Publications by authors named "Xiating Peng"

29 Publications

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A genetic variant conferred high expression of CAV2 promotes pancreatic cancer progression and associates with poor prognosis.

Eur J Cancer 2021 Jul 8;151:94-105. Epub 2021 May 8.

Department of Epidemiology and Biostatistics, Key Laboratory for Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Sciences and Technology, Wuhan, China. Electronic address:

Aim: This study aimed to identify the functional genes and genetic variants associated with the prognosis of pancreatic ductal adenocarcinoma (PDAC) and reveal the mechanism underlying their prognostic roles.

Methods: First, we implement a two-stage exome-wide association study in a total of 1070 patients to identify the genetic variant correlated with PDAC prognosis. Then we performed fine mapping through bioinformatics analysis and dual-luciferase reporter assays to reveal the causal functional variant and prognostic gene. Next, we established the gene knockdown, knockout, and overexpression cell lines with small interfering RNA, CRISPR/Cas9, and lentivirus, respectively, and investigated the gene function on cell proliferation and migration in vivo and in vitro. Finally, we performed the RNA-seq to elucidate downstream genes and mechanisms altering PDAC prognosis.

Results: We identified the CAV1-CAV2 locus tagged by rs8940 was significantly associated with PDAC prognosis, and rs10249656 in the 3'untranslated region of CAV2 was the real functional variant, which upregulated CAV2 expression through abolishing miR-548s binding. We observed upregulated CAV2 in PDAC and the higher expression correlated with worse prognosis. Transient knockdown of CAV2 inhibited PDAC migration without affecting proliferation rate. Knockout of CAV2 suppressed PDAC progression and metastasis, whereas stable overexpression of CAV2 promoted. Overexpressed CAV2 promoted the PDAC progression and metastasis via perturbing genes in the focal adhesion (CCND1, IGTA1, and ZYX) and extracellular matrix organisation (PLOD2, CAST, and ITGA1) pathways mechanically.

Conclusion: These findings shed light on an important role of CAV2 on PDAC progression and the prognostic impact of its genetic variation.
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http://dx.doi.org/10.1016/j.ejca.2021.04.008DOI Listing
July 2021

Identification of genetic variants in mA modification genes associated with pancreatic cancer risk in the Chinese population.

Arch Toxicol 2021 03 21;95(3):1117-1128. Epub 2021 Jan 21.

Department of Epidemiology and Biostatistics, Key Laboratory for Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.

N6-Methyladenosine (mA) is the most prevalent modification of RNA in eukaryotes, and is associated with many cellular processes and even the development of cancers. We hypothesized that single-nucleotide polymorphisms (SNPs) in mA modification genes, including its "writers", "erasers" and "readers", might affect the mA functions and associate with the susceptibility to pancreatic ductal adenocarcinoma (PDAC). We first conducted a two-stage case-control study in Chinese population to interrogate all SNPs in 22 mA modification genes. In the discovery stage, a total of 2735 SNPs were genotyped in 980 patients and 1991 controls. Then, the promising SNP was replicated in another independent population consisting of 858 cases and 2084 controls. As a result, we found the rs7495 in 3'UTR of hnRNPC was significantly associated with increased risk of PDAC in both stages (combined odds ratio = 1.22, 95% confidence interval = 1.12-1.32, P = 2.39 × 10). To further reveal the biological function of rs7495 and hnRNPC, we performed a series of biochemical experiments. Luciferase reporter assays indicated that rs7495G allele promoted hnRNPC expression through disrupting a putative binding site for has-miR-183-3p. Cell viability assay demonstrated that knockdown of hnRNPC suppressed the proliferation of PDAC cells. RNA-seq analysis suggested that as an mA "reader", hnRNPC played an important role in RNA biological processes. In conclusion, our findings elucidated that rs7495G could confer higher risk of PDAC via promoting the expression of hnRNPC through a miRNA-mediated manner. These results provided a novel insight into the critical role of mA modification in tumorigenesis.
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http://dx.doi.org/10.1007/s00204-021-02978-5DOI Listing
March 2021

Regulatory Variant as Predictor of Epirubicin-Based Neoadjuvant Chemotherapy in Luminal A Breast Cancer.

Front Oncol 2020 25;10:571517. Epub 2020 Sep 25.

Department of VIP Medical Services, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

Epirubicin combined with docetaxel is the cornerstone of neoadjuvant chemotherapy (NAC) for breast cancer. The efficacy of NAC for luminal A breast cancer patients is very limited, and single nucleotide polymorphism is one of the most important factors that influences the efficacy. Our study is aimed to explore genetic markers for the efficacy of epirubicin combined with docetaxel for NAC in patients with luminal A breast cancer. A total of 421 patients with two stages of luminal A breast cancer were enrolled in this study from 2 centers. Among them 231 patients were included in the discovery cohort and 190 patients are in the replication cohort. All patients received epirubicin 75 mg/m and docetaxel 75 mg/m on day 1, in a 21-day cycle, a cycle for 2-6 cycles. Before treatment, 2 ml of peripheral blood was collected from each patient to isolate genomic DNA. Fourteen functional variants potentially regulating epirubicin/docetaxel response genes were prioritized by CellMiner and bioinformatics approaches. Moreover, biological assays were performed to determine the effect of genetic variations on response to chemotherapy. The patients carrying rs6484711 variant A allele suffered a poor response to epirubicin and docetaxel for NAC (OR = 0.37, 95% CI: 0.18-0.74, = 0.005) in combined stage. Moreover, expression quantitative trait loci (eQTL) analyses and luciferase reporter assays revealed that rs6484711 A allele significantly increased the expression of . Subsequent biological assays illustrated that upregulation of significantly reduced the apoptosis rate of breast cancer cells and enhanced the chemo-resistance to epirubicin. Our study demonstrated rs6484711 polymorphism regulating expression might predict efficacy to epirubicin based NAC in luminal A breast cancer patients. These results provided valuable information about potential role of genetic variations in individualized chemotherapy.
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http://dx.doi.org/10.3389/fonc.2020.571517DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7545368PMC
September 2020

Functional characterization of a low-frequency V1937I variant in FASN associated with susceptibility to esophageal squamous cell carcinoma.

Arch Toxicol 2020 06 9;94(6):2039-2046. Epub 2020 May 9.

