Publications by authors named "Juncheng Dai"

211 Publications

Air Pollution, Genetic Factors and the Risk of Lung Cancer: A Prospective Study in the UK Biobank.

Am J Respir Crit Care Med 2021 Jul 12. Epub 2021 Jul 12.

Nanjing Medical University School of Public Health, 572407, Department of Epidemiology, Center for Global Health, Nanjing, China.

Both genetic and environmental factors contribute to lung cancer, but the degree to which air pollution modifies the impact of genetic susceptibility on lung cancer remains unknown. To investigate whether air pollution and genetic factors jointly contribute to incident lung cancer. We analyzed data from 455,974 participants (53% women) without previous cancer at baseline in the UK Biobank. The concentrations of particulate matter (PM, PM and PM), nitrogen dioxide (NO), and nitrogen oxides (NO) were estimated by land-use regression models, and the association between air pollutants and incident lung cancer was investigated using a Cox proportional hazard model. Furthermore, we constructed a polygenic risk score and evaluated whether air pollutants modified the effect of genetic susceptibility on the development of lung cancer. The results showed significant associations between the risk of lung cancer and PM (hazard ratio [HR]: 1.63, 95% confidence interval [CI]: 1.33-2.01; per 5 μg/m), PM (1.53, 1.20-1.96; per 10 μg/m), NO (1.10, 1.05-1.15; per 10 μg/m), and NO (1.13, 1.07-1.18; per 20 μg/m). There were additive interactions between air pollutants and the genetic risk. Compared with participants with low genetic risk and low air pollution, those with high air pollution and high genetic risk had the highest risk of lung cancer (PM: HR: 1.71, 95% CI:1.45-2.02; PM: 1.77, 1.50-2.10; NO: 1.77, 1.42-2.22; NO: 1.67, 1.43-1.95). Long-term exposure to air pollution may increase the risk of lung cancer, especially in those with high genetic risk.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1164/rccm.202011-4063OCDOI Listing
July 2021

Associations Between Sleep Quality and Health Span: A Prospective Cohort Study Based on 328,850 UK Biobank Participants.

Front Genet 2021 15;12:663449. Epub 2021 Jun 15.

Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China.

Objective: To examine the associations between sleep quality and health span using a prospective cohort design based on the UK Biobank (UKB).

Materials And Methods: This longitudinal cohort study enrolled 328,850 participants aged between 37 and 73 years from UKB to examine the associations between sleep quality and risk of terminated health span. End of health span was defined by eight events strongly associated with longevity (cancer, death, congestive heart failure, myocardial infarction, chronic obstructive pulmonary disease, stroke, dementia, and diabetes), and a sleep score was generated according to five sleep behavioral factors (sleep duration, chronotype, sleeplessness, daytime sleepiness, and snoring) to characterize sleep quality. The hazard ratio (HR) and 95% confidence intervals (CIs) were calculated by multivariate-adjusted Cox proportional hazards model. Moreover, we calculated population attributable risk percentage (PAR%) to reflect the public health significance of healthy sleep quality.

Results: Compared with poor sleep quality, participants with healthy sleep quality had a 15% (HR: 0.85, 95% CI: 0.81-0.88) reduced risk of terminated health span, and those of less-healthy sleep quality had a 12% (HR: 0.88, 95% CI: 0.85-0.92) reduced risk. Linear trend results indicated that the risk of terminated health span decreased by 4% for every additional sleep score. Nearly 15% health span termination events in this cohort would have been prevented if a healthy sleep behavior pattern was adhered to (PAR%: 15.30, 95% CI: 12.58-17.93).

Conclusion: Healthy sleep quality was associated with a reduced risk of premature end of health span, suggesting healthy sleep behavior may extend health span. However, further studies are suggested for confirmation of causality and potential mechanism.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fgene.2021.663449DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8239359PMC
June 2021

Single-cell RNA-Seq reveals a highly coordinated transcriptional program in mouse germ cells during primordial follicle formation.

Aging Cell 2021 Jul 26;20(7):e13424. Epub 2021 Jun 26.

Department of Biotechnology, Beijing Institute of Radiation Medicine, Beijing, China.

The assembly of primordial follicles in mammals represents one of the most critical processes in ovarian biology. It directly affects the number of oocytes available to a female throughout her reproductive life. Premature depletion of primordial follicles contributes to the ovarian pathology primary ovarian insufficiency (POI). To delineate the developmental trajectory and regulatory mechanisms of oocytes during the process, we performed RNA-seq on single germ cells from newborn (P0.5) ovaries. Three cell clusters were classified which corresponded to three cell states (germ cell cyst, cyst breakdown, and follicle) in the newborn ovary. By Monocle analysis, a uniform trajectory of oocyte development was built with a series of genes showed dynamic changes along the pseudo-timeline. Gene Ontology term enrichment revealed a significant decrease in meiosis-related genes and a dramatic increase in oocyte-specific genes which marked the transition from a germ cell to a functional oocyte. We then established a network of regulons by using single-cell regulatory network inference and clustering (SCENIC) algorithm and identified possible candidate transcription factors that may maintain transcription programs during follicle formation. Following functional studies further revealed the differential regulation of the identified regulon Id2 and its family member Id1, on the establishment of primordial follicle pool by using siRNA knockdown and genetic modified mouse models. In summary, our study systematically reconstructed molecular cascades in oocytes and identified a series of genes and molecular pathways in follicle formation and development.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/acel.13424DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8282241PMC
July 2021

Association of assisted reproductive technology, germline de novo mutations and congenital heart defects in a prospective birth cohort study.

Cell Res 2021 Jun 9. Epub 2021 Jun 9.

State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, Jiangsu, China.

Emerging evidence suggests that children conceived through assisted reproductive technology (ART) have a higher risk of congenital heart defects (CHDs) even when there is no family history. De novo mutation (DNM) is a well-known cause of sporadic congenital diseases; however, whether ART procedures increase the number of germline DNM (gDNM) has not yet been well studied. Here, we performed whole-genome sequencing of 1137 individuals from 160 families conceived through ART and 205 families conceived spontaneously. Children conceived via ART carried 4.59 more gDNMs than children conceived spontaneously, including 3.32 paternal and 1.26 maternal DNMs, after correcting for parental age at conception, cigarette smoking, alcohol drinking, and exercise behaviors. Paternal DNMs in offspring conceived via ART are characterized by C>T substitutions at CpG sites, which potentially affect protein-coding genes and are significantly associated with the increased risk of CHD. In addition, the accumulation of non-coding functional mutations was independently associated with CHD and 87.9% of the mutations were originated from the father. Among ART offspring, infertility of the father was associated with elevated paternal DNMs; usage of both recombinant and urinary follicle-stimulating hormone and high-dosage human chorionic gonadotropin trigger was associated with an increase of maternal DNMs. In sum, the increased gDNMs in offspring conceived by ART were primarily originated from fathers, indicating that ART itself may not be a major reason for the accumulation of gDNMs. Our findings emphasize the importance of evaluating the germline status of the fathers in families with the use of ART.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41422-021-00521-wDOI Listing
June 2021

Identification of A-to-I RNA editing profiles and their clinical relevance in lung adenocarcinoma.

