Remote modulation of lncRNA GCLET by risk variant at 16p13 underlying genetic susceptibility to gastric cancer

The integrated analytical strategy identified both genetic and epigenetic biomarkers for gastric cancer etiology. The biological effects of susceptibility loci are rarely reported in gastric tumorigenesis. We conducted a large-scale cross-ancestry genetic study in 18,852 individuals and identified the potential causal variant rs3850997 T>G at 16p13 significantly associated with a decreased risk of gastric cancer [odds ratio (OR) = 0.87, 95% confidence interval (CI) = 0.83 to 0.91, P = 2.13 × 10−9]. This risk effect was mediated through the mapped long noncoding RNA GCLET (Gastric Cancer Low-Expressed Transcript; ORindirect = 0.987, 95% CI = 0.975 to 0.999, P = 0.018). Mechanistically, rs3850997 exerted an allele-specific long-range regulatory effect on GCLET by affecting the binding affinity of CTCF. Furthermore, GCLET increased FOXP2 expression by competing with miR-27a-3p, and this regulation remarkably affected in vitro, in vivo, and clinical gastric cancer phenotypes. The findings highlight the genetic functions and implications for the etiology and pathology of cancers.

[1]  Hongbing Shen,et al.  Remote modulation of lncRNA GCLET by risk variant at 16p13 underlying genetic susceptibility to gastric cancer. , 2020, Science advances.

[2]  Zhibin Wang,et al.  Crosstalk of Genetic Variants, Allele-Specific DNA Methylation, and Environmental Factors for Complex Disease Risk , 2019, Front. Genet..

[3]  Lennart Martens,et al.  LNCipedia 5: towards a reference set of human long non-coding RNAs , 2018, Nucleic Acids Res..

[4]  Alireza Salimi Chirani,et al.  Global estimate of gastric cancer in Helicobacter pylori–infected population: A systematic review and meta‐analysis , 2018, Journal of cellular physiology.

[5]  J. Clements,et al.  Post-GWAS in prostate cancer: from genetic association to biological contribution , 2018, Nature Reviews Cancer.

[6]  Y. Kamatani,et al.  Genome‐wide association study identifies gastric cancer susceptibility loci at 12q24.11‐12 and 20q11.21 , 2018, Cancer science.

[7]  E. Zhang,et al.  A novel long noncoding RNA HOXC-AS3 mediates tumorigenesis of gastric cancer by binding to YBX1 , 2018, Genome Biology.

[8]  A. Jemal,et al.  Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries , 2018, CA: a cancer journal for clinicians.

[9]  Y. Ba,et al.  Exosomal miR-27a Derived from Gastric Cancer Cells Regulates the Transformation of Fibroblasts into Cancer-Associated Fibroblasts , 2018, Cellular Physiology and Biochemistry.

[10]  E. Leucci.  Cancer development and therapy resistance: spotlights on the dark side of the genome. , 2018, Pharmacology & therapeutics.

[11]  W. Gong,et al.  Evaluation of GWAS-Identified Genetic Variants for Gastric Cancer Survival , 2018, EBioMedicine.

[12]  A. Chen-Plotkin,et al.  The Post-GWAS Era: From Association to Function. , 2018, American journal of human genetics.

[13]  J. Mendell,et al.  Functional Classification and Experimental Dissection of Long Noncoding RNAs , 2018, Cell.

[14]  H. Ashktorab,et al.  Racial Disparity in Gastrointestinal Cancer Risk. , 2017, Gastroenterology.

[15]  G. Jin,et al.  Genome-wide association studies identified loci contribute to phenotypic variance of gastric cancer , 2017, Gut.

[16]  Shanyong Zhang,et al.  MicroRNA-27a contributes to the malignant behavior of gastric cancer cells by directly targeting PH domain and leucine-rich repeat protein phosphatase 2 , 2017, Journal of Experimental & Clinical Cancer Research.

[17]  Hongbing Shen,et al.  Identification of new susceptibility loci for gastric non-cardia adenocarcinoma: pooled results from two Chinese genome-wide association studies , 2015, Gut.

[18]  N. Eriksson,et al.  Nature Genetics Advance Online Publication Meta-analysis of 375,000 Individuals Identifies 38 Susceptibility Loci for Migraine , 2022 .

[19]  A. Jemal,et al.  Cancer statistics in China, 2015 , 2016, CA: a cancer journal for clinicians.