Department of Epidemiology and Biostatistics, Key Laboratory for Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Metabolic reprogramming has been regarded as one of the core hallmarks of cancer and increased de novo fatty acid synthesis has been documented in multiple tumors including esophageal squamous cell carcinoma (ESCC). Our previous exome-wide analyses found a Val1937Ile variant (rs17848945) in the 34th exon of fatty acid synthase (FASN) that showed a strong association with the risk of ESCC. In this study, we performed a series of functional assays to investigate the biological functions underlying this variant in the development of ESCC. We demonstrated that FASN was upregulated in ESCC and both knockdown and knockout of FASN significantly inhibited ESCC cell proliferation, suggesting a tumor promoter role for this gene in ESCC. Furthermore, the results showed that overexpression of FASN[I] in the ESCC cells substantially enhanced cell proliferation, compared with overexpression of FASN[V], or the control vector. Intriguingly, we found that the FASN[I] variant can enhance the enzyme activity of FASN, and, thus, increase the amount of the FASN end-product, palmitate in the ESCC cells. We also observed elevated palmitate levels in the plasma of the FASN[I] genotype carriers among a total of 632 healthy Chinese adults. In conclusion, our results suggested that the FASN V1937I variant influenced ESCC cell proliferation and susceptibility by altering the catabolic activity of FASN on palmitate. These findings may highlight an important role of palmitate metabolism in the development of ESCC and may contribute to the personalized medicine of this disease.
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http://dx.doi.org/10.1007/s00204-020-02738-xDOI Listing
June 2020

N-methyladenosine mRNA methylation of regulates AKT signalling to promote PTEN-deficient pancreatic cancer progression.

Gut 2020 12 20;69(12):2180-2192. Epub 2020 Apr 20.

Department of Epidemiology and Biostatistics, Key Laboratory for Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Sciences and Technology, Wuhan 430030, China, Huazhong University of Science and Technology Tongji Medical College, Wuhan, China

Objective: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers worldwide. Thus far, most drugs have failed to significantly improve patient survival. N-methyladenosine (mA) plays an important role in the progression of PDAC, but its aberrant regulation driven by germline variants in human diseases remains unclear.

Design: We first performed an exome-wide association analysis in 518 PDAC patients with overall survival and replicated in an independent population containing 552 PDAC patients. Then, a series of biochemical experiments in vitro and in vivo were conducted to investigate potential mechanisms of the candidate variant and its target gene underlying the PDAC progression. Moreover, the PIK3CB-selective inhibitor KIN-193 was used to block PDAC tumour growth.

Results: We identified a missense variant rs142933486 in that is significantly associated with the overall survival of PDAC by reducing the mA level, which facilitated its mRNA and protein expression levels mediated by the mA 'writer' complex (METTL13/METTL14/WTAP) and the mA 'reader' YTHDF2. The upregulation of is widely found in PDAC tumour tissues and significantly correlated with the poor prognosis of PDAC, especially in PTEN-deficient patients. We further demonstrated that overexpression substantially enhanced the proliferation and migration abilities of PTEN-deficient PDAC cells and activated AKT signalling pathway. Remarkably, KIN-193, a PIK3CB-selective inhibitor, is shown to serve as an effective anticancer agent for blocking PTEN-deficient PDAC.

Conclusions: These findings demonstrate aberrant mA homoeostasis as an oncogenic mechanism in PDAC and highlight the potential of as a therapeutic target for this disease.
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http://dx.doi.org/10.1136/gutjnl-2019-320179DOI Listing
December 2020

Risk SNP-Mediated Enhancer-Promoter Interaction Drives Colorectal Cancer through Both and .

Cancer Res 2020 05 3;80(9):1804-1818. Epub 2020 Mar 3.

Department of Epidemiology and Biostatistics, Key Laboratory for Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Sciences and Technology, Wuhan, China.

Although genome-wide association studies (GWAS) have identified more than 100 colorectal cancer risk loci, most of the biological mechanisms associated with these loci remain unclear. Here we first performed a comprehensive expression quantitative trait loci analysis in colorectal cancer tissues adjusted for multiple confounders to test the determinants of germline variants in established GWAS susceptibility loci on mRNA and long noncoding RNA (lncRNA) expression. Combining integrative functional genomic/epigenomic analyses and a large-scale population study consisting of 6,024 cases and 10,022 controls, we then prioritized rs174575 with a C>G change as a potential causal candidate for colorectal cancer at 11q12.2, as its G allele was associated with an increased risk of colorectal cancer (OR = 1.26; 95% confidence interval = 1.17-1.36; = 2.57 × 10). rs174575 acted as an allele-specific enhancer to distally facilitate expression of both FADS2 and lncRNA AP002754.2 via long-range enhancer-promoter interaction loops, which were mediated by E2F1. AP002754.2 further activated a transcriptional activator that upregulated FADS2 expression. FADS2, in turn, was overexpressed in colorectal cancer tumor tissues and functioned as a potential oncogene that facilitated colorectal cancer cell proliferation and xenograft growth and by increasing the metabolism of PGE2, an oncogenic molecule involved in colorectal cancer tumorigenesis. Our findings represent a novel mechanism by which a noncoding variant can facilitate long-range genome interactions to modulate the expression of multiple genes including not only mRNA, but also lncRNA, which provides new insights into the understanding of colorectal cancer etiology. SIGNIFICANCE: This study provides an oncogenic regulatory circuit among several oncogenes including , and underlying the association of rs174575 with colorectal cancer risk, which is driven by long-range enhancer-promoter interaction loops. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/9/1804/F1.large.jpg.
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http://dx.doi.org/10.1158/0008-5472.CAN-19-2389DOI Listing
May 2020

A functional variant in TNXB promoter associates with the risk of esophageal squamous-cell carcinoma.

Mol Carcinog 2020 04 13;59(4):439-446. Epub 2020 Feb 13.

Department of Epidemiology and Biostatistics, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Our previous study identified a tag single-nucleotide polymorphism (SNP) rs204900 in TNXB associated with risk of esophageal squamous-cell carcinoma (ESCC) in the Chinese population. However, the functional role of TNXB and causal variants had not been interrogated in that study. In the present study, we explored the effects of TNXB expression in the development of ESCC and searched for functional variants in this gene. We found TNXB was downregulated in ESCC tumors. Using small interfering RNAs and CRISPR-Cas9 methods, we identified that both knockdown and knockout of TNXB significantly promoted ESCC cell growth in vitro, suggesting a tumor suppressor role of this gene in ESCC. Through further fine-mapping analysis, we identified that a noncoding variant in the promoter of TNXB, rs411337, predisposed to ESCC risk (odds ratio = 1.36, 95% confidence interval: 1.22-1.51, P = 9.10 × 10 ). These findings revealed the functional mechanism of TNXB in the development of ESCC and may contribute to the prevention and treatment of this disease in the future.
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http://dx.doi.org/10.1002/mc.23166DOI Listing
April 2020

Genetic variants in m6A modification genes are associated with esophageal squamous-cell carcinoma in the Chinese population.