Sci China Life Sci 2021 May 27. Epub 2021 May 27.

Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, 211166, China.

Adenosine-to-inosine (A-to-I) RNA editing is a widespread posttranscriptional modification that has been shown to play an important role in tumorigenesis. Here, we evaluated a total of 19,316 RNA editing sites in the tissues of 80 lung adenocarcinoma (LUAD) patients from our Nanjing Lung Cancer Cohort (NJLCC) and 486 LUAD patients from the TCGA database. The global RNA editing level was significantly increased in tumor tissues and was highly heterogeneous across patients. The high RNA editing level in tumors was attributed to both RNA (ADAR1 expression) and DNA alterations (mutation load). Consensus clustering on RNA editing sites revealed a new molecular subtype (EC3) that was associated with the poorest prognosis of LUAD patients. Importantly, the new classification was independent of classic molecular subtypes based on gene expression or DNA methylation. We further proposed a simplified model including eight RNA editing sites to accurately distinguish the EC3 subtype in our patients. The model was further validated in the TCGA dataset and had an area under the curve (AUC) of the receiver operating characteristic curve of 0.93 (95%CI: 0.91-0.95). In addition, we found that LUAD cell lines with the EC3 subtype were sensitive to four chemotherapy drugs. These findings highlighted the importance of RNA editing events in the tumorigenesis of LUAD and provided insight into the application of RNA editing in the molecular subtyping and clinical treatment of cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11427-020-1928-0DOI Listing
May 2021

Potential functional variants of KIAA genes are associated with breast cancer risk in a case control study.

Ann Transl Med 2021 Apr;9(7):549

Department of Epidemiology, International Joint Research Center on Environment and Human Health, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China.

Background: KIAA genes identified in the Kazusa cDNA-sequencing project may play important roles in biological processes and are involved in carcinogenesis of many cancers. Genetic variants of KIAA genes are implicated in the abnormal expression of these genes and are linked to susceptibility of several human complex diseases.

Methods: The differentially expressed KIAA genes were screened and identified in The Cancer Genome Atlas (TCGA) database of breast cancer. A total of 48 variants located in the 28 KIAA genes were selected to investigate the associations between polymorphism and breast cancer in 1,032 cases and 1,063 cancer-free controls in a Chinese population.

Results: Two coding variants, which included a SNP rs2306369 in and a SNP rs1205434 in , were identified to be associated with the incidences of breast cancer. Logistic regression analysis showed that the SNP rs2306369 G allele was associated with a decreased risk of breast cancer (additive model: OR =0.81, 95% CI: 0.66-0.99, P=0.038), whereas the SNP rs1205434 A allele was involved with a higher risk of breast cancer (additive model: OR =1.19, 95% CI: 1.02-1.38, P= 0.025). Further stratified analysis revealed that the SNP rs1205434 showed a significant difference for age at menarche strata (heterogeneity test P=0.009). Multiplicative interaction analysis indicated that there was positive multiplicative interaction between the SNP rs1205434 and menarche age (OR =1.09, 95% CI: 1.01-1.17, P=0.036). Additionally, expression quantitative trait loci analysis revealed that the SNP rs1205434 A allele could decrease the expression in the Genotype-Tissue Expression (GTEx) database (P=0.002). The Kaplan-Meier plotter showed that breast cancer patients with high expression have significantly better outcomes than those with low levels of expression (HR =0.84, 95% CI: 0.72-0.99, P=0.033).

Conclusions: The results indicate that the genetic variants (rs2306369 and rs1205434) in the coding region of and respectively may affect Chinese females' breast cancer susceptibility and act as potential predictive biomarkers for breast cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.21037/atm-20-6108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8105804PMC
April 2021

Investigation of the relationships between sleep behaviors and risk of healthspan termination: a prospective cohort study based on 323,373 UK-Biobank participants.

Sleep Breath 2021 May 6. Epub 2021 May 6.

Department of Epidemiology and Biostatistics, Center for Global Health, School of Public Health, Nanjing Medical University, 101 Longmian Road, Nanjing, 211166, China.

Objectives: To examine the associations between four sleep behaviors and the risk of healthspan termination.

Methods: This study included 323,373 participants, free of terminated healthspan at baseline, from the UK-Biobank (UKB). We applied multivariable-adjusted Cox regression models to estimate the risk of terminated healthspan based on four sleep behaviors (insomnia/sleeplessness, napping, daytime sleepiness, and difficulty getting up from bed), which were self-reported and measured on Likert scales from "usually" to "never/rarely" experiences. In this study, healthspan was defined based on eight events that are strongly associated with longevity (congestive heart failure, myocardial infarction, chronic obstructive pulmonary disease, stroke, dementia, diabetes, cancer, and death).

Results: Participants who reported the following unhealthy sleep behaviors had a significantly higher risk of terminated healthspan: "usually experience sleeplessness/insomnia" (HR = 1.05, 95% CI: 1.03-1.07; P < 0.001); "usually nap" (HR = 1.22, 95% CI: 1.18-1.26; P < 0.01); "excessive daytime sleepiness" (HR = 1.25, 95% CI: 1.19-1.32; P < 0.001); and "difficult getting up from bed" (HR = 1.08, 95% CI: 1.05-1.10; P < 0.001). The corresponding population attributable risk percentage (PAR%) indicated that about 7% of healthspan termination in this cohort would have been eliminated if all participants had healthy sleep behaviors.

Conclusion: Participants who reported "usually experience sleeplessness/insomnia," "usually nap," "excessive daytime sleepiness," and "difficult getting up from bed" had increased risk of shortened healthspan. Therefore, adherence to healthy sleep behavior is significant for the extension of healthspan.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11325-021-02394-0DOI Listing
May 2021

A cross-tissue transcriptome-wide association study identifies novel susceptibility genes for lung cancer in Chinese populations.

Hum Mol Genet 2021 Apr 28. Epub 2021 Apr 28.

Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China.

