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It remains controversial who would benefit from adjuvant chemotherapy (ACT) in patients with early-stage non-small cell lung cancer (NSCLC). We aim to construct a polygenic hazard score (PHS) to predict prognosis and ACT benefit among NSCLC patients.We conducted a retrospective study including 1,395 stage I-II NSCLC patients. We performed a genome-wide association study (GWAS) on overall survival (OS) in patients treated with ACT (SYSUCC ACT set, n=404), and then developed a PHS using LASSO Cox regression in a random subset (training, n=202) and tested it in the remaining set (test, n=202). The PHS was further validated in two independent datasets (SYSUCC surgery set, n=624; PLCO cohort, n=367).The GWAS-derived PHS consisting of 37 single-nucleotide polymorphisms (SNPs) was constructed to classify patients into high and low PHS groups. For patients treated with ACT, those with low PHS had better clinical outcomes than high PHS (test set: HR =0.21, P0.001; PLCO ACT set: HR =0.33, P=0.260). Similar results were found in the extended validation cohorts including patients with or without ACT (SYSUCC: HR =0.48, P0.001; PLCO: HR =0.60, P=0.033). Within subgroup analysis by treatment or clinical factors, we further observed consistent results for the prognostic value of the PHS. Notably, ACT significantly improved OS in stage II patients with low PHS (HR =0.26, P0.001), while there was no ACT survival benefit among patients with high PHS (HR =0.97, P=0.860).The PHS improved prognostic stratification and could help identify patients who were most likely to benefit from ACT in early-stage NSCLC.

Background Distant metastasis is the leading cause of death for esophageal squamous cell carcinoma (ESCC) with limited treatment options and unsatisfactory effectiveness. Bromodomain (BRD) containing proteins are emerging targets for cancer therapy with promising effects. As a unique member of BRD family, the function and molecular mechanism of ATAD2 in cancer development is seldomly investigated. Methods The clinical impact of ATAD2 was assessed both at RNA and protein level in 75 and 112 ESCC patients separately. The biological function of ATAD2 was investigated in vitro and in vivo. Signaling pathway and downstream effectors of ATAD2 were identified by RNA sequencing, luciferase reporter, co-immunoprecipitation, chromatin immunoprecipitation, immunofluorescence and western blot assay. Results We found that elevated ATAD2 expression was significantly associated with lymph node metastasis, advanced clinical stage as well as poor survival of ESCC patients. Silencing ATAD2 significantly suppressed ESCC cell migration and invasion in vitro, and inhibited tumor growth and lung metastasis in vivo. Mechanically, we identified a new cofactor, C/EBPβ. ATAD2 directly interacted with C/EBPβ and promoted its nuclear translocation, which directly bound to the promoter region of TGF-β1 and activated its expression. Further, we demonstrated that TGF-β1 activated its downstream effectors in a Smad3 dependent manner. In addition, we further found that ATAD2 promoted ESCC metastasis through TGF-β signaling induced Snail expression and the subsequent epithelial-mesenchymal transition. Conclusion Our findings demonstrated the pro-metastatic function of ATAD2 and uncovered the new molecular mechanism by regulating C/EBPβ/TGF-β1/Smad3/Snail signaling pathway, thus providing a potential target for the treatment of ESCC metastasis.

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 Prevotella and Moryella, and species Prevotella melaninogenica and Prevotella tannerae were significantly enriched in drinkers; meanwhile, the genus Lautropia, Haemophilus and Porphyromonas, and species Haemophilus parainfluenzae 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.

Background Nasopharyngeal carcinoma (NPC) is closely associated with genetic factors and Epstein-Barr virus infection, showing strong familial aggregation. Individuals with a family history suffer elevated NPC risk, requiring effective genetic counseling for risk stratification and individualized prevention. Methods We performed whole-exome sequencing on 502 familial NPC patients and 404 unaffected relatives and controls. We systematically evaluated the established cancer predisposition genes and investigated novel NPC susceptibility genes, making comparisons with 21 other familial cancers in the UK biobank (N = 5218). Results Rare pathogenic mutations in the established cancer predisposition genes were observed in familial NPC patients, including ERCC2 (1.39%), TP63 (1.00%), MUTYH (0.80%), and BRCA1 (0.80%). Additionally, 6 novel susceptibility genes were identified. RAD54L, involved in the DNA repair pathway together with ERCC2, MUTYH, and BRCA1, showed the highest frequency (4.18%) in familial NPC. Enrichment analysis found mutations in TP63 were enriched in familial NPC, and RAD54L and EML2 were enriched in both NPC and other Epstein-Barr virus–associated cancers. Besides rare variants, common variants reported in the studies of sporadic NPC were also associated with familial NPC risk. Individuals in the top quantile of common variant-derived genetic risk score while carrying rare variants exhibited increased NPC risk (odds ratio = 13.47, 95% confidence interval = 6.33 to 28.68, P = 1.48 × 10–11); men in this risk group showed a cumulative lifetime risk of 24.19%, much higher than those in the bottom common variant-derived genetic risk score quantile and without rare variants (2.04%). Conclusions This study expands the catalog of NPC susceptibility genes and provides the potential for risk stratification of individuals with an NPC family history.