Carcinogenesis 2020 07;41(6):761-768

Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

N 6-methyladenosine (m6A) is an abundant modification in RNAs that affects RNA metabolism, and it is reported to be closely related to cancer occurrence and metastasis. In this study, we focused on evaluating the associations between genetic variants in m6A modification genes and the risk of esophageal squamous-cell carcinoma (ESCC). By integrating data of our previous genome-wide association studies and the predictions of several annotation tools, we identified a single nucleotide polymorphism, rs2416282 in the promoter of YTHDC2, that was significantly associated with the susceptibility of ESCC (odds ratio = 0.84, 95% CI: 0.77-0.92, P = 2.81 × 10-4). Through further functional experiments in vitro, we demonstrated that rs2416282 regulated YTHDC2 expression. Knockdown of YTHDC2 substantially promoted the proliferation rate of ESCC cells by affecting several cancer-related signaling pathways. Our results suggested that rs2416282 contributed to ESCC risk by regulating YTHDC2 expression. This study provided us a valuable insight into the roles of genetic variants in m6A modification genes for ESCC susceptibility and may contribute to the prevention of this disease in the future.
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http://dx.doi.org/10.1093/carcin/bgaa012DOI Listing
July 2020

Genetic Predisposition to Colon and Rectal Adenocarcinoma Is Mediated by a Super-enhancer Polymorphism Coactivating and .

Cancer Epidemiol Biomarkers Prev 2020 04 27;29(4):850-859. Epub 2020 Jan 27.

State Key Laboratory of Environment Health (Incubation), Key Laboratory of Environment & Health (Ministry of Education), Ministry of Environmental Protection Key Laboratory of Environment and Health (Wuhan), Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Background: Genome-wide association studies (GWAS) have identified dozens of loci associated with colon and rectal adenocarcinoma risk. As tissue-specific super-enhancers (SE) play important roles in tumorigenesis, we systematically investigate SEs and inner variants in established GWAS loci to decipher the underlying biological mechanisms.

Methods: Through a comprehensive bioinformatics analysis on multi-omics data, we screen potential single-nucleotide polymorphisms (SNP) in cancer-specific SEs, and then subject them to a two-stage case-control study containing 4,929 cases and 7,083 controls from the Chinese population. A series of functional assays, including reporter gene assays, electrophoretic mobility shift assays (EMSA), CRISPR-Cas9 genome editing, chromosome conformation capture (3C) assays, and cell proliferation experiments, are performed to characterize the variant's molecular consequence and target genes.

Results: The SNP rs11064124 in 12p13.31 is found significantly associated with the risk of colon and rectal adenocarcinoma with an odds ratio (OR) of 0.87 [95% confidence interval (CI), 0.82-0.92, = 8.67E-06]. The protective rs11064124-G weakens the binding affinity with vitamin D receptor (VDR) and increases the enhancer's activity and interactions with two target genes' promoters, thus coactivating the transcription of and , which are both putative tumor suppressor genes for colon and rectal adenocarcinoma.

Conclusions: Our integrative study highlights an SE polymorphism rs11064124 and two susceptibility genes and in 12p13.31 for colon and rectal adenocarcinoma.

Impact: These findings suggest a novel insight for genetic pathogenesis of colon and rectal adenocarcinoma, involving transcriptional coactivation of diverse susceptibility genes via the SE element as a gene regulation hub.
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http://dx.doi.org/10.1158/1055-9965.EPI-19-1116DOI Listing
April 2020

Evaluation of polymorphisms in microRNA-binding sites and pancreatic cancer risk in Chinese population.

J Cell Mol Med 2020 02 27;24(3):2252-2259. Epub 2019 Dec 27.

State Key Laboratory of Environment Health (Incubation), Key Laboratory of Environment & Health (Ministry of Education), Ministry of Environmental Protection Key Laboratory of Environment and Health (Wuhan), Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

As promising biomarkers and therapy targets, microRNAs (miRNAs) are involved in various physiological and tumorigenic processes. Genetic variants in miRNA-binding sites can lead to dysfunction of miRNAs and contribute to disease. However, systematic investigation of the miRNA-related single nucleotide polymorphisms (SNPs) for pancreatic cancer (PC) risk remains elusive. We performed integrative bioinformatics analyses to select 31 SNPs located in miRNA-target binding sites using the miRNASNP v2.0, a solid database providing miRNA-related SNPs for genetic research, and investigated their associations with risk of PC in two large case-control studies totally including 1847 cases and 5713 controls. We observed that the SNP rs3802266 is significantly associated with increased risk of PC (odds ratio (OR) = 1.21, 95% confidence intervals (CI) = 1.11-1.31, P = 1.29E-05). Following luciferase reporter gene assays show that rs3802266-G creates a stronger binding site for miR-181a-2-3p in 3' untranslated region (3'UTR) of the gene ZHX2. Expression quantitative trait loci (eQTL) analysis suggests that ZHX2 expression is lower in individuals carrying rs3802266-G with increased PC risk. In conclusion, our findings highlight the involvement of miRNA-binding SNPs in PC susceptibility and provide new clues for PC carcinogenesis.
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http://dx.doi.org/10.1111/jcmm.14906DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7011162PMC
February 2020

Three functional variants were identified to affect RPS24 expression and significantly associated with risk of colorectal cancer.

Arch Toxicol 2020 01 23;94(1):295-303. Epub 2019 Oct 23.