Although dozens of susceptibility loci have been identified for lung cancer in genome-wide association studies (GWASs), the susceptibility genes and underlying mechanisms remain unclear. In this study, we conducted a cross-tissue transcriptome-wide association study (TWAS) with UTMOST based on summary statistics from 13 327 lung cancer cases and 13 328 controls and the genetic-expression matrix over 44 human tissues in the Genotype-Tissue Expression (GTEx) project. After further evaluating the associations in each tissue, we revealed 6 susceptibility genes in known loci and identified 12 novel ones. Among those, five novel genes, including DCAF16 (Pcross-tissue = 2.57 × 10-5, PLung = 2.89 × 10-5), CBL (Pcross-tissue = 5.08 × 10-7, PLung = 1.82 × 10-4), ATR (Pcross-tissue = 1.45 × 10-5, PLung = 9.68 × 10-5), GYPE (Pcross-tissue = 1.45 × 10-5, PLung = 2.17 × 10-3) and PARD3 (Pcross-tissue = 5.79 × 10-6, PLung = 4.05 × 10-3), were significantly associated with the risk of lung cancer in both cross-tissue and lung tissue models. Further colocalization analysis indicated that rs7667864 (C > A) and rs2298650 (G > T) drove the GWAS association signals at 4p15.31-32 (OR = 1.09, 95%CI: 1.04-1.12, PGWAS = 5.54 × 10-5) and 11q23.3 (OR = 1.08, 95%CI: 1.04-1.13, PGWAS = 5.55 × 10-5), as well as the expression of DCAF16 (βGTEx = 0.24, PGTEx = 9.81 × 10-15; βNJLCC = 0.29, PNJLCC = 3.84 × 10-8) and CBL (βGTEx = -0.17, PGTEx = 2.82 × 10-8; βNJLCC = -0.32, PNJLCC = 2.61 × 10-7) in lung tissue. Functional annotations and phenotype assays supported the carcinogenic effect of these novel susceptibility genes in lung carcinogenesis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/hmg/ddab119DOI Listing
April 2021

Relationships of sleep traits with lung cancer risk: a prospective cohort study in UK Biobank.

Sleep 2021 Apr 5. Epub 2021 Apr 5.

Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China.

Study Objectives: To prospectively investigate the association between sleep traits and lung cancer risk, accounting for the interactions with genetic predisposition of lung cancer.

Methods: We included 469,691 individuals free of lung cancer at recruitment from UK Biobank, measuring sleep behaviors with a standardized questionnaire and identifying incident lung cancer cases through linkage to national cancer and death registries. We estimated multivariable adjusted hazard ratios (HR) for lung cancer (2,177 incident cases) across four sleep traits (sleep duration, chronotype, insomnia and snoring), and examined the interaction and joint effects with a lung cancer polygenic risk score.

Results: A U-shaped association was observed for sleep duration and lung cancer risk, with a 18% higher risk (95% confidence interval (CI): 1.07-1.30) for short sleepers and a 17% higher risk (95%CI: 1.02-1.34) for long sleepers compared with normal sleepers (7-8 h/day). Evening preference was associated with elevated lung cancer risk compared with morning preference (HR: 1.25; 95%CI: 1.07-1.46), but no association was found for insomnia or snoring. Compared to participants with favorable sleep traits and low genetic risk, those with both unfavorable sleep duration (<7 hours or >8 hours) or evening preference and high genetic risk showed the greatest lung cancer risk (HRsleep duration: 1.83; 95%CI: 1.47-2.27; HRchronotype: 1.85; 95%CI: 1.34-2.56).

Conclusions: Both unfavorable sleep duration and evening chronotype were associated with increased lung cancer incidence, especially for those with low to moderate genetic risk. These results indicate that sleep behaviors as modifiable risk factors may have potential implications for lung cancer risk.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/sleep/zsab089DOI Listing
April 2021

Analysis of the interaction effect of 48 SNPs and obesity on type 2 diabetes in Chinese Hans.

BMJ Open Diabetes Res Care 2020 11;8(2)

Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, China.

Introduction: Both environmental and genetic factors contribute to type 2 diabetes (T2D) risk. Dozens of T2D susceptibility loci have been identified by genome-wide association study. However, these loci account for only a small fraction of the familial T2D risk. We hypothesized that the gene-obesity interaction may contribute to the missing heritability.

Research Design And Method: Forty-eight T2D-associated variants were genotyped using the TaqMan OpenArray Genotyping System and iPLEX Sequenom MassARRAY platform in two separate studies. Obesity was defined according to multiple indexes (body mass index (BMI), waist circumference and waist-hip ratio). Multiplicative interactions were tested using general logistic regression to assess the gene-obesity interaction effect on T2D risk among a total of 6206 Chinese Hans.

Results: After adjusting for the main effects of genes and obesity, as well as covariates (age, sex, smoking and alcohol consumption status), robust multiplicative interaction effects were observed between rs10811661 in and multiple obesity indices (p ranged from 0.001 to 0.043 for BMI, waist circumference and waist-hip ratio). Obese individuals with the TT genotype had a drastically higher risk of T2D than normal weight individuals without the risk allele (OR=17.58, p<0.001). There were no significant differences between subgroups in the stratification analysis. Plausible biological explanations were established using a public database. However, there were no significant interaction effects between the other 47 single nucleotide polymorphism (SNPs) and obesity.

Conclusion: Our findings indicated that the gene-obesity interaction significantly increases T2D risk in Chinese Hans. The interaction effect identified in our study may help to explain some of the missing heritability in the context of T2D susceptibility. In addition, the interaction effect may play a role in the precise prevention of T2D in Chinese individuals.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/bmjdrc-2020-001638DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7674088PMC
November 2020

Integrated gene-based and pathway analyses using UK Biobank data identify novel genes for chronic respiratory diseases.

Gene 2021 Jan 10;767:145287. Epub 2020 Nov 10.

Department of Epidemiology and Biostatistics, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China; Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Medicine, Nanjing Medical University, Nanjing 211166, China. Electronic address:

Background: Chronic respiratory diseases have become a non-negligible cause of death globally. Although smoking and environmental exposures are primary risk factors for chronic respiratory diseases, genetic factors also play an important role in determining individual's susceptibility to diseases. Here we performed integrated gene-based and pathway analyses to systematically illuminate the heritable characteristics of chronic respiratory diseases.

Methods: UK (United Kingdom) Biobank is a very large, population-based prospective study with over 500,000 participants, established to allow detailed investigations of the genetic and nongenetic determinants of the diseases. Utilizing the GWAS-summarized data downloaded from UK Biobank, we conducted gene-based analysis to obtain associations of susceptibility genes with asthma, chronic obstructive pulmonary disease(COPD) and pneumonia using FUSION and MAGMA software. Across the identified susceptibility regions, functional annotation integrating multiple functional data sources was performed to explore potential regulatory mechanisms with INQUISIT algorithm. To further detect the biological process involved in the development of chronic respiratory diseases, we undertook pathway enrichment analysis with the R package (clusterProfiler).

Results: A total of 195 susceptibility genes were identified significantly associated with chronic respiratory diseases (P < 0.05), and 24/195 located out of known susceptibility regions (e.g. WDPCP in 2p15). Within the identified susceptibility regions, functional annotation revealed an aggregation of credible variants in promoter-like and enhancer-like histone modification regions and such regulatory mechanisms were specific to lung tissues. Furthermore, 110 genes with INQUISIT score ≥1 may influence diseases susceptibility through exerting effects on coding sequences, proximal promoter and distal enhancer regulations. Pathway enrichment results showed that these genes were enriched in immune-related processes and nicotinic acetylcholine receptors pathways.