Nasopharyngeal carcinoma (NPC), the most common head and neck cancer, is characterized by distinct geographic distribution and familial aggregation. Multiple risk factors, including host genetics, environmental factor and EBV infection, have been linked to the development of NPC, particularly in the familial clustering cases. However, the cause of NPC endemicity remains enigmatic due possibly to the complicated interplay between these risk factors. Recently, positive Epstein-Barr virus (EBV) DNA loads at nasopharyngeal (NP) cavity has been found to reflect NPC development and applied in NPC screening. To examine whether the increased NP EBV loads could aggregate in the families and be affected by host genetics and environmental factor, EBV loads were obtained by 510 NP brushing samples from eligible unaffected individuals, who have 2 or more relatives affected with NPC, in 116 high-risk NPC families. The correlation of relative pairs was estimated using S.A.G.E. (version 6.4, 2016), and host heritability of NP EBV loads was calculated with variance component models using SOLAR (version 8.4.2, 2019). In result, significant correlations of EBV loads were observed between parent-offspring pairs and sibling-sibling pairs (P

Background Colorectal cancer (CRC) is the leading cause of cancer death worldwide. Screening is a confirmed way to reduce the incidence and mortality rates of CRC. This study aimed to identify a fecal-based, noninvasive, and accurate method for detection of colorectal cancer (CRC) and advanced adenoma (AA). Methods Through detection in tissue (n = 96) and fecal samples (n = 88) and tested in an independent group of fecal samples (n = 294), the methylated DNA marker ITGA4 and bacterial markers Fusobacterium nucleatum (Fn) and Pepetostreptococcusanaerobius (Pa) were identified from the candidate biomarkers for CRC and AA detection. A prediction score (pd-score) was constructed using the selected markers and fecal immunochemical test (FIT) for distinguishing AA and CRC from healthy subjects by logistic regression method. The diagnostic performance of the pd-score was compared with FIT and validated in the external validation cohort (n = 117) and in a large CRC screening cohort. Results The pd-score accurately identified AA and CRC from healthy subjects with an area under the curve (AUC) of 0.958, at a specificity of 91.37%; the pd-score showed sensitivities of 95.38% for CRC and 70.83% for AA, respectively. In the external validation cohort, the sensitivities of the pd-score for CRC and AA detection were 94.03% and 80.00%, respectively. When applied in screening, the pd-score identified 100% (11/11) of CRC and 70.83% (17/24) of AA in participants with both colonoscopy results and qualified fecal samples, showing an improvement by 41.19% compared to FIT. Conclusions The current study developed a noninvasive and well-validated approach for AA and CRC detection, which could be applied widely as a diagnostic and screening test.

Background Nasopharyngeal carcinoma (NPC), an Epstein–Barr virus (EBV) associated cancer, exhibits an extremely high incidence in southern Chinese. Given that human leukocyte antigen (HLA) plays critical roles in antigen presentation and relates to NPC susceptibility, it is speculated that certain HLA variants may affect EBV reactivation, which is a key pathogenic factor of NPC. Therefore, we attempted to identify HLA alleles associated with the indicator of EBV reactivation, Zta‐IgA, in healthy males from NPC endemic area. Methods HLA alleles of 1078 healthy males in southern China from the 21‐RCCP study were imputed using genome‐wide single nucleotide polymorphism data. EBV Zta‐IgA in blood samples were measured using an enzyme‐linked immunosorbent assay. Multiple logistic regression analysis was used to evaluate the effect of HLA allele on Zta‐IgA serological status and its potential joint association with smoking. The binding affinity for Zta‐peptide was predicted using NetMHCIIpan 4.0. Results HLA‐DRB1*09:01 was found to be associated with a higher risk of Zta‐IgA seropositivity (odds ratio = 1.80, 95% confidence interval = 1.32–2.45; p = 1.82 × 10−4). Compared with non‐smokers without HLA‐DRB1*09:01, the effect size increased to 2.19‐ and 3.70‐fold for the light and heavy smokers carrying HLA‐DRB1*09:01, respectively. Furthermore, HLA‐DRB1*09:01 showed a stronger binding affinity to Zta peptide than other HLA‐DRB1 alleles. Conclusions Our study highlighted the pivotal role of genetic HLA variants in EBV reactivation and the etiology of NPC. Smokers with HLA‐DRB1*09:01 have a significantly higher risk of being Zta‐IgA seropositive, which indicates the necessity of smoking cessation in certain high‐risk populations and also provide clues for further research on the etiology of NPC., We conducted an association study for human leukocyte antigen (HLA) alleles and Epstein–Barr virus Zta‐IgA serological status in healthy males from a nasopharyngeal carcinoma endemic area. We found that HLA‐DRB1*09:01 was associated with a high risk of Zta‐IgA seropositivity and the effect increased when combined with smoking. In silico prediction indicated that HLA‐DRB1*09:01 had a distinctive binding motif pattern and a stronger binding affinity to Zta peptide in comparison with other HLA‐DRB1 alleles.

Additional file 2: Table S2. Univariate and multivariate analyses of overall survival in all patients.

Additional file 3: Table S3. KEGG pathways of overlapping genes from DAVID analysis.

Additional file 1: Table S1. Primers used for quantitative real-time PCR.