Key Laboratory of Environment and Health, Ministry of Education and Ministry of Environmental Protection, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

GWAS-identified 10q22.3 loci with lead SNP rs704017 are significantly associated with CRC risk in both Asian and European populations. However, the functional mechanism of this region is unclear. In this study, we performed a fine-mapping analysis to identify the causal SNPs. To identify potential functional SNPs in linkage disequilibrium with the lead SNP, we searched for the potential target genes using a Hi-C database and an RNA interfering-based on-chip approach. The results indicated that rs12263636 (r = 0.41) showed the highest potential to be functional. It resided in a region with enhancer markers and a topologically associating domain. We found that RPS24 was the only gene that significantly promoted the proliferation rate of CRC cells and might have promoter-enhancer interaction with rs12263636. Dual-luciferase reporter assays confirmed that the risk alleles of two variants (rs3740253 and rs7071351) in RPS24 promoter could increase the expression of luciferase. Case control study consisting of 1134 cases and 2039 health controls confirmed that both the two variants were associated with risk of CRC (rs3740253: P = 0.0079, OR = 1.15, 95% CI 1.04-1.28; rs7071351: P = 0.0085, OR = 1.15, 95% CI 1.04-1.28). And plasmid containing mutant haplotypes containing all the three mutations (rs12263636 or rs3740253 and rs7071351) could most significantly increase luciferase expression, compared with any haplotype of the three mutations. The study explained the functional mechanism for the 10q22.3 loci and provided new insights into the prevention and treatment of CRC.
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http://dx.doi.org/10.1007/s00204-019-02600-9DOI Listing
January 2020

ANKLE1 N -Methyladenosine-related variant is associated with colorectal cancer risk by maintaining the genomic stability.

Int J Cancer 2020 06 6;146(12):3281-3293. Epub 2019 Nov 6.

Key Laboratory for Environment and Health (Ministry of Education), Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Sciences and Technology, Wuhan, China.

The N -Methyladenosine (m A) modification plays an important role in many biological processes, especially tumor development. However, little is still known about how it affects colorectal cancer (CRC) carcinogenesis. Here, we first systematically investigate the association of variants related to m A modification with the CRC risk in 1,062 CRC cases and 2,184 controls by using our exome-wide association data and followed by two replication sets including 7,341 CRC cases and 7,902 controls. The variant rs8100241 located in ANKLE1 was significantly associated with CRC risk (odds ratio = 0.88, 95% confidence interval = 0.84-0.92, p = 4.85 × 10 ) in 8,403 cases and 10,086 controls. This variant was previously identified to be associated with the susceptibility of breast cancer with BRCA1 mutation triple negative breast cancer. Further functional analysis indicated that overexpression of the rs8100241[A] allele significantly increased the ANKLE1 m A level and facilitated the ANKLE1 protein expression compared to that of rs8100241[G] allele. We further found the ANKLE1 m A modification was catalyzed by the "writer" complex (METTL3, METTL14, or WTAP) and recognized by the "reader" YTHDF1. Mechanistically, we found that the ANKLE1 functions as a potential tumor suppressor that inhibits cell proliferation and facilitates the genomic stability. An elevated frequency of micronucleated cells, increased cell proliferation, and colony formation ability were observed when ANKLE1 knockdown. Our study illustrated that the germline missense variant can increase CRC risk by influencing ANKLE1 m A level, highlighting a clinical potential of variants-associated m A modification as a risk marker for CRC prevention.
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http://dx.doi.org/10.1002/ijc.32677DOI Listing
June 2020

A functional variant in the boundary of a topological association domain is associated with pancreatic cancer risk.

Mol Carcinog 2019 10 24;58(10):1855-1862. Epub 2019 Jun 24.

State Key Laboratory of Environment Health (Incubation), Key Laboratory of Environment & Health (Ministry of Education), Ministry of Environmental Protection Key Laboratory of Environment and Health (Wuhan), Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

As the proper binding of CCCTC-binding factor (CTCF) in the boundaries of topological association domains (TADs) was important for chromatin structures and gene regulation, we hypothesized that single nucleotide polymorphisms (SNPs) affecting CTCF binding in TAD boundaries might contribute to pancreatic cancer (PC) susceptibility. We first genome widely screened out potential SNPs via bioinformatics analysis on Hi-C data, ChIP-seq data, and CTCF binding motif, then tested their associations with PC risk in a previous genome-wide association studies (GWASs) data set (981 cases and 1,991 controls), followed by another independent replication set (1,208 cases and 1,465 controls). Electrophoretic mobility shift assays (EMSAs), expression Quantitative Trait Loci (eQTL) analyses and cell proliferation experiments were performed to uncover the biological mechanisms. The positive SNP rs2001389 was found significantly associated with PC risk with odds ratio (OR) being 1.166 (95% confidence interval (CI) = 1.075-1.264, P = 2.143E-04) in the combined study. The allele G of rs2001389 weakened the binding activity with CTCF, and it was related to the lower expression of a putative antioncogene MFSD13A whose knockdown promoted proliferation of PC cells. By integrating analysis on multiomics data, association studies and functional assays, we proposed that the common variant rs2001389 and the gene MFSD13A might be genetic modifiers of PC tumorigenesis.
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http://dx.doi.org/10.1002/mc.23077DOI Listing
October 2019

Systematic Functional Interrogation of Genes in GWAS Loci Identified ATF1 as a Key Driver in Colorectal Cancer Modulated by a Promoter-Enhancer Interaction.

Am J Hum Genet 2019 07 13;105(1):29-47. Epub 2019 Jun 13.

Department of Epidemiology and Biostatistics, Key Laboratory for Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Sciences and Technology, Wuhan 430030, China. Electronic address:

Genome-wide association studies (GWASs) have identified approximately 100 colorectal cancer (CRC) risk loci. However, the causal genes in these loci have not been systematically interrogated. We conducted a high-throughput RNA-interference functional screen to identify the genes essential for proliferation in the CRC risk loci of Asian populations. We found that ATF1, located in the 12q13.12 region, functions as an oncogene that facilitates cell proliferation; ATF1 has the most significant effect of the identified genes and promotes CRC xenograft growth by affecting cell apoptosis. Next, by integrating a fine-mapping analysis, a two-stage affected-control study consisting of 6,213 affected individuals and 10,388 controls, and multipronged experiments, we elucidated that two risk variants, dbSNP: rs61926301 and dbSNP: rs7959129, that located in the ATF1 promoter and first intron, respectively, facilitate a promoter-enhancer interaction, mediated by the synergy of SP1 and GATA3, to upregulate ATF1 expression, thus synergistically predisposing to CRC risk (OR = 1.77, 95% CI = 1.42-2.21, p = 3.16 × 10; P = 1.20 × 10; P = 6.50 × 10). Finally, we performed RNA-seq and ChIP-seq assays in CRC cells treated with ATF1 overexpression in order to dissect the target programs of ATF1. Results showed that ATF1 activates a subset of genes, including BRAF, NRAS, MYC, BIRC2, DAAM1, MAML2, STAT1, ID1, and NKD2, related to apoptosis, Wnt, TGF-β, and MAPK pathways, and these effects could cooperatively increase the risk of CRC. These findings reveal the clinical potential of ATF1 in CRC development and illuminate a promoter-enhancer interaction module between the ATF1 regulatory elements dbSNP: rs61926301 and dbSNP: rs7959129, and they bring us closer to understanding the molecular drivers of cancer.
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http://dx.doi.org/10.1016/j.ajhg.2019.05.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6612518PMC
July 2019

A genetic variant in PIK3R1 is associated with pancreatic cancer survival in the Chinese population.