Conclusions: This study implemented an integrated gene-based and pathway strategy to explore the underlying biological mechanisms and our findings may serve as promising targets for future clinical treatments of chronic respiratory diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.gene.2020.145287DOI Listing
January 2021

Comprehensive characterization of functional eRNAs in lung adenocarcinoma reveals novel regulators and a prognosis-related molecular subtype.

Theranostics 2020 14;10(24):11264-11277. Epub 2020 Sep 14.

Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China.

As the transcriptional products of active enhancers, enhancer RNAs (eRNAs) are essential for the initiation of tumorigenesis. However, the landscape and functional characteristics of eRNAs in Chinese lung adenocarcinoma, and the clinical utility of eRNA-based molecular subtypes remain largely unknown. A genome-wide profiling of eRNAs was performed in 80 Chinese lung adenocarcinoma patients with RNA-seq data. Functional eRNAs and associated genes were identified between paired adenocarcinoma and adjacent samples. Unsupervised clustering of functional eRNAs was conducted and the associations with molecular characteristics and clinical outcomes were accessed by integrating whole-genome sequencing data and clinical data. Additionally, 481 lung adenocarcinoma patients were used for the validation based on The Cancer Genome Atlas (TCGA) dataset. A total of 3297 eRNAs with sufficient expression were identified, which were globally upregulated in adenocarcinoma samples compared to matched-adjacent pairs ( 7.61×10). Further analyses indicated that these upregulated eRNAs were correlated with copy number amplification (CNA) status (Cor = 0.22, 0.045), and eRNA-correlated genes were primarily involved in cell cycle and immune system-related pathways. Based on the co-expression analysis of eRNAs with protein-coding genes, we defined 188 functional eRNAs and their correlated genes were overrepresented in cancer driver genes (ER = 1.98, 5.95×10) and clinically-actionable genes (ER = 2.19, 3.44×10). The eRNA-based consensus clustering further identified a novel molecular subtype with immune deficiency and a high-level of genomic alterations, which was associated with poor clinical outcomes of lung adenocarcinoma patients (OS: HR = 1.91, 0.015; PFI: HR = 1.64, 0.034). The genome-wide identification and characterization of eRNAs reveal novel regulators for the development of lung cancer, which provides a new biological dimension for the understanding of eRNAs during lung carcinogenesis and emphasize the clinical utility of eRNA-based molecular subtypes in the treatment of lung adenocarcinoma.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7150/thno.47039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7532687PMC
June 2021

Using structural analysis to explore the role of hepatitis B virus mutations in immune escape from liver cancer in Chinese, European and American populations.

J Biomol Struct Dyn 2020 Oct 8:1-11. Epub 2020 Oct 8.

Key Laboratory of DGHD, MOE, Institute of Life Sciences, Southeast University, Nanjing, China.

Hepatitis B virus (HBV) infection is an important problem threatening human health. After HBV virus invades human body, it may assemble a complete virus particle in the cytoplasm to trigger the immune reaction, especially the interaction between the HBV virus and the host that mediated by CD8 T cell. We collected the sequences of HBV from the HBVdb database, then screened candidate mutation sites in Chinese, European and American populations based on conservation and physicochemical properties. After that we constructed the three-dimensional structure of Major histocompatibility complex class I (MHC I) -peptide complexes, performed molecular docking, run molecular dynamics to compare the binding free energy, stability, and affinity of MHC I-peptide complexes with the aim to estimate the effect of peptide mutation. The specific HBV virus subtypes of the Chinese, European and American population were studied and the candidate mutation sites were used to predict the mutant peptide antigen. Finally, based on physical and chemical properties and peptide antigen prediction scores, 21 HBV mutation sites were selected. Then combined with specific Human lymphocyte antigen (HLA) subtypes, 11 mutations were found to have a significant negative impact on affinity, stability and binding free energy. Overall, our work found important potential mutations, which provide an evaluation of HBV mutations and a clue of it in immunotherapy.Communicated by Ramaswamy H. Sarma.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/07391102.2020.1830852DOI Listing
October 2020

Genetic risk, incident gastric cancer, and healthy lifestyle: a meta-analysis of genome-wide association studies and prospective cohort study.

Lancet Oncol 2020 10;21(10):1378-1386

Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK.

Background: Genetic variants and lifestyle factors have been associated with gastric cancer risk, but the extent to which an increased genetic risk can be offset by a healthy lifestyle remains unknown. We aimed to establish a genetic risk model for gastric cancer and assess the benefits of adhering to a healthy lifestyle in individuals with a high genetic risk.

Methods: In this meta-analysis and prospective cohort study, we first did a fixed-effects meta-analysis of the association between genetic variants and gastric cancer in six independent genome-wide association studies (GWAS) with a case-control study design. These GWAS comprised 21 168 Han Chinese individuals, of whom 10 254 had gastric cancer and 10 914 geographically matched controls did not. Using summary statistics from the meta-analysis, we constructed five polygenic risk scores in a range of thresholds (p=5 × 10 p=5 × 10 p=5 × 10 p=5 × 10, and p=5 × 10) for gastric cancer. We then applied these scores to an independent, prospective, nationwide cohort of 100 220 individuals from the China Kadoorie Biobank (CKB), with more than 10 years of follow-up. The relative and absolute risk of incident gastric cancer associated with healthy lifestyle factors (defined as not smoking, never consuming alcohol, the low consumption of preserved foods, and the frequent intake of fresh fruits and vegetables), was assessed and stratified by genetic risk (low [quintile 1 of the polygenic risk score], intermediate [quintile 2-4 of the polygenic risk score], and high [quintile 5 of the polygenic risk score]). Individuals with a favourable lifestyle were considered as those who adopted all four healthy lifestyle factors, those with an intermediate lifestyle adopted two or three factors, and those with an unfavourable lifestyle adopted none or one factor.

Findings: The polygenic risk score derived from 112 single-nucleotide polymorphisms (p<5 × 10) showed the strongest association with gastric cancer risk (p=7·56 × 10). When this polygenic risk score was applied to the CKB cohort, we found that there was a significant increase in the relative risk of incident gastric cancer across the quintiles of the polygenic risk score (p<0·0001). Compared with individuals who had a low genetic risk, those with an intermediate genetic risk (hazard ratio [HR] 1·54 [95% CI 1·22-1·94], p=2·67 × 10) and a high genetic risk (2·08 [1·61-2·69], p<0·0001) had a greater risk of gastric cancer. A similar increase in the relative risk of incident gastric cancer was observed across the lifestyle categories (p<0·0001), with a higher risk of gastric cancer in those with an unfavourable lifestyle than those with a favourable lifestyle (2·03 [1·46-2·83], p<0·0001). Participants with a high genetic risk and a favourable lifestyle had a lower risk of gastric cancer than those with a high genetic risk and an unfavourable lifestyle (0·53 [0·29-0·99], p=0·048), with an absolute risk reduction of 1·12% (95% CI 0·62-1·56).