[20]  G. Parmigiani,et al.  Familial Risk and Heritability of Cancer Among Twins in Nordic Countries. , 2016, JAMA.

[21]  L. Dai,et al.  Competing endogenous RNA networks and gastric cancer. , 2015, World journal of gastroenterology.

[22]  P. Zhang,et al.  Genome-wide association study of gastric adenocarcinoma in Asia: a comparison of associations between cardia and non-cardia tumours , 2015, Gut.

[23]  K. Pooley,et al.  Genetic variation and gastric cancer risk: a field synopsis and meta-analysis , 2015, Gut.

[24]  Neva C. Durand,et al.  A 3D Map of the Human Genome at Kilobase Resolution Reveals Principles of Chromatin Looping , 2014, Cell.

[25]  N. Hu,et al.  PLCE1 mRNA and Protein Expression and Survival of Patients with Esophageal Squamous Cell Carcinoma and Gastric Adenocarcinoma , 2014, Cancer Epidemiology, Biomarkers & Prevention.

[26]  V. Corces,et al.  CTCF: an architectural protein bridging genome topology and function , 2014, Nature Reviews Genetics.

[27]  Kai Zhang,et al.  A prostate cancer susceptibility allele at 6q22 increases RFX6 expression by modulating HOXB13 chromatin binding , 2014, Nature Genetics.

[28]  P. Pandolfi,et al.  The multilayered complexity of ceRNA crosstalk and competition , 2014, Nature.

[29]  Iuliana Ionita-Laza,et al.  Sequence kernel association tests for the combined effect of rare and common variants. , 2013, American journal of human genetics.

[30]  K. Sun,et al.  iSeeRNA: identification of long intergenic non-coding RNA transcripts from transcriptome sequencing data , 2013, BMC Genomics.

[31]  J. Kocher,et al.  CPAT: Coding-Potential Assessment Tool using an alignment-free logistic regression model , 2013, Nucleic acids research.

[32]  Yan Cui,et al.  CTCFBSDB 2.0: a database for CTCF-binding sites and genome organization , 2012, Nucleic Acids Res..

[33]  Sergey I. Nikolenko,et al.  BayesHammer: Bayesian clustering for error correction in single-cell sequencing , 2012, BMC Genomics.

[34]  Jake K. Byrnes,et al.  Bayesian refinement of association signals for 14 loci in 3 common diseases , 2012, Nature Genetics.

[35]  Bauke Ylstra,et al.  Comprehensive genomic meta-analysis identifies intra-tumoural stroma as a predictor of survival in patients with gastric cancer , 2012, Gut.

[36]  Wen Tan,et al.  A genome-wide association study identifies new susceptibility loci for non-cardia gastric cancer at 3q13.31 and 5p13.1 , 2011, Nature Genetics.

[37]  Manolis Kellis,et al.  PhyloCSF: a comparative genomics method to distinguish protein coding and non-coding regions , 2011, Bioinform..

[38]  William Stafford Noble,et al.  FIMO: scanning for occurrences of a given motif , 2011, Bioinform..

[39]  Bin Liu,et al.  Genome-wide association study of esophageal squamous cell carcinoma in Chinese subjects identifies a susceptibility locus at PLCE1 , 2010, Nature Genetics.

[40]  N. Hu,et al.  A shared susceptibility locus in PLCE1 at 10q23 for gastric adenocarcinoma and esophageal squamous cell carcinoma , 2010, Nature Genetics.

[41]  J. Marchini,et al.  Genotype imputation for genome-wide association studies , 2010, Nature Reviews Genetics.

[42]  P. Donnelly,et al.  A Flexible and Accurate Genotype Imputation Method for the Next Generation of Genome-Wide Association Studies , 2009, PLoS genetics.

[43]  Alessandro Giuliani,et al.  Genome-wide expression profile of sporadic gastric cancers with microsatellite instability. , 2009, European journal of cancer.

[44]  Yusuke Nakamura,et al.  Genetic variation in PSCA is associated with susceptibility to diffuse-type gastric cancer , 2008, Nature Genetics.

[45]  J. Pritchard,et al.  A Map of Recent Positive Selection in the Human Genome , 2006, PLoS biology.

[46]  Michael Zuker,et al.  Mfold web server for nucleic acid folding and hybridization prediction , 2003, Nucleic Acids Res..