Cancer Med 2019 07 6;8(7):3575-3582. Epub 2019 May 6.

Department of Epidemiology and Biostatistics, Key Laboratory for Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Sciences and Technology, Wuhan, China.

Pancreatic cancer is one of the deadliest malignancies with few early detection tests or effective therapies. PI3K-AKT signaling is recognized to modulate cancer progression. We previously identified that a genetic variant in PKN1 increased pancreatic cancer risk through the PKN1/FAK/PI3K/AKT pathway. In order to investigate the associations between genetic variations in that pathway and pancreatic cancer prognosis, we conducted a two-stage survival analysis in a total of 547 Chinese pancreatic cancer patients. Consequently, a variant, rs13167294 A>C in PIK3R1, was significantly associated with poor survival in both stages and with hazard ratio being 1.32 (95% CI = 1.13-1.56, P = 0.0007) in the combined analysis. Function annotation and prediction suggested that genetic variants in this locus might affect overall survival of pancreatic cancer patients by regulating PIK3R1 expression.
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http://dx.doi.org/10.1002/cam4.2228DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6601582PMC
July 2019

Integrative analysis identifies genetic variant modulating MICA expression and altering susceptibility to persistent HBV infection.

Liver Int 2019 10 14;39(10):1927-1936. Epub 2019 May 14.

Department of Epidemiology and Biostatistics, MOE Key Laboratory of Environment & Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Background & Aims: Genome-wide association studies have identified multiple genetic signals associated with the risk of persistent hepatitis B virus (HBV) infection and HBV-related hepatocellular carcinoma. However, the majority of the associated variants may only be markers of functional variants and the underlying biological mechanisms remain elusive. We hypothesized that the functional variants with modulating transcription factor (TF) binding affinity in genome-wide association studies-identified loci may influence the risk of persistent HBV infection in Chinese people.

Methods: A systematic bioinformatics approach was implemented to prioritize potential functional variants that may influence TF binding. A two-stage case-control study, including 1595 HBV-persistent carriers and 1590 subjects with HBV natural clearance, was conducted to examine the associations between candidate variants and susceptibility to persistent HBV infection. Biological assays were carried out to elucidate the underlying mechanism of the associated genetic variants.

Results: Twelve candidate variants were identified, and rs2523454 G > A increased the risk of persistent HBV infection (dominant model: OR  = 1.37, 95% CI = 1.19-1.58, P = 1.610 × 10 ). Functional assays indicated that the rs2523454 A allele significantly decreased transcriptional activity compared to the G allele by influencing TF-binding affinity. In addition, expression quantitative trait loci analyses revealed that the A allele was associated with the reduced expression of MICA (P < 0.01).

Conclusions: Our findings suggest that the germline G > A variation at rs2523454 may influence TF-DNA interaction, downregulate the expression of MICA and play an important role in the development of persistent HBV infection in the Chinese population.
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http://dx.doi.org/10.1111/liv.14127DOI Listing
October 2019

CancerSplicingQTL: a database for genome-wide identification of splicing QTLs in human cancer.

Nucleic Acids Res 2019 01;47(D1):D909-D916

Key Laboratory of Environmental Health of Ministry of Education, Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, PR China.

Alternative splicing (AS) is a widespread process that increases structural transcript variation and proteome diversity. Aberrant splicing patterns are frequently observed in cancer initiation, progress, prognosis and therapy. Increasing evidence has demonstrated that AS events could undergo modulation by genetic variants. The identification of splicing quantitative trait loci (sQTLs), genetic variants that affect AS events, might represent an important step toward fully understanding the contribution of genetic variants in disease development. However, no database has yet been developed to systematically analyze sQTLs across multiple cancer types. Using genotype data from The Cancer Genome Atlas and corresponding AS values calculated by TCGASpliceSeq, we developed a computational pipeline to identify sQTLs from 9 026 tumor samples in 33 cancer types. We totally identified 4 599 598 sQTLs across all cancer types. We further performed survival analyses and identified 17 072 sQTLs associated with patient overall survival times. Furthermore, using genome-wide association study (GWAS) catalog data, we identified 1 180 132 sQTLs overlapping with known GWAS linkage disequilibrium regions. Finally, we constructed a user-friendly database, CancerSplicingQTL (http://www.cancersplicingqtl-hust.com/) for users to conveniently browse, search and download data of interest. This database provides an informative sQTL resource for further characterizing the potential functional roles of SNPs that control transcript isoforms in human cancer.
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http://dx.doi.org/10.1093/nar/gky954DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6324030PMC
January 2019

AWESOME: a database of SNPs that affect protein post-translational modifications.

Nucleic Acids Res 2019 01;47(D1):D874-D880

Key Laboratory for Environment and Health (Ministry of Education), Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Sciences and Technology, Wuhan, 430030, China.

Protein post-translational modifications (PTMs), including phosphorylation, ubiquitination, methylation, acetylation, glycosylation et al, are very important biological processes. PTM changes in some critical genes, which may be induced by base-pair substitution, are shown to affect the risk of diseases. Recently, large-scale exome-wide association studies found that missense single nucleotide polymorphisms (SNPs) play an important role in the susceptibility for complex diseases or traits. One of the functional mechanisms of missense SNPs is that they may affect PTMs and leads to a protein dysfunction and its downstream signaling pathway disorder. Here, we constructed a database named AWESOME (A Website Exhibits SNP On Modification Event, http://www.awesome-hust.com), which is an interactive web-based analysis tool that systematically evaluates the role of SNPs on nearly all kinds of PTMs based on 20 available tools. We also provided a well-designed scoring system to compare the performance of different PTM prediction tools and help users to get a better interpretation of results. Users can search SNPs, genes or position of interest, filter with specific modifications or prediction methods, to get a comprehensive PTM change induced by SNPs. In summary, our database provides a convenient way to detect PTM-related SNPs, which may potentially be pathogenic factors or therapeutic targets.
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http://dx.doi.org/10.1093/nar/gky821DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6324025PMC
January 2019

Exome-wide analysis identifies three low-frequency missense variants associated with pancreatic cancer risk in Chinese populations.