Interpretation: Chinese individuals at an increased risk of incident gastric cancer could be identified by use of our newly developed polygenic risk score. Compared with individuals at a high genetic risk who adopt an unhealthy lifestyle, those who adopt a healthy lifestyle could substantially reduce their risk of incident gastric cancer.

Funding: National Key R&D Program of China, National Natural Science Foundation of China, 333 High-Level Talents Cultivation Project of Jiangsu Province, and China Postdoctoral Science Foundation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S1470-2045(20)30460-5DOI Listing
October 2020

Comprehensive functional annotation of susceptibility variants identifies genetic heterogeneity between lung adenocarcinoma and squamous cell carcinoma.

Front Med 2021 Apr 5;15(2):275-291. Epub 2020 Sep 5.

National Institute of Occupational Health (STAMI), Oslo, Pb 5330, Norway.

Although genome-wide association studies have identified more than eighty genetic variants associated with non-small cell lung cancer (NSCLC) risk, biological mechanisms of these variants remain largely unknown. By integrating a large-scale genotype data of 15 581 lung adenocarcinoma (AD) cases, 8350 squamous cell carcinoma (SqCC) cases, and 27 355 controls, as well as multiple transcriptome and epigenomic databases, we conducted histology-specific meta-analyses and functional annotations of both reported and novel susceptibility variants. We identified 3064 credible risk variants for NSCLC, which were overrepresented in enhancer-like and promoter-like histone modification peaks as well as DNase I hypersensitive sites. Transcription factor enrichment analysis revealed that USF1 was AD-specific while CREB1 was SqCC-specific. Functional annotation and gene-based analysis implicated 894 target genes, including 274 specifics for AD and 123 for SqCC, which were overrepresented in somatic driver genes (ER = 1.95, P = 0.005). Pathway enrichment analysis and Gene-Set Enrichment Analysis revealed that AD genes were primarily involved in immune-related pathways, while SqCC genes were homologous recombination deficiency related. Our results illustrate the molecular basis of both well-studied and new susceptibility loci of NSCLC, providing not only novel insights into the genetic heterogeneity between AD and SqCC but also a set of plausible gene targets for post-GWAS functional experiments.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11684-020-0779-4DOI Listing
April 2021

Identification of Recurrent Variants in and across Multiple Cancers in the Chinese Population.

Biomed Res Int 2020 15;2020:6739823. Epub 2020 Aug 15.

State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, Jiangsu 211100, China.

and as important DNA repair genes have been thoroughly investigated in abundant studies. The potential relationships of pathogenic variants between multicancers have been verified in Caucasians but few in Chinese. In this study, we performed a two-stage study to screen pathogenic variants or variants of uncertain significance (VUS) with 7580 cancer cases and 4874 cancer-free controls, consisting of a discovery stage with 70 familial breast cancer cases and a subsequent validation stage with 7510 cases (3217 breast cancer, 1133 cervical cancer, 2044 hepatocellular carcinoma, and 1116 colorectal cancer). 48 variants were obtained from 70 familial breast cancer cases after exon detection, and finally, 20 pathogenic variants or VUS were selected for subsequent validation. Four recurrent variants in sporadic cases ( c.4801A>T, c.3257del, c.440del, and c.7409dup) were identified and three of them were labeled Class 5 by ENIGMA. Two variants ( c.3257del and c.440del) were specific in breast cancer cases, while c.7409dup and c.4307T>C were detected in two hepatocellular carcinoma patients and the c.4801A>T variant in one cervical cancer patient, respectively. Moreover, c.3257del was the most frequent variant observed in Chinese sporadic breast cancer and showed increased proliferation of -overexpressing triple-negative breast cancer cell lines (MDA-MB-231) in vitro. In addition to the known founder deleterious mutations, our findings highlight that the recurrently pathogenic variants in breast cancer cases could be taken as candidate genetic screening loci for a more efficient genetic screening of the Chinese population.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1155/2020/6739823DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7448236PMC
May 2021

Transcriptome-wide association study for persistent hepatitis B virus infection and related hepatocellular carcinoma.

Liver Int 2020 09 13;40(9):2117-2127. Epub 2020 Jul 13.

Department of Epidemiology, School of Public Health, Nanjing Medical University, Nanjing, China.

Background & Aims: Previous genome-wide association studies (GWAS) have identified multiple susceptible variants associated with persistent hepatitis B virus (HBV) infection. However, most of these variants are located in the noncoding regions, which make it difficult to determine the effective genes underlying these associations. We performed a two-stage study, in the first stage we integrated RNA sequencing data of liver tissues and high-density genotyping data from the Genotype-Tissue Expression (GTEx) project with our previous GWAS data to conduct a transcriptome-wide association study (TWAS) on HBV infection. Firstly, the cis-heritable genes were screened by a genetic relatedness matrix of genome-wide complex trait analysis (GCTA) from GTEx data. Then, the genetic expression of 2587 cis-heritable genes was predicted by restricted maximum likelihood (REML) of genome-wide efficient mixed-model association (GEMMA) in our GWAS data with 951 HBV carrier cases and 937 HBV cleared controls. Next, we investigated the associations between predictive expression levels and persistent HBV infection risk. Gene set enrichment analysis (GSEA) was applied to infer the function of the identified genes. To identify the causal single nucleotide polymorphisms (SNPs) of HBV infection risk, we conducted the expression quantitative trait loci (eQTL)-based stepwise logistic regression analysis in the regions around 1 Mb of these genes and validated the association between 994 health controls and 994 HBV-persistent infection cases by genotyping experiment. In the second stage, 1538 HBV-related hepatocellular carcinoma (HCC) cases and 1465 persistent HBV infection controls were collected to determine the effect of these variants on HBV-related HCC as well, which were examined by the additive model in logistic regression analysis. We identified seven genes associated with HBV infection. In the classic human leukocyte antigen (HLA) region, three novel genes BAK1, HLA-DOB and C4A (Z range from -3.95 to -3.64, P range from 7.84 × 10 to 2.00 × 10 ), as well as two genes (HLA-DPA1 and HLA-DPB1) were reported by previous GWAS. In the non-HLA region, immune related at newly identified loci, PARP9 (Z = 3.69, P = 2.20 × 10 ) at 3q21.1. At 22q11.21, we identified TMEM191A (Z = 3.55, P = 3.80 × 10 ) as a target gene in addition to the reported non-cis-heritable gene UBE2L3. After further stepwise logistic regression analysis and validation, we identified eight variants independently associated with persistent HBV infection. Among those variants, the additive model showed that two SNPs associated with HBV-related HCC risk (rs9272714 and rs9394194, OR range from 1.20 to 1.25, P range from 1.19 × 10 to 3.97 × 10 ). By integrating transcriptome data, our study not only identified new susceptibility loci of persistent HBV infection but also determined the potential target genes at reported loci, which provided insight into the genetic aetiology of persistent HBV infection and related HCC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/liv.14577DOI Listing
September 2020

Genetic Variations in miR-30 Family Member Regulatory Regions Are Associated with Breast Cancer Risk in a Chinese Population.

