain-of-function (GOF) properties in regulating acute response and long-term tumorigenesis is unclear. Using “knockin” mouse strains ...expressing varying R246S mutant levels, we show that the DN effect on transactivation is universally observed after acute p53 activation, whereas the effect on cellular outcome is cell-type specific. Reducing mutant p53 levels abrogated the DN effect. Mutant p53's DN effect protected against radiation-induced death but did not accentuate tumorigenesis. Furthermore, the R246S mutant did not promote tumorigenesis compared to p53−/− mice in various models, even when MDM2 is absent, unlike the R172H mutant. Together, these data demonstrate that mutant p53's DN property only affects acute responses, whereas GOF is not universal, being mutation-type specific.
► DN effect of mutant p53 is cell-type specific, apparent upon acute p53 activation ► Hypomorphic expression of mutant p53 abrogates DN effects ► DN effect on acute cell death does not promote long-term tumorigenesis ► Mutant p53's gain-of-function property is mutation-type specific
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
MXene has given great promises to supercapacitor electrode material due to its high conductivity and redox properties. However, the self-agglomeration of the MXene lamella will reduce its contact ...area with the electrolyte and generate a tortuous transportation pathway of the electrolyte ions, thereby reducing its capacitive performance and rate capability. In this work, we engineered the electrolyte ion channels by adjusting the MXene lamella size and inserting holey graphene (HG) nanosheets into the interlayer of the MXene flakes. The developed MXene/HG electrode can not only avoid the self-restacking of MXene but also provide unimpeded ion transport channels. As a result, the supercapacitive and rate performances of the small MXene lamella-based MXene/HG (S-MXene/HG) supercapacitor are prominently ameliorated. By adjusting the content of HG, the S-MXene/HG
0.05
electrode exhibits excellent gravimetric capacitance of 446 F·g
−1
and a rate capability of 77.5%. The S-MXene/HG
0.05
-based symmetric supercapacitor provides an impressive energy density of 14.84 Wh·kg
−1
with excellent cyclic stability of 96% capacitance retention after 10,000 cycles. This demonstration of the engineering of the ion channels shows great potential in two-dimensional material-based supercapacitor electrodes.
Graphical abstract
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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