Nat Commun 2018 09 11;9(1):3688. Epub 2018 Sep 11.

Department of Epidemiology and Biostatistics, Key Laboratory for Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Sciences and Technology, 430030, Wuhan, China.

Germline coding variants have not been systematically investigated for pancreatic ductal adenocarcinoma (PDAC). Here we report an exome-wide investigation using the Illumina Human Exome Beadchip with 943 PDAC cases and 3908 controls in the Chinese population, followed by two independent replicate samples including 2142 cases and 4697 controls. We identify three low-frequency missense variants associated with the PDAC risk: rs34309238 in PKN1 (OR = 1.77, 95% CI: 1.48-2.12, P = 5.35 × 10), rs2242241 in DOK2 (OR = 1.85, 95% CI: 1.50-2.27, P = 4.34 × 10), and rs183117027 in APOB (OR = 2.34, 95% CI: 1.72-3.16, P = 4.21 × 10). Functional analyses show that the PKN1 rs34309238 variant significantly increases the level of phosphorylated PKN1 and thus enhances PDAC cells' proliferation by phosphorylating and activating the FAK/PI3K/AKT pathway. These findings highlight the significance of coding variants in the development of PDAC and provide more insights into the prevention of this disease.
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http://dx.doi.org/10.1038/s41467-018-06136-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6134090PMC
September 2018

Integrative functional genomics identifies regulatory genetic variant modulating RAB31 expression and altering susceptibility to breast cancer.

Mol Carcinog 2018 12 19;57(12):1845-1854. Epub 2018 Sep 19.

Department of Epidemiology and Biostatistics and Ministry of Education Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.

Despite the successes of genome-wide association study (GWAS) in identifying breast cancer (BC) risk-associated variants, only a small fraction of the heritability can be explained. The greatest challenge in the post-GWAS is to identify causal variants and underlying mechanisms responsible for BC susceptibility. In this study, we integrated functional genomic data from ENCODE ChIP-seq, ANNOVAR, and the TRANSFAC matrix to identify potentially regulatory variants with modulating FOXA1-binding affinity across the whole genome, and then conducted a two-stage case-control study including 2164 cases and 2382 controls to investigate the associations between candidate SNPs and BC susceptibility. We identified a BC susceptibility SNP, rs6506689 G>T, with an odds ratio (OR) of 1.23 (95% confidence interval = 1.07-1.40, P = 0.003) under a dominant model in the combined study. Biological assays indicated that the germline G>T variation at rs6506689 creates a FOXA1-binding site and up-regulates the expression of RAB31, thus playing an important role in the development of BC. Our results highlight the importance of regulatory genetic variants in the development of BC by influencing TF-DNA interaction and provide critical insights to pinpoint causal genetic variants.
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http://dx.doi.org/10.1002/mc.22902DOI Listing
December 2018

A Rare Missense Variant in TCF7L2 Associates with Colorectal Cancer Risk by Interacting with a GWAS-Identified Regulatory Variant in the MYC Enhancer.

Cancer Res 2018 09 19;78(17):5164-5172. Epub 2018 Jul 19.

Key Laboratory for Environment and Health (Ministry of Education), Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Sciences and Technology, Wuhan, China.

Genome-wide association studies (GWAS) of colorectal cancer have identified several common susceptible variants in gene regulatory regions. However, low-frequency or rare coding risk variants have not been systematically investigated in patients with colorectal cancer from Chinese populations. In this study, we performed an exome-wide association analysis with 1,062 patients with colorectal cancer and 2,184 controls from a Chinese population. Promising associations were further replicated in two replication sets: replication stage I with 2,478 cases and 3,880 controls, and replication stage II with 3,761 cases and 4,058 controls. We identified two variants significantly associated with colorectal cancer risk: a novel rare missense variant in [rs138649767, OR = 2.08, 95% confidence interval (CI): 1.69-2.57, = 5.66 × 10] and a previous European GWAS-identified 3'-UTR variant in (rs11169571, OR = 1.18, 95% CI: 1.13-1.24, = 1.65 × 10). We found a significant interaction between the missense variant rs138649767 and a previous GWAS-identified regulatory variant rs6983267 in the enhancer ( = 0.0002). Functional analysis of this variant revealed that TCF7L2 with rs138649767-A allele harbored the ability to activate the enhancer with rs6983267-G allele and enhance colorectal cancer cell proliferation. In addition, the rs11169571 variant significantly correlated with expression by affecting hsa-miR-1283 and hsa-miR-520d-5p binding. Further ChIP-seq and gene coexpression analyses showed that oncogenes and were activated by ATF1 in colorectal cancer. These results widen our understanding of the molecular basis of colorectal cancer risk and provide insight into pathways that might be targeted to prevent colorectal cancer. Exome-wide association analysis identifies a rare missense variant in and a common regulatory variant in as susceptibility factors of colorectal cancer. http://cancerres.aacrjournals.org/content/canres/78/17/5164/F1.large.jpg .
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http://dx.doi.org/10.1158/0008-5472.CAN-18-0910DOI Listing
September 2018

A Rare Variant P507L in TPP1 Interrupts TPP1-TIN2 Interaction, Influences Telomere Length, and Confers Colorectal Cancer Risk in Chinese Population.

Cancer Epidemiol Biomarkers Prev 2018 09 11;27(9):1029-1035. Epub 2018 Jun 11.