Biomed Res Int 2020 27;2020:8781348. Epub 2020 Mar 27.

Department of Epidemiology, International Joint Research Center on Environment and Human Health, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China.

MicroRNAs (miRNAs) of the miR-30 family are closely linked with tumor metastasis and play key roles in the complex malignant phenotypes of cancers by targeting many tumor-related genes. Deregulated expression of miR-30 family members has been commonly observed in breast cancer. However, associations between the genetic variants in the regulatory region of miR-30 family and the risk of breast cancer are still limited, especially in the Chinese Han population. In the present study, we conducted a case-control analysis wherein 1064 breast cancer patients and 1073 healthy controls underwent genotyping of 10 SNPs in the regulatory region of miR-30 family members. Multivariate logistic regression analyses illustrated that the rs763354 variant in the miR-30a regulatory region was linked with a significant decrease in breast cancer risk in an additive model (adjusted OR = 0.86, 95% CI: 0.75-0.98, = 0.022). Further, eQTL analyses also indicated that this SNP was associated with miR-30a expression levels in breast cancer samples compiled in the TCGA database ( = 0.020). The Kaplan-Meier plotter showed that breast cancer patients with higher miR-30a expression have significantly better outcomes than do patients expressing low levels of this miRNA (HR = 0.75, 95% CI: 0.61-0.91, = 0.0041). Together, these findings suggest that the miR-30a rs763354 SNP is an important regulator of breast cancer risk, thus making it a potentially viable prognostic biomarker and one that can be used to guide therapeutic treatment in affected patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1155/2020/8781348DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7140140PMC
January 2021

RNA-seq analysis identified hormone-related genes associated with prognosis of triple negative breast cancer.

J Biomed Res 2020 Jan;34(2):129-138

Department of Epidemiology, Center for Global Health, School of Public Health.

Triple negative breast cancer (TNBC) is an aggressive subtype of breast cancer that currently lacks effective biomarkers and therapeutic targets required to investigate the diagnosis and treatment of TNBC. Here we performed a comprehensive differential analysis of 165 TNBC samples by integrating RNA-seq data of breast tumor tissues and adjacent normal tissues from both our cohort and The Cancer Genome Atlas (TCGA). Pathway enrichment analysis was conducted to evaluate the biological function of TNBC-specific expressed genes. Further multivariate Cox proportional hazard regression was performed to evaluate the effect of these genes on TNBC prognosis. In this report, we identified a total of 148 TNBC-specific expressed genes that were primarily enriched in mammary gland morphogenesis and hormone levels related pathways, suggesting that mammary gland morphogenesis might play a unique role in TNBC patients differing from other breast cancer types. Further survival analysis revealed that nine genes ( , , , , , , , , and ) were significantly associated with the prognosis of TNBC patients, while three of them ( , , and ) were involved in the hormone-related pathways. These findings indicated the vital role of the hormone-related genes in TNBC tumorigenesis and may provide some independent prognostic markers as well as novel therapeutic targets for TNBC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7555/JBR.34.20190111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7183303PMC
January 2020

Association Analysis of Driver Gene-Related Genetic Variants Identified Novel Lung Cancer Susceptibility Loci with 20,871 Lung Cancer Cases and 15,971 Controls.

Cancer Epidemiol Biomarkers Prev 2020 07 10;29(7):1423-1429. Epub 2020 Apr 10.

National Institute of Occupational Health (STAMI), Oslo, Norway.

Background: A substantial proportion of cancer driver genes (CDG) are also cancer predisposition genes. However, the associations between genetic variants in lung CDGs and the susceptibility to lung cancer have rarely been investigated.

Methods: We selected expression-related single-nucleotide polymorphisms (eSNP) and nonsynonymous variants of lung CDGs, and tested their associations with lung cancer risk in two large-scale genome-wide association studies (20,871 cases and 15,971 controls of European descent). Conditional and joint association analysis was performed to identify independent risk variants. The associations of independent risk variants with somatic alterations in lung CDGs or recurrently altered pathways were investigated using data from The Cancer Genome Atlas (TCGA) project.

Results: We identified seven independent SNPs in five lung CDGs that were consistently associated with lung cancer risk in discovery ( < 0.001) and validation ( < 0.05) stages. Among these loci, rs78062588 in (1q21.3) was a new lung cancer susceptibility locus (OR = 0.86, = 1.65 × 10). Subgroup analysis by histologic types further identified nine lung CDGs. Analysis of somatic alterations found that in lung adenocarcinomas, rs78062588[C] allele ( in 1q21.3) was associated with elevated somatic copy number of (OR = 1.16, = 0.02). In lung adenocarcinomas, rs1611182 ( in 6p22.1) was associated with truncation mutations of the transcriptional misregulation in cancer pathway (OR = 0.66, = 1.76 × 10).

Conclusions: Genetic variants can regulate functions of lung CDGs and influence lung cancer susceptibility.

Impact: Our findings might help unravel biological mechanisms underlying lung cancer susceptibility.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1055-9965.EPI-19-1085DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8120681PMC
July 2020

Family-based whole-genome sequencing identifies compound heterozygous protein-coding and noncoding mutations in tetralogy of Fallot.

Gene 2020 May 9;741:144555. Epub 2020 Mar 9.

State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 211166, China; Department of Epidemiology and Biostatistics, Center for Global Health, Nanjing Medical University, Nanjing 211166, China. Electronic address:

Tetralogy of Fallot (TOF) is one of most serious cyanotic congenital heart disease (CHD) and the prevalence is estimated to be 1 in 3000 live births worldwide. Though multiple studies have found genetic variants as risk factors for TOF, they could only explain a small fraction of the pathogenesis. Here, we performed whole genome sequencing (WGS) for 6 individuals derived from 2 families to evaluate pathogenic mutations located in both coding and noncoding regions. We characterized the annotated deleterious coding mutations and impaired noncoding mutations in regulatory elements by various data analysis. Additionally, functional assays were conducted to validate function regulatory elements and noncoding mutations. Interestingly, a compound heterozygous pattern with pathogenic coding and noncoding mutations was identified in probands. In proband 1, biallelic mutations (g.139409115A > T, encoding p.Asn685Ile; g.139444949C > A) in NOTCH1 exon and its regulatory element were detected. In vitro experiments revealed that the regulatory element acted as a silencer and the noncoding mutation decreased the expression of NOTCH1. In proband 2, we also found compound heterozygous mutations (g. 216235029C > T, encoding p.Val2281Met; g. 216525154A > C) which potentially regulated the function of FN1 gene. In summary, our study firstly reported an instance of newly identified noncoding mutation in regulatory element within the compound heterozygous pattern in TOF. The results provided a deeper understanding of TOF genetic architectures.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.gene.2020.144555DOI Listing
May 2020

Identification of genetic features associated with fine particulate matter (PM2.5) modulated DNA damage using improved random forest analysis.