Department of Epidemiology and Biostatistics, and State Key Laboratory of Environment Health, MOE (Ministry of Education) Key Laboratory of Environment & Health, Ministry of Environmental Protection Key Laboratory of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Telomere dysfunction triggers cellular senescence and constitutes a driving force for cancer initiation. Genetic variants in genes involved in telomere maintenance may contribute to colorectal cancer susceptibility. In this study, we firstly captured germline mutations in 192 patients with colorectal cancer by sequencing the coding regions of 13 core components implicated in telomere biology. Five potential functional variants were then genotyped and assessed in a case-control set with 3,761 colorectal cancer cases and 3,839 healthy controls. The promising association was replicated in additional 6,765 cases and 6,906 controls. Functional experiments were used to further clarify the potential function of the significant variant and uncover the underlying mechanism in colorectal cancer development. The two-stage association studies showed that a rare missense variant rs149418249 (c.1520 and p.P507L) in the 11th exon of (also known as , gene ID 65057) was significantly associated with colorectal cancer risk with the ORs being 2.90 [95% confidence interval (CI), 1.04-8.07; = 0.041], 2.50 (95% CI, 1.04-6.04; = 0.042), and 2.66 (95% CI, 1.36-5.18; = 0.004) in discovery, replication, and the combined samples, respectively. Further functional annotation indicated that the TPP1 P507L substitution interrupted TPP1-TIN2 interaction, impaired telomerase processivity, and shortened telomere length, which subsequently facilitated cell proliferation and promoted colorectal cancer development. A rare variant P507L in TPP1 confers increased risk of colorectal cancer through interrupting TPP1-TIN2 interaction, impairing telomerase processivity, and shrinking telomere length. These findings emphasize the important role of telomere dysfunction in colorectal cancer development, and provide new insights about the prevention of this type of cancer. .
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http://dx.doi.org/10.1158/1055-9965.EPI-18-0099DOI Listing
September 2018

Exome-wide analyses identify low-frequency variant in CYP26B1 and additional coding variants associated with esophageal squamous cell carcinoma.

Nat Genet 2018 03 29;50(3):338-343. Epub 2018 Jan 29.

Department of Etiology and Carcinogenesis, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

Genome-wide association studies have identified common variants associated with risk of esophageal squamous cell carcinoma (ESCC). However, these common variants cannot explain all heritability of ESCC. Here we report an exome-wide interrogation of 3,714 individuals with ESCC and 3,880 controls for low-frequency susceptibility loci, with two independent replication samples comprising 7,002 cases and 8,757 controls. We found six new susceptibility loci in CCHCR1, TCN2, TNXB, LTA, CYP26B1 and FASN (P = 7.77 × 10 to P = 1.49 × 10), and three low-frequency variants had relatively high effect size (odds ratio > 1.5). Individuals with the rs138478634-GA genotype had significantly lower levels of serum all-trans retinoic acid, an anticancer nutrient, than those with the rs138478634-GG genotype (P = 0.0004), most likely due to an enhanced capacity of variant CYP26B1 to catabolize this agent. These findings emphasize the important role of rare coding variants in the development of ESCC.
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http://dx.doi.org/10.1038/s41588-018-0045-8DOI Listing
March 2018

A functional variant in GREM1 confers risk for colorectal cancer by disrupting a hsa-miR-185-3p binding site.

Oncotarget 2017 Sep 23;8(37):61318-61326. Epub 2017 May 23.

Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

The transforming growth factor beta (TGF-β) pathway has been implicated in carcinogenesis of intestinal canal. Except for common variants indentified by genome-wide association studies, variants with lower frequency can also explain a part of the disease heritability, especially those in gene regulatory regions. In this study, we searched for colorectal cancer (CRC) related functional low-frequency variants (minor allele frequency 1-5%) in untranslated regions (UTR) involved in the TGF-β signaling using a next-generation sequencing based approach. A case-control study including 1,841 CRC cases and 1,837 controls was performed to identify CRC associated variants and biological experiments were applied to further explore the potential functions of the significant variants. Three low-frequency UTR variants were selected as our candidates and subsequent association analyses showed that a low-frequency variant rs12915554 in the 3' UTR of GREM1 was significantly associated with CRC risk (Additive model: OR=1.43, 95%CI: 1.04-1.95, =0.026). Functional annotations suggested that rs12915554 variation increased the expression of GREM1 by perturbing a hsa-miR-185-3p binding site. Moreover, higher expression level of GREM1 was investigated in colon tumor tissues compared with adjacent normal tissues using TCGA data. In conclusion, low-frequency UTR variant rs12915554 in the gene GREM1 was in relation to CRC susceptibility in a Chinese population and this variation might promote CRC development through enhancing GREM1 expression in a miRNA-mediated posttranscriptional manner.
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http://dx.doi.org/10.18632/oncotarget.18095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5617425PMC
September 2017

BRCA1 missense polymorphisms are associated with poor prognosis of pancreatic cancer patients in a Chinese population.

Oncotarget 2017 May;8(22):36033-36039

Key Laboratory of Environment and Health, Ministry of Education and Ministry of Environmental Protection, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Pancreatic cancer is a highly lethal disease with limited prognostic marker. BRAC1 and BRCA2 are two classic tumor suppressor genes which play an important role in DNA repair. Somatic mutations and germline genetic variants on BRCA1/2 have been found associated with the tumorigenesis of pancreatic cancer. However, the correlations between BRCA1/2 polymorphism and pancreatic cancer prognosis remained unknown. In this study, we genotyped three tag missense variants on BRCA1/2 in 603 sporadic pancreatic cancer patients in a Chinese population. We found rs1799966 on BRCA1 was associated with poor prognosis of pancreatic cancer patients with hazard ratio being 1.23 (95% CI: 1.09-1.40, P = 0.0010). Further stratification analyses showed that significant correlation was particularly in locally advanced stage patients with hazard ratio being 1.36 (95% CI: 1.13-1.64, P = 0.0014), but not in patients in local stage (P = 0.1139) or metastatic stage (P = 0.5185). Two missense variants (rs766173 and rs144848) on BRAC2 showed no significant correlation with pancreatic cancer patients' overall survival. In conclusion, we identified a germline missense variant on BRAC1 significantly associated with poor prognosis of pancreatic cancer patients with locally advanced stage. These results may contribute to the precision medicine of this disease.
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http://dx.doi.org/10.18632/oncotarget.16422DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5482636PMC
May 2017

Breast cancer risk-associated variants at 6q25.1 influence risk of hepatocellular carcinoma in a Chinese population.