Gene 2020 May 9;740:144570. Epub 2020 Mar 9.

Department of Biostatistics, School of Public Health, Nanjing Medical University, Nanjing 211166, China; China International Cooperation Center (CICC) for Environment and Human Health, Nanjing Medical University, Nanjing 211166, China. Electronic address:

Recent studies have found multiple single nucleotide variants (SNVs) associated with DNA damage. However, previous association analysis may ignore the potential interaction effects between SNVs. Therefore, we used an improved random forest (RF) analysis to identify the SNVs related to personal DNA damage in exon-focused genome-wide association study (GWAS). A total of 301 subjects from three independent centers (Zhuhai, Wuhan, and Tianjin) were retained for analysis. An improved RF procedure was used to systematically screen key SNVs associated with DNA damage. Furthermore, we used genetic risk score (GRS) and mediation analysis to investigate the integrative effect and potential mechanism of these genetic variants on DNA damage. Besides, gene set enrichment analysis was conducted to identify the pathways enriched by key SNVs using the Data-driven Expression Prioritized Integration for Complex Traits (DEPICT). Finally, a set of 24 SNVs with the lowest mean square errors (MSE) were identified by improved RF analysis. Both weighted and unweighted GRSs were associated with increased DNA damage levels (P < 0.001 and P < 0.001). Gene set enrichment analysis indicated that these loci were significantly enriched in several biological features associated with DNA damage. These findings suggested the role of SNVs in modifying DNA damage levels. It may be convincing that this improved RF analysis can effectively identify SNVs associated with DNA damage levels.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.gene.2020.144570DOI Listing
May 2020

A nomogram to predict overall survival of patients with early stage non-small cell lung cancer.

J Thorac Dis 2019 Dec;11(12):5407-5416

Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China.

Background: Nomograms have been widely used for estimating cancer prognosis. The aim of this study was to construct a clinical nomogram that would well predict overall survival of early stage non-small cell lung cancer (NSCLC) patients after surgery resection.

Methods: A total of 443 patients diagnosed with pathologic stage I and II NSCLC who had undergone curative resection without neoadjuvant chemotherapy or radiotherapy were recruited and analyzed. The log-rank test and multivariate Cox regression analysis were used to select the most significant predictors in the final nomogram for predicting overall survival. Furthermore, the model was validated by bootstrap methods and measured by concordance index (C-index) and calibration plots.

Results: Four independent predictors for overall survival were identified and included into the delineation of the nomogram (tumor differentiation, station of sampled lymph nodes, pathologic T and pathologic N). The model showed comparatively stable discrimination (bootstrap-corrected C-index =0.622, 95% CI: 0.572-0.672) and good calibration.

Conclusions: We successfully developed a nomogram incorporating available clinicopathological variables to predict overall survival of early stage NSCLC patients after surgery resection, which might help clinician select better appropriate treatment decisions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.21037/jtd.2019.11.53DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6988073PMC
December 2019

Cross-Cancer Pleiotropic Analysis Reveals Novel Susceptibility Loci for Lung Cancer.

Front Oncol 2019 15;9:1492. Epub 2020 Jan 15.

Department of Epidemiology and Biostatistics, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China.

Genome-wide association studies (GWASs) have identified hundreds of single nucleotide polymorphisms (SNPs) associated with cancer risk, several of which have shown pleiotropic effects across cancers. Therefore, we performed a systematic cross-cancer pleiotropic analysis to detect the effects of GWAS-identified variants from non-lung cancers on lung cancer risk in 12,843 cases and 12,639 controls from four lung cancer GWASs. The overall association between variants in each cancer and risk of lung cancer was explored using sequential kernel association test (SKAT) analysis. For single variant analysis, we combined the result of specific study using fixed-effect meta-analysis. We performed functional exploration of significant associations based on features from public databases. To further detect the biological mechanism underlying identified observations, pathway enrichment analysis were conducted with R package "clusterProfiler." SNP-set analysis revealed the overall associations between variants of 8 cancer types and lung cancer risk. Single variant analysis identified 6 novel SNPs related to lung cancer risk after multiple correction ( < 0.10), including rs1707302 (1p34.1, OR = 0.93, 95% CI: 0.90-0.97, = 7.60 × 10), rs2516448 (6p21.33, OR = 1.07, 95% CI: 1.03-1.11, = 1.00 × 10), rs3869062 (6p22.1, OR = 0.91, 95% CI: 0.86-0.96, = 7.10 × 10), rs174549 (11q12.2, OR = 0.90, 95% CI: 0.87-0.94, = 1.00 × 10), rs7193541 (16q23.1, OR = 0.93, 95% CI: 0.90-0.96, = 1.20 × 10), and rs8064454 (17q12, OR = 1.07, 95% CI: 1.03-1.11, = 4.30 × 10). The eQTL analysis and functional annotation suggested that these variants might modify lung cancer susceptibility through regulating the expression of related genes. Pathway enrichment analysis showed that genes modulated by these variants play important roles in cancer carcinogenesis. Our findings demonstrate the pleiotropic associations between non-lung cancer susceptibility loci and lung cancer risk, providing important insights into the shared mechanisms of carcinogenesis across cancers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fonc.2019.01492DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6974684PMC
January 2020

Systematic analyses of genetic variants in chromatin interaction regions identified four novel lung cancer susceptibility loci.

J Cancer 2020 1;11(5):1075-1081. Epub 2020 Jan 1.

Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China.

Genome-wide association studies (GWAS) have reported 45 single-nucleotide polymorphisms (SNPs) that may contribute to the susceptibility of lung cancer, with the majority in non-coding regions. However, no study has ever systematically evaluated the association between SNPs in physical chromatin interaction regions and lung cancer risk. In this study, we integrated the chromatin interaction information (Hi-C data) of lung cancer cell line and conducted a meta-analysis with two Asian GWASs (7,127 cases and 6,818 controls) to evaluate the association of potentially functional SNPs in chromatin interaction regions with lung cancer risk. We identified four novel lung cancer susceptibility loci located at 1q21.1 (rs17160062, =4.00×10), 2p23.3 (rs670343, =4.87×10), 2p15 (rs9309336, =3.24×10) and 17q21.2 (rs9252, =1.51×10) that were significantly associated with lung cancer risk after correction for multiple tests. Functional annotation result indicated that these SNPs may contribute to the development of lung cancer by affecting the availability of transcription factor binding sites. The HaploReg analysis suggested that rs9309336 may affect binding motif of transcription factor Foxp1. Expression quantitative trait loci analysis revealed that rs9309336 and rs17160062 could regulate the expressions of cancer-related genes ( and ). Our results revealed that variants in chromatin interaction regions could contribute to the development of lung cancer by regulating the expression of target genes, which providing novel implications for the understanding of functional variants in the development of lung cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7150/jca.35127DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6959073PMC
January 2020

Association Between Levels of Sex Hormones and Risk of Esophageal Adenocarcinoma and Barrett's Esophagus.