Carcinogenesis 2017 04;38(4):447-454

Key Laboratory of Environment and Health, Ministry of Education and Ministry of Environmental Protection, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

The gender disparity observed in the incidence of hepatocellular carcinoma (HCC) suggests an important role of estrogens in HCC pathogenesis. In this study, we conducted a case-control study to investigate whether breast cancer risk-associated single nucleotide polymorphisms (SNPs) located at estrogens loci identified by genome-wide association studies (GWASs) also predispose to HCC in a Chinese population. Three candidate SNPs at 6q25.1 were genotyped in 2025 HCC cases and 2032 healthy controls. Differential expression analyses and expression quantitative trait loci (eQTL) analyses were conducted to further explore the potential function of significant SNPs and genes they reside in. Two of the three candidate SNPs (rs9383951 and rs9485372) were observed to be significantly associated with HCC risk. Under a dominant model, the odds ratios (OR) for rs9383951 and rs9485372 were 1.28 (95% CI: 1.10-1.49, P = 0.002) and 1.34 (95% CI: 1.17-1.53, P = 2.75 × 10-5), respectively. We also found a significant accumulative effect of these two SNPs and there was a gradual increase in OR with a greater number of hazard genotypes. Moreover, the association between rs9383951 and HCC risk was specific in males. Lower ESR1 and TAB2 expressions were investigated in hepatic tumor tissues than adjacent normal tissues. We found a significant association between rs9383951 and ESR1 expression (P = 0.047). Besides, ESR1 expression was significantly correlated with the expression of TAB2. Taken together, our study identified two genetic variants at 6q25.1 newly associated with HCC risk, suggesting ESR1 and estrogen signaling may play a role in mediating susceptibility to HCC in Chinese population.
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http://dx.doi.org/10.1093/carcin/bgx024DOI Listing
April 2017

A low-frequency variant in SMAD7 modulates TGF-β signaling and confers risk for colorectal cancer in Chinese population.

Mol Carcinog 2017 07 6;56(7):1798-1807. Epub 2017 Mar 6.

Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

The TGF-β pathway plays an essential role in regulating cell proliferation and differentiation. GWASs and candidate approaches have identified a battery of genetic variants in the TGF-β pathway contributing to colorectal cancer (CRC). However, most of the significant variants are common variants and their functions remain ambiguous. To identify causal variants with low-frequency in the TGF-β pathway contributing to CRC susceptibility in Chinese population, we performed targeted sequencing of 12 key genes in TGF-β signaling in CRC patients followed by a two-stage case-control study with a total of 5109 cases and 5169 controls. Bioinformatic annotations and biochemical experiments were applied to reveal the potential functions of significant variants. Seven low-frequency genetic variants were captured through targeted sequencing. The two stage association studies showed that missense variant rs3764482 (c. 83C>T; p. S28F) in the gene SMAD7 was consistently and significantly associated with CRC risk. Compared with the wild type, the ORs for variant allele were 1.37 (95%CI: 1.10-1.70, P = 0.005), 1.55 (95%CI: 1.30-1.86, P = 1.15 × 10 ), and 1.48 (1.29-1.70, P = 2.44 × 10 ) in stage 1, stage 2, and the combined analyses, respectively. Functional annotations revealed that the minor allele T of rs3764482 was more effective than the major allele C in blocking the TGF-β signaling and inhibiting the phosphorylation of receptor-regulated SMADs (R-SMADs). In conclusion, low-frequency coding variant rs3764482 in SMAD7 is associated with CRC risk in Chinese population. The rs3764482 variant may block the TGF-β signaling via impeding the activation of downstream genes, leading to cancer cell proliferation, thus contributing to CRC pathogenesis.
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http://dx.doi.org/10.1002/mc.22637DOI Listing
July 2017

A functional variant rs4442975 modulating FOXA1-binding affinity does not influence the risk or progression of breast cancer in Chinese Han population.

Oncotarget 2016 Dec;7(49):81691-81697

Department of Epidemiology and Biostatistics and State Key Laboratory of Environment Health (Incubation), Ministry of Education Key Laboratory of Environment & Health, Ministry of Environmental Protection Key Laboratory of Environment and Health (Wuhan), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, PR China.

The DNA-binding protein FOXA1 has been shown to regulate nearly all estrogen receptor-chromatin interactions, thereby influencing target gene expression levels in breast cancer (BC) cells. Recently, the rs4442975 T-allele, which disrupts the recruitment of FOXA1 and interacts with the IGFBP5 promoter, was associated to BC susceptibility in a European population. We conducted a hospital-based case-control study that included 1227 cases and 1285 controls to explore the potential association between rs4442975 and BC risk in Chinese Han population, and the effect of this SNP on BC progression was also observed in cases. No significant associations between rs4442975 and BC risk were observed under any genetic models, with an odds ratio of 0.96 (95% confidence interval = 0.81-1.15) under the additive model. When stratified based on estrogen or progesterone receptor expression, smoking or drinking habits, or menopausal status, similar negative associations were observed for all subgroups. No significant associations were observed between rs4442975 and traditional progression factors such as tumor size, nodal status, distant metastasis, or TNM staging. These results reveal that rs4442975 may not confer a risk of BC occurrence or progression in the Chinese Han population, which indicates a distinct association related to genetic heterogeneity across ethnic populations.
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http://dx.doi.org/10.18632/oncotarget.13168DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5348423PMC
December 2016

A single nucleotide polymorphism in the 3'-UTR of STAT3 regulates its expression and reduces risk of pancreatic cancer in a Chinese population.

Oncotarget 2016 Sep;7(38):62305-62311

State Key Laboratory of Environment Health (Incubation), MOE (Ministry of Education) Key Laboratory of Environment and Health, Ministry of Environmental Protection Key Laboratory of Environment and Health (Wuhan), and Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Pancreatic cancer (PC) is one of the deadliest solid malignancies carrying a gloomy 5-year survival rate less than 5%. The signal transducer and activator of transcription 3 (STAT3) is a common transcriptional regulator, whose aberrant expression has been widely found in human cancers, including PC. Our current study aimed to illustrate the roles of common variants, in the three prime untranslated region (3'UTR) of STAT3, in modifying the risk of PC through two-stage case-control studies integrating biological experiments. We first explored the associations between two common variants (rs1053004 and rs1053005) and PC risk in 774 PC cases and 777 controls. Only rs1053004 T > C showed a significant association with a reduced risk of PC with an odds ratio (OR) and 95% confidence interval (CI) of 0.85 (0.74-0.98). Then we attempted to validate the association in another 940 cases and 1398 controls, and the significant association persisted with OR (95%CI) of 0.86 (0.76-0.97). Dual luciferase reporter gene assays indicated that C allele conferred a higher expression of STAT3 in three PC cell lines including Panc-1 (P = 3.0 × 10-3), BxPC-3 (P = 6.7 × 10-5) and SW1990 (P = 4.0 × 10-3). In conclusion, the current study provided evidence that rs1053004 T > C in 3'UTR of STAT3 may decrease the risk of PC through up-regulating the gene expression.
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http://dx.doi.org/10.18632/oncotarget.11607DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5308728PMC
September 2016