Clin Gastroenterol Hepatol 2020 11 19;18(12):2701-2709.e3. Epub 2019 Nov 19.

Upper Gastrointestinal Surgery, Department of Molecular Medicine and Surgery, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden; School of Cancer and Pharmaceutical Sciences, King's College London, London, United Kingdom.

Background & Aims: Esophageal adenocarcinoma (EAC) occurs most frequently in men. We performed a Mendelian randomization analysis to investigate whether genetic factors that regulate levels of sex hormones are associated with risk of EAC or Barrett's esophagus (BE).

Methods: We conducted a Mendelian randomization analysis using data from patients with EAC (n = 2488) or BE (n = 3247) and control participants (n = 2127), included in international consortia of genome-wide association studies in Australia, Europe, and North America. Genetic risk scores or single-nucleotide variants were used as instrumental variables for 9 specific sex hormones. Logistic regression provided odds ratios (ORs) with 95% CIs.

Results: Higher genetically predicted levels of follicle-stimulating hormones were associated with increased risks of EAC and/or BE in men (OR, 1.14 per allele increase; 95% CI, 1.01-1.27) and in women (OR, 1.28; 95% CI, 1.03-1.59). Higher predicted levels of luteinizing hormone were associated with a decreased risk of EAC in men (OR, 0.92 per SD increase; 95% CI, 0.87-0.99) and in women (OR, 0.93; 95% CI, 0.79-1.09), and decreased risks of BE (OR, 0.88; 95% CI, 0.77-0.99) and EAC and/or BE (OR, 0.89; 95% CI, 0.79-1.00) in women. We found no clear associations for other hormones studied, including sex hormone-binding globulin, dehydroepiandrosterone sulfate, testosterone, dihydrotestosterone, estradiol, progesterone, or free androgen index.

Conclusions: In a Mendelian randomization analysis of data from patients with EAC or BE, we found an association between genetically predicted levels of follicle-stimulating and luteinizing hormones and risk of BE and EAC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cgh.2019.11.030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7580878PMC
November 2020

Genetic Association of Plasma Homocysteine Levels with Gastric Cancer Risk: A Two-Sample Mendelian Randomization Study.

Cancer Epidemiol Biomarkers Prev 2020 02 20;29(2):487-492. Epub 2019 Nov 20.

Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China.

Background: The association of plasma homocysteine level (PHL) with gastric cancer risk was reported in observational studies. However, the causality is challenging due to confounding factors and the lack of evidence from well-designed cohort studies. Herein, we performed a two-sample Mendelian randomization (MR) analysis to investigate whether PHL is causally related to gastric cancer risk.

Methods: We performed the MR analysis based on the results from genome-wide association studies consisting of 2,631 patients with gastric cancer and 4,373 controls. An externally weighted genetic risk score (wGRS) was constructed with 15 SNPs with well-established associations with PHL. We utilized logistic regression model to estimate associations of PHL-related SNPs and wGRS with gastric cancer risk in total population and in strata by sex, age, and study site, in addition to a series of sensitivity analyses.

Results: High genetically predicted PHL was associated with an increased gastric cancer risk (per SD increase in the wGRS: OR = 1.07; 95% confidence interval, 1.01-1.12; = 0.011), which was consistent in sensitivity analyses. Subgroup analyses provided evidence of a stronger association with gastric cancer risk in women than in men. MR-Egger and weighted median regression suggested that potentially unknown pleiotropic effects were not biasing the association between PHL and gastric cancer risk.

Conclusions: These results revealed that genetically predicted high PHL was associated with an increased gastric cancer risk, suggesting that high PHL may have a causal role in the etiology of gastric cancer.

Impact: These findings provide causal inference for PHL on gastric cancer risk, suggesting a causal role of high PHL in the etiology of gastric cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1055-9965.EPI-19-0724DOI Listing
February 2020

Mendelian randomization study of telomere length and lung cancer risk in East Asian population.

Cancer Med 2019 12 11;8(17):7469-7476. Epub 2019 Oct 11.

Department of Epidemiology, School of Public Health, Nanjing Medical University, Nanjing, China.

Associations between telomere length and cancer risk have been investigated in many epidemiological studies, but the results are controversial. These associations may be biased by reverse causation or confounded by environmental exposures. To avoid potential biases, we used Mendelian randomization method to evaluate whether TL is the causal risk factor for lung cancer. We conducted Mendelian randomization analysis in two published East Asian GWAS studies (7127 cases and 6818 controls). We used both weighted genetic risk score and inverse-variance weighting method to estimate the relationship between TL and lung cancer risk. Nonlinear test also used to detect potential association trends. We observed that increased weight GRS was associated with increased risk of lung cancer (OR = 2.25, 95%CI: 1.81-2.78, P = 1.18 × 10 ). In different subtypes, weight GRS was significantly associated with lung adenocarcinoma risk (OR = 2.69, 95% CI: 2.11-3.42, P = 7.20 × 10 ); while lung squamous cell carcinoma showed a marginal association (OR = 1.45, 95% CI = 1.01-2.10, P = .047). Nonlinear analysis suggested a log-linear dose-response relationship between increased weight GRS and lung cancer risk. Our results indicated that longer TL increases lung cancer risk. Those biological mechanisms changes caused by long TL may play an important role in lung carcinogenesis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cam4.2590DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6885879PMC
December 2019

RNAIndel: discovering somatic coding indels from tumor RNA-Seq data.

Bioinformatics 2020 03;36(5):1382-1390

Computational Biology, St Jude Children's Research Hospital, Memphis, TN 38105, USA.

Motivation: Reliable identification of expressed somatic insertions/deletions (indels) is an unmet need due to artifacts generated in PCR-based RNA-Seq library preparation and the lack of normal RNA-Seq data, presenting analytical challenges for discovery of somatic indels in tumor transcriptome.

Results: We present RNAIndel, a tool for predicting somatic, germline and artifact indels from tumor RNA-Seq data. RNAIndel leverages features derived from indel sequence context and biological effect in a machine-learning framework. Except for tumor samples with microsatellite instability, RNAIndel robustly predicts 88-100% of somatic indels in five diverse test datasets of pediatric and adult cancers, even recovering subclonal (VAF range 0.01-0.15) driver indels missed by targeted deep-sequencing, outperforming the current best-practice for RNA-Seq variant calling which had 57% sensitivity but with 14 times more false positives.

Availability And Implementation: RNAIndel is freely available at https://github.com/stjude/RNAIndel.

Supplementary Information: Supplementary data are available at Bioinformatics online.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/bioinformatics/btz753DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7523641PMC
